Revised Manuscript ID CJP-2016-11-0031R1

Page 1of64 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/cjp2.64. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen Davidson, Davidson,

[email protected] mail: INTelephone: USA. Indianapolis, 46202, 4010, Room Medicine, Case Western Reserve University, Clevelan ReserveUniversity, Western Case Medicine, Fluorescence EDITED HERRINGTON and Laboratory Medicine, Indiana University School IndianaSchool University LaboratoryMedicine, and Lian to andrequests reprint Addresscorrespondence 2 of Number tables, pages,46; of text number Total SurgicalPathology FISH in Head: Running 1 University School of Medicine, Indianapolis, Indian Indianapolis, of Medicine, UniversitySchool Pathology, University of Michigan, Ann Arbor, MI; Arbor, Ann MI; Michigan, of University Pathology, Liang Cheng, Department of Pathology and Laboratory Medicine, Medicine, Laboratory andDepartment of Pathology 1 1

in situ situ in

Accepted Article1,2 , Shaobo Zhang, Shaobo , Hybridization in Surgical Pathology: Principles and Principles in Pathology: Surgical Hybridization This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch

1 , Lisha Wang, LishaWang, ,

3 , Gregory T MacLennan, Gregory , MacLennan, T Revised Manuscript ID CJP2016110031R1 IDCJP2016110031R1 Manuscript Revised ; Number of figures, 6. 6. of Number figures, ; a; g Cheng, M.D., Department of Pathology of Pathology Department M.D., gCheng, 4 2 Departments of Pathology and Laboratory and of Pathology Departments of Medicine, 350 West 11 West 350 ofMedicine, Department of Urology, Indiana Departmentof Urology, d, Ohio. d, 3 Michigan Center for Translational Translational for MichiganCenter 3174916442; Fax: E 3174916419; Fax: 3174916442;

4 , Darrell , D. Applications Applications th Street, IUHPL Street, based on results of FISH, demand for demand technology the FISH, of results basedon polysomy. These chromosome alterations may have dia have may alterations chromosome These polysomy. decade, fluorescence fluorescence decade, an diagnostic,therapeutic, oncogenesimportant has chromos tumourspecific of recurrent Identification ABSTRACT within a routine pathology practice workflow. As mo As workflow. pathologya practice routine within rapidanal a FISH affords cytogenetics, traditional and medicine genomic in growingrapidly areas most FISHdetected alterations are chromosome deletions, are chromosome alterations FISHdetected diagnosis differential medicine, therapy, precision (FISH hybridization situ in Fluorescence KeyWords: sur in application forclinical strategies focuson and practic atheoretical provide reviewto is this animportant has become decisions cancertreatment re changes of chromosomal assessment FISH medicine. m being rapid progressis but technicalchallenges, testing into genomic Integrating types. many tumour

Accepted Article in situ situ in This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch hybridization (FISH) analysis of tumour samples has samples tumour analysis(FISH) of hybridization

gical pathology practice. gical practice. pathology

al survey of FISH detected translocations with a with translocations survey FISH detected al of ysis of formalinfixed, paraffinembedded cells cells paraffinembedded ysisof formalinfixed,

ade to overcome these challenges in precision precision in challenges these adeovercome to omal translocations and novel fusion fusion novel and translocations omal d prognostic implications. Over past the prognosticd implications. cancer treatment decisions poses many poses decisions cancer treatment will become more widespread. Common Common morewidespread. become will tool for the surgical pathologist. The aim of The aim for pathologist. surgical the tool gains, translocations, amplifications, and amplifications, gains, translocations, re diagnostic and treatment decisions are decisions and treatment rediagnostic ), molecular genetics/cytogenetics, targeted targeted genetics/cytogenetics, ),molecular surgical pathology practice. Unlike Unlike practice. pathology surgical gnostic and therapeutic implications for implications gnosticand therapeutic levant to differential diagnosisand differential to levant been one of the beenone Page 2of64 Page 3of64 binding to interphase chromosomes of cytology speci chromosomes interphase to binding 1. separated chromosome parts join.[79] These fusion These fusion join.[79] parts chromosome separated of Translocation loci. genetic gain of with or loss w can be balanced, Translocations parts. chromosome re a chromosome refers to translocation Chromosomal 2. ofuse fluor the FISH involves diagnostictool.[4] as to referred simply FISH,hereinafter Interphase resolution, sensitivity, specificity, and accessibi sensitivity, specificity, resolution, and bioinformati genomic of availability widespread fluorescence microscopy in Advances DNAsequences. wi labeled were that probes RNA directly with 1980s Fluorescencelabe autoradiography.[13] by followed was first hybridization situ in 1960s, In late the applicable to surgical pathology. pathology. surgical applicableto review focuses This thesedifficulties. overcoming cha many poses technical decisions cancertreatment 6 types[5, many for tumour therapeuticimplications alte chromosome These and polysomy. amplifications, del chromosome are alterations FISHdetected Common

Acceptedoverview An translocations: Chromosomal Article Introduction

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch lity of fluorescence lityfluorescence of performed with radioisotopelabeled probes probes radioisotopelabeled with performed

ten creates fusion genes when two otherwise two geneswhen fusion creates ten escence labeled fragments of DNA (probes) of DNA (probes) fragments escencelabeled FISH, is the usual clinical application of this of this application clinical usual the FISH,is on FISH based detection of translocations of translocations FISH on baseddetection ]. Integrating precise genomic testing into testing into Integratinggenomic ]. precise c resources, have greatly improved the the greatlyimproved chave resources, llenges, but rapid progress is being made in in beingis made rapid progress but llenges, genes may behave as a hybrid chimeric ahybrid as genes behave may

th fluorophores complementary to specific specific to complementary fluorophores th led probe technology started in the early the in started technology probe led mens or paraffin embedded tissue sections. sections. tissue embedded or paraffin mens ithout net loss of material, or unbalanced, orof unbalanced, material, loss net ithout arrangement involving nonhomologous nonhomologous involving arrangement rations may have diagnostic and diagnostic have may rations and digital imaging, as well as as well imaging, anddigital etions, gains, translocations, translocations, gains, etions, in situ situ in hybridization (FISH). (FISH). hybridization previously unrelated gene elements into a new fusio a new into elements gene previouslyunrelated angiogenic growth factor gene ( growthfactor angiogenic COL1A1. The pathognomonic fusion protein of dermatofibrosar protein fusion The pathognomonic activating not only endothelial cells but also fibr also but cells endothelial only activating not overstimu in factor growth results overabundanceof transcription factor transcription may be transformed into sarcomas. Constitutive acti sarcomas. Constitutive into transformed may be a oncogenes fusion gainof function tyrosinekinase regulat to unresponsiveness causing region, control gene by overexpres tumorigenesis oncogene,inducing sequencing[1020]. hybridi genomic comparative karyotyping,microarray detectable several is by translocation Chromosomal invariably chromosomes, or between intrachromosomal centromere involv or without with loci involved the re Intrachromosomal samechromosome. the in regions chromosome different two involve may Translocations Fusion gene detection, therefore, is at the heart o heart the at therefore, is gene Fusion detection, Most Ewing sarcoma cases result from result Ewingcases sarcoma Most half about underlies mechanism This domain. kinase fusion of the dimerization unregulated from results

Accepted coll fibroblast essential of the amalgamation This Article

FLI1 Some chromosomal translocationsnotdetectable are

, leading to aberrant expression of Ewingt sarcoma expression aberrant leading to , This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch PDGFB EWSR1FLI1 EWSR1FLI1 ) leads to increased growth factor release. An An release. growth factor increased to )leads

oblasts and inflammatory cells.[10] cells.[10] and inflammatory oblasts f FISH diagnostic testing. testing. FISHdiagnostic f gene protein containing the active the ALK genecontaining protein ory control factors. For example, receptor example, For factors. control ory re a mechanism whereby mesenchymal cells cells mesenchymal whereby rea mechanism ement. Chromosome rearrangement, whether whether rearrangement, Chromosome ement. n gene that may or may not betranscribed. not or may may gene n that vation of the insulin family insulin of the kinase vation methods, including FISH, metaphase FISH, including methods, lation of receptor tyrosine kinase PDGFR, PDGFR, kinase tyrosine of receptor lation of inflammatory myofibroblastic tumours. tumours. myofibroblastic ofinflammatory gene fusion deregulating the ETS ETS the deregulating genefusion coma protuberans (DFSP) is is (DFSP) coma protuberans sion, or they may interrupt an important an important interrupt may or they sion, zation, SNParray, and next generation next SNParray, and zation, s or may exchange information between between information exchange or may s arrangement may cause transposition of transposition cause may arrangement leads to a neoteric juxtaposition of juxtaposition a neoteric to leads agen gene(agen by split-FISH, whetherby COL1A1 ransforming genes. ransforming ) with the the )with PDGFB ALK

Page 4of64 Page 5of64 probes (probes physical distance between the fusion partners after partners fusion the between physicaldistance products with uncharacterized fusion partners. partners. fusion uncharacterized with products 1 apart ( apart continues to grow. With some exceptions, sarcoma tr sarcoma exceptions, some grow.With to continues specific havedocumented well of sarcomas 30% About 3. and some fusion products with uncharacterized fusio uncharacterized with products fusion andsome both It candetect scale. genomewide comprehensive analysi RNA and allows events genefusion andnovel generation sequ a next favoured. is RNAseq, method light the at beresolved reliably cannot distances fusi the distance between physical short relatively intrachr involving those especially translocations, optica the in a decrease or either an increase show especially those involving intrachromosomal inversi intrachromosomal involving those especially distance between optical the or decreased increased genomewide scale. It can detect both cryptic intra detect both can It genomewidescale. c through analysis RNA and allow events genefusion tech generation sequencing anext favored.RNAseq, level microscopic light the at resolved reliably be ) or by fusion probes ( probes )fusion or by

Chromosomal translocations mainly associated with s with associated mainly translocations Chromosomal Some chromosomal translocations are not detectable not are chromosomal translocations Some Fig.2

Accepted probethe sets tool, diagnostic a reliable ). be To Article Fig. 2 Fig. This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch ). To be a reliable diagnostic tool, the probe sets probe the tool, diagnostic ). beaTo reliable

microscopic level. In this scenario, a PCRbased aPCRbased Inscenario, this level. microscopic . In this scenario, a PCRbased method is is method Ina PCRbased scenario, this . omosomal inversion or deletion, have a or deletion, inversion omosomal on partners after translocation. These small These small partnerstranslocation. on after l distance between probe signals. Some signals.Some probe distance between l translocation. These small distances cannot distances small These translocation. chromosomal rearrangements and some fusion fusion and some rearrangements chromosomal probe signals. Some translocations, translocations, Some probesignals. on or deletion, have a relatively short ashort relatively have or deletion, on n partners[14, 2126]. ( 2126]. partners[14, n anslocations form fusion genes with the 5′ 5′ the genes with fusion form anslocations nique, can detect both known and novel and novel known both detect can nique, cryptic intrachromosomal rearrangements rearrangements cryptic intrachromosomal encing technique, can detect both known known detect both can technique, encing DNA sequencing at a comprehensive a at DNAsequencing s through cDNA sequencing at aat sequencing cDNA through s translocations, and the percentagethe and translocations, by FISH, whether by splitapart ( splitapart by FISH,whether by must reproducibly show either show reproducibly must arcomas

Fig.1 must reproducibly reproducibly must ) or by fusion fusion by )or Fig. balanced chromosomal rearrangement in most Ewing sa Ewing most in rearrangement chromosomal balanced pulmonary myxoid sarcoma, inflammatory myofibroblas inflammatory sarcoma, pulmonarymyxoid particular tumour type, potentially making them ide them making potentially type, particulartumour terminal of an terminal transcription factors. These proteins join the amin the join proteins These factors. transcription diagnosis. The fusion partners of partners fusion Thediagnosis. usually affecting bone and extraosseous tissues of tissues extraosseous and bone usuallyaffecting cel blue round of small composed are Ewingsarcomas sarcoma Ewing 3.1 associated fusion genes contain a member of the a ofmember the genescontain associatedfusion characteristi morphological sharing similar tumours genefusions Recurrent segmenttransactivation. by ove and promoter a strong contributing genesegment neuroectodermal tumor, synovial sarcoma, liposarcom synovialsarcoma, tumor, neuroectodermal enti common many include FISHidentifiablesarcomas tumorsp basedon analysis FISH confirmed by can be Ov associated sarcomas. for the therapeuticmeaning translo oftheserecurring identify which to is now fo have been translocations recurring 400 Morethan TAF15 gene products valuable both for diagnostic and for and for for diagnostic both genevaluable products therap actualareor potential proteins fusion Some as the protooncogene partner. Most fusion genes fusion Most partner. as protooncogene the

ETS Accepted Article

gene family member. This fusion not only abrogates not fusion This genefamilymember.

TET o terminal of the terminal o cations truly has diagnostic, mechanistic, or mechanistic, diagnostic, truly cations has children and young adults. There is a specific There ayoung specific is adults. andchildren eutic targets, making the detection of fusion of fusion detection the making targets, eutic therapeutic purposes. therapeutic purposes. al molecular diagnostic markers.[10, 2729] 2729] markers.[10, diagnostic molecularal in soft tissue sarcomas tend to occur sarcomas to in tend tissue soft in cs.[27] Roughly half of the sarcoma the Roughly cs.[27] half of und in soft tissue sarcomas. The challenge The challenge sarcomas. tissue soft in und er 30 subtypes of the mesenchymal tumor tumor mesenchymal of the ersubtypes 30 gene family, including gene family, rexpression of the 3′ protooncogene protooncogene 3′ of the rexpression ecific chimeric fusion sequences.[28] sequences.[28] fusion chimeric ecific a, round cell Ewinglike sarcoma, Ewinglike a,cell round ls with highly malignant behaviour, behaviour, highlymalignant with ls ties: Ewing sarcoma/primitive Ewing sarcoma/primitive ties: rcomas, providing a valuable tool for tool a valuable rcomas, providing tic tumor, and others ( and others tumor, tic are strongly associated with a with associated strongly are EWSR1 the RNA splicing RNA the gene with the carboxy carboxy the genewith FUS, EWSR1FUS, Table 1 Table ). ). , and , Page 6of64 Page 7of64 biopsy tissues, since a variety of soft tissue tumo tissue soft of sincea variety biopsytissues, patients with localized tumours expressing the most the expressing tumours localized with patients ERG partner. As many as 90% of the translocations invol translocations of the as 90% partner.many As those of the more common moreofcommon the those of thes consequences functional The Ewingsarcomas. The diagnosis of myxoid liposarcoma may be challeng be may liposarcoma of myxoid Thediagnosis liposarcoma Myxoid 3.2 time.[31] this at types fusion rendering gene fusions of DNAdamage inducible tran inducible DNAdamage of genefusions rendering translocations Chromosomal liposarcomas. of all 33% 10 about represents liposarcoma Myxoid liposarcoma. fused to fusedto and the downstream carboxyterminal region of region carboxyterminal downstream andthe uncontrolled cell division, and survival in the fac the in and survival celldivision, uncontrolled transcri regulating the and growth cell controlling respectively, are characteristic ofliposarc myxoid characteristic are respectively, The fusion gene encodes a protein containing the up the containing agene protein encodes The fusion 11q24.[30] chromosome t(11;22)(q24;q12) translocation, which juxtaposes juxtaposes which translocation, t(11;22)(q24;q12) function of function translocation, t(21;22)(q22;12), resulting in in resulting t(21;22)(q22;12), translocation, FLI1 EWSS1

Acceptedcurrently is prognosticdata limited 6), but exon Article

but also removes essential transactivating contro transactivating removes essential also but

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch EWSR1FLI1 fusion. One study suggested a better outcome for for outcome a better study suggested One fusion. FLI1

urs with myxoid change may mimic myxoid myxoid mimic may change myxoid with urs e of otherwise lethal additional mutations. The mutations. additional oflethal otherwise e EWSR1ERG ption of downstream genes responsible for genes responsible of downstream ption oma; one of these is identifiable in more than morethan in identifiable one of theseis oma; EWSR1 common t(11;22) transcript ( transcript t(11;22) common ve the stream aminoterminal domain of domain aminoterminal stream . This fusion protein uniquely functions in in uniquely functions protein fusion This . e variant fusion proteins are similar to to are similar proteins fusion evariant t(12,16)(q13;p11) and t(12;22)(q13;q12), t(12;22)(q13;q12), and t(12,16)(q13;p11) % of all adult sarcomas and approximately and approximately sarcomas adult %of all script 3 ( 3 script ing by histology alone, especially on small small alone,on especially histology by ing at 22q12 with the the with 22q12 at EWSR1 available for the less common common less the for available fusion, represents only 10% of all of all only 10% represents fusion, DDIT3 gene in the form ofform the genein l regions of the regions l ) with )with FLI1 FUS EWSR1 or gene on ETS EWSR1 EWSR1 gene exon 7 7 exon , ,

sarcoma. A characteristic t(X;18)(p11;q11) transloc t(X;18)(p11;q11) characteristic sarcoma.A i The FISH test 33] Xp11.[32, chromosome locatedon chromosome 18 with either synovial sarcoma X breakp sarcoma either synovial with 18 chromosome virtually all tumours. The translocation fuses syno translocation The tumours. virtuallyall t(X;18)(p11;q1 by characterized is sarcoma Synovial sarcoma Synovial 3.3 t(12;16)(q13;p11). kit, probe apartrearrangement include are FISH probes used Commonly of cases. 95% synovialsarcomas. myofibroblastic origin. Recurrent fusions of the tw of the fusions Recurrent origin. myofibroblastic there now is but from pericytes, derive to thought fibrob beof to presumed and anyat site, occurring of soft a family comprises tumour fibrous Solitary tumour fibrous Solitary 3.4 and signal transducer and activator of transcriptio and andsignal transducer region 12q13, have been identified in solitary fibr in identified have been 12q13, region induces cell proliferation and activates expression and activates cell proliferation induces identified the the identified response (EGR)binding domain of domain response(EGR)binding 35] The fusion product contains the activation doma activation the contains product The fusion 35] derived from an inverted intrachromosomal fusion of fusion intrachromosomal aninverted derivedfrom

NAB2STAT6 Accepted Article

The t(X;18) translocation has not been found in oth beenin found not has translocation t(X;18) The

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch translocation by whole exome sequencing of 17 soli of sequencing 17 exome bytranslocation whole NAB2[36] .Overexpression of the

n 6 ( 6 n ous tumours. The tumours. ous of evidence to support a fibroblastic or afibroblastic evidencesupport to vial sarcoma translocation gene ( sarcoma vial translocation lastic differentiation. The tumours were tumours The differentiation. lastic tissue lesions usually affecting adults, adults, usually affecting lesions tissue o genes, NGFIA–binding protein 2 ( 2 protein genes, o NGFIA–binding ation or variants were found in 90% of 90% in found were or variants ation in of in 1) translocation, which is present in presentin is which 1)translocation, the the EGFR STAT6 s highly specific and sensitive for synovial for synovial sensitive and highly s specific oint 1 ( 1 oint d in the Vysis Vysis the in d NAB2 STAT6 STAT6 responsive genes. Chmielecki et alet genes.Chmielecki responsive ), both located near chromosomal located near ), both chromosomal SSX1 and fused to the early growth growth early the fused to NAB2STAT6 ) (66%) or )(66%) STAT6 NAB2STAT6 DDIT3 er sarcomas. ersarcomas. genes on 12q13.[34, 12q13.[34, genes on dual colour, break colour, dual SSX2 tary fibrous fusion gene fusion is SS18 fusion gene fusion (33%), NAB2 ) on )on ) Page 8of64 Page 9of64 preferred method of detection. STAT6 immunostaining STAT6 of detection. preferredmethod fibrous tumours by exome sequencing. Since the the Since sequencing. exome by tumours fibrous gene This wasfusion and matched blood.[34] tumours or translocations. Mohajeri et al used 6 independent m independent 6 used alet Mohajeri translocations. 12q13, the break apart designed probe may detect so detect may probe apartdesigned break the 12q13, It should be noted that the the that It benoted should evaluated.[37] tumours fibrous directly binds the ETS variant 5 ( 5 variant ETS directlythe binds activityof upregulates expression of this oncogene. Four cases oncogene. Four this of upregulatesexpression PCR), and FISH methods.[39] FISH was positive for FISH for was positive and FISH methods.[39] PCR), reverse cytogenetic, of conventional acombination t(4;19)(q35;q13), resulting in fusion of capicuaho of fusion in resulting t(4;19)(q35;q13), recu have a to beenfound have sarcoma” “Ewinglike anyabnormalitie cytogenetic the exhibit of to fail clinically sarcomas that of subset Therea small is sarcoma cellEwing-like Round 3.5 very close proximity of the 2 genes (overlapping en genes 2 (overlapping of the veryclose proximity detecting detecting ( DUX4 STAT6 ).[38] Fusion of the Cterminal fragment of fragment Cterminal of the Fusion ).[38] rearrangement to identify to rearrangement NAB2STAT6 CIC

Acceptedtarge downstream of its expression and deregulates Article fusion product and is now becoming standard practi becomingstandard now and is product fusion This article isprotected by copyright. All rights reserved. NAB2STAT6 NAB2STAT6 The JournalofPathology:ClinicalResearch ETV5 NAB2–STAT6 ) promoter at a previously unrecognized site and site unrecognized aat previously ) promoter fusion is not consistently detected by FISH due to FISHdueby to detected consistently not is fusion

NAB2 s reported for these tumours. Recently cases of cases Recently thesetumours. reported s for and histologically mimic Ewing sarcoma but Ewing but sarcoma mimic andhistologically fusion in 37 of 41 (90%) of the solitaryof the (90%) of 41 37 in fusion molog( DUX4 olecular genetic techniques directed at directed genetictechniques olecular ds)[36] and, in this setting, RTPCR is the the is setting, this RTPCR and,in ds)[36] transcription polymerase chain reaction (RT chain reaction polymerase transcription of me but not all of the all not but me CICDUX4 rrent chromosomal translocation, translocation, chromosomal rrent confirmed in 29 of 55 (55%) solitary (55%) solitary of 55 29 in confirmed CICDUX4 and is highly sensitive and specific for specific for and highlysensitive is with with CIC STAT6 ) and double homeobox 4 4 homeobox )and double CIC fusion in all four tumours. The four tumours. all in fusion sarcoma were identified using wereidentified sarcoma ts. ts. genes are both located near near genes arelocated both enhances the transcriptional transcriptional the enhances CICDUX4 NAB2STAT6 ce. ce. fusion protein protein fusion

NAB2 NAB2 the the ALK, CLTCALK, CARSALK, ATICALK, SEC31AALK, SEC31AALK, ATICALK, CARSALK, CLTCALK, ALK, behave in a benign fashion, they may be difficult t difficult they be may fashion, behavea benign in 2p23 with multiple fusion partners,including multiple with 2p23 instance, Therapy targeting tumour cells with with cells tumour Therapytargeting neoplasms. similar my inflammatory for distinguishing useful may prove inflammatory myofibroblastic tumours that lack that tumours inflammatorymyofibroblastic know is Currently,44] little remission.[43, tumour Besides reported six (10%) reportedsix myof negativeinflammatory ALK fusion in found also leading to elevated expression of ALK chimeric prot expression elevated leading to carcinoma. Roughly half of inflammatory myofibrobla ofinflammatory half carcinoma.Roughly urinary bladder but occasionally diagnosed at vario at diagnosed occasionally but urinary bladder ce a spindle is tumour myofibroblastic Inflammatory tumour myofibroblastic Inflammatory 3.6 CICDUX4 rapiddi and features histopathological distinctive ALK

the fusion gene overexpresses overexpresses gene fusion the sarcoma as a new translocationassociated sarcoma. newtranslocationassociated as a sarcoma , ,

AcceptedROS1 Article

ROS1 ROS1 and

NTRK3 This article isprotected by copyright. All rights reserved. related translocations in a group of 62 cases. Most cases. a of 62 group in relatedtranslocations The JournalofPathology:ClinicalResearch gene rearrangements, gene rearrangements, ALK ALK gene rearrangement has been shown to induce partia to has been shown gene rearrangement due to promoter swapping. swapping. promoter due to TPM3ALK, RANBP2ALK, TPM4ALK, EML4 TPM4ALK, RANBP2ALK, TPM3ALK,

ALK ALK sease progression may warrant classification of classification warrant may progression sease o differentiate from sarcoma or sarcomatoid or sarcomatoid sarcoma from differentiate o n about the pathogenesis of the 50% of 50% of the pathogenesis the about n us body sites. Although these tumours usually thesetumours Although bodyus sites. ein.[40] The ein.[40] ll neoplasm most frequently found in the the in frequently found most neoplasm ll ofibroblastic tumour from morphologically morphologically from tumour ofibroblastic translocation. translocation. stic tumours have tumours stic ibroblastic tumours.[45] Antonescu et alet Antonescu tumours.[45] ibroblastic YWHAE–ROS1 YWHAE–ROS1 and PPFIBP1ALK.[41, 42] 42] PPFIBP1ALK.[41,

ALK translocations involve translocations involve and ALK ALK ETV6–NTRK3 ETV6–NTRK3 of the patients were were of patients the rearrangements rearrangements In each are l l Page 10of64 Page 11of64 part sarcomas. This translocation is also found in in found also is translocation This partsarcomas. generate fusion proteins that function as transcrip function that proteins fusion generate ARMS of and 5580% 1522% for reportedlyaccounting array comparative genomic hybridization and FISH. F and FISH. hybridization genomic comparative array a 17 investigated alet Selvarajah arrest. override The cases.[12] all in transcription of transcription protein The fusion Xp11.[47] chromosome locatedon translocations involving involving translocations aggres a highly is (ARMS) Alveolarrhabdomyosarcoma Rhabdomyosarcoma Alveolar 3.8 frequent which cellcarcinoma) renal (translocation 17q25 and the transcription factor for the immunogl the factor for transcription and the 17q25 rearrangement involves the alveolar soft partsarco alveolar the soft involves rearrangement many si in body arising sarcomas part Alveolarsoft his ahas characteristic sarcoma part Alveolarsoft sarcoma part soft Alveolar 3.7 myofibroblastic tumour cases showed showed cases tumour myofibroblastic lung the in were located tumours and the children,

AcceptedTFE3ASPSCR1 Article TFE3 [der(17)t(X;17)(p11;q25)] translocation is found i found is translocation [der(17)t(X;17)(p11;q25)] regulated genes and may confer resistance to cell to resistance confer genesand may regulated PAX3FOXO1 This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch

TFGROS1 TFGROS1 [t(2;13)(q35;q14)] or [t(2;13)(q35;q14)]

lveolar soft part sarcomas from 11 patients by patients 11 from sarcomas part soft lveolar tional activators with oncogenic effects. FISH effects. oncogenic with activators tional a distinctive subset of renal cell carcinoma cellcarcinoma of renal subset adistinctive topathology but a controversial histogenesis. histogenesis. controversial a but topathology fusions, t(3;6)(q12;q22). t(3;6)(q12;q22). fusions, ma locus ( locus ma or abdomen.[46] Two (3.2%) inflammatory (3.2%) Two inflammatory orabdomen.[46] ly has a papillary architecture. architecture. lyahas papillary tes have a diagnostic translocation. The translocation. have tes a diagnostic obulin heavy chain enhancer 3 (chainenhancer 3 heavy obulin ISH the identified is capable of inducing aberrant capableaberrant is of inducing sive soft tissue sarcoma associated with with associated sarcoma tissue soft sive , respectively.[48] These translocations These translocations respectively.[48] , ASPSCR1 PAX7FOXO1 ) located on chromosome chromosome on )located n 80% of alveolar soft soft of alveolar 80% n cycle arrest signals and signals arrest cycle ASPSCR1 [t(1;13)(p36;q14)] [t(1;13)(p36;q14)] TFE3 TFE3 fusion fusion ) gene, ) 4.1 superfamily normally expressed only in certain neur certain in only expressed normally superfamily kina a tyrosine is (ALK) kinase lymphoma Anaplastic 4.1.1 FISH analysis using the the using FISHanalysis than and specificity testingsensitivity higher has epithelial solid tumours ( tumours solid epithelial of the adenocarcinomas as cancers, such epithelial also been oncogenes have fusion of number Agrowing 4. smaller subset of tumours (6%) an bear of tumours subset smaller clear cell sarcomas are associated with associated are cellsarcomas clear recurr of frequency local a high aggressive with is the typically in sex, of either adults middleaged a rare is tissue mesench of soft Clearcellsarcoma tissue soft sarcoma of Clear cell 3.9 bydetectable PCR. not rearrangements the the paraffine formalinfixed, from extracted usingRNA In prognosis. tumour to unrelated is translocation

EWSR1ATF1 Chromosomal translocations mainly associated with with associated mainly translocations Chromosomal Chromosomal translocations Chromosomal translocations tumoursother solid in EML4-ALK

Accepted Article

(31/33) or (31/33) translocation translocation

FOXO1 Table 2 Table This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch EWSR1CREB1 splitapart probe adds the ability to detect varian detect to ability the adds probe splitapart ). EWSR1ATF1 EWSR1ATF1 EWSR1CREB1 EWSR1CREB1 fusion gene (2/33).[51] gene (2/33).[51] fusion

RTPCR assay for these fusion transcripts.[49] transcripts.[49] assay fusion for these RTPCR soft tissue of the lower extremities. The tumour The tumour lowerof the extremities. tissue soft a group of 33 clear cell sarcomas, RTPCR RTPCR cellsarcomas, clear aof 33 group ymal malignancy mainly occurring in young to occurring in mainly ymalmalignancy ence and distant metastasis. Almost all (90%) all Almost metastasis. anddistant ence lung, prostate, colon, kidney, breast, andother kidney, colon, breast, lung, prostate, ons of the developing central nervous nervous central developing of the ons mbedded tissues demonstrated transcripts of transcripts demonstrated tissues mbedded se member of the insulin receptor insulin seofmember the translocation, t(12;22)(q13;q12), while a while t(12;22)(q13;q12), translocation, associated with some common adult adult common some associated with translocation.[50] Thespecific translocation.[50] lung cancer lung t t FOXO1

Page 12of64 Page 13of64 protein involved in microtubule assembly, results i assembly, results microtubule in involved protein proteins including AKT1, MAPK1, MAPK3, IRS1,and PL MAPK3, MAPK1, AKT1, including proteins be neversmokers. Their cancers tend to be adenocar be to cancerstend Their beneversmokers. kinase.[52, 53] The 53] kinase.[52, nucleophosmin gene ( nucleophosmin activate rearrangement chromosome a which t(2;5) in system. Fusions of system.Fusions towards higher grade. Several genes may serve as fu as serve genes may grade.Several higher towards CROS oncogene ( 1 CROS 4.1.2 signals. greenand orange 42, 54, 55]. The common FISH test for FISH test The common 55]. 54, 42, canc cancer, colorectal breast carcinoma, celllung covering the companion FISH detection kit ( kit FISH detection companion antica a novel approved FDA the that simultaneously role of FISH triage for guiding guiding for triage roleof FISH general, a sample is considered positive if >15% if of positive considered is asample general, College the by recommended is probekit apartFISH lung adenocarcinoma cases.[5860] cases.[5860] lungadenocarcinoma f activated constitutively a lead to rearrangements translocation are significantly younger than most p youngermost than significantly are translocation

ROS1 ALK

Accepted translocation Article

gene and 3′ flanking region of 3′ region flanking and gene ALK ALK ROS1 NPM1 with echinoderm microtubuleassociated proteinlik echinoderm microtubuleassociated with fusion oncogene was first identified in anaplastic in identified first oncogene was fusion This article isprotected by copyright. All rights reserved. ) is a receptor tyrosine kinase of the insulin rece insulin of the kinase a tyrosine receptor ) is The JournalofPathology:ClinicalResearch ) on chromosome 5. 5. chromosome )on ALK ALK targeted therapy.[56, 57] A FDA approved Vysis Vysis approved AFDA 57] targetedtherapy.[56, ROS1 FISH probe kit, Abbott Molecular), highlighting th Molecular), highlighting Abbott kit, FISH probe ALK activation stimulates other downstream signaling signaling otherdownstream stimulates activation rearrangement uses dual colour labeled probes colour dual uses rearrangement

ALK ALK usion kinase, and are detected in 1.2–1.7% of 1.2–1.7% in detected and are kinase, usion er, renal cancer, and other tumour types [41, types [41, tumour andother cancer, er, renal n constitutive activation of the ALKof the activation constitutive n atients with lung cancer and are more likely to to likely and are more lung cancer with atients cells are positive for positive are cells sion partners for partnersfor sion cinoma, and their tumours have a tendency have a tendency tumours andtheir cinoma, ncer drug (crizotinib, Pfizer) and its and its Pfizer) (crizotinib, ncerdrug of American Pathologists (CAP). In (CAP). Pathologists American of ( s the ALK kinase by fusion with the the with fusion by ALK kinase the s fusions have been reported in nonsmall nonsmall in have beenfusions reported Fig.3 CG2.[59] Patients with with Patients CG2.[59] ). The year 2013 was the first time yeartime was first the 2013 ). The ROS1 ALK ptor family. The family. The ptor largecell lymphoma, lymphoma, largecell including e( 4 separation of the EML4 ROS1 SDC4 ALK ),a e critical e

break ROS1 , ,

positive tumours of these primary sites.[62, 63] Th 63] ofsites.[62, these primary tumours positive ROS1 Novel chromosomal translocations involving the the involving translocations chromosomal Novel RET RET systematic investigation of tyrosine kinase inhibit kinase oftyrosine systematicinvestigation ROS kinase activation.[61] A dual probeAdual breakapa activation.[61] kinase ROS SLC34A2 rearrangement as with as with rearrangement 4.1.3 4.1.3 (1/20) of epithelioid haemangioendotheliomas.[6366 of epithelioid (1/20) tumours myofibroblastic of inflammatory (2/26) 7.7% adenocarcinomas gastricof (3/495) carcinomas,0.6% of chol (2/23) types: 8.7% othertumour in low also growth and differentiation[67, 68]. Several68]. and differentiation[67, growth ty receptor a cellsurface and encodes superfamily, screening are used to evaluate the the evaluate to arescreeningused defines a clinically distinct subset of nonsmall c of nonsmall subset clinicallydistinct definesa

recently[61, 67]. The rearranged during transfectio during The rearranged recently[61,67].

small cell lung carcinomas, including celllung carcinomas, small gene translocation occurs in approximately 1–2% of 1–2% occursapproximately in gene translocation . . RET fusions are also found in meningioma, cholangiocar meningioma, in found also are fusions , , translocation translocation

Accepted Article CD74

, , GOPC ALK , and , This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch rearrangement. Criteria similar to those used for used those to similar rearrangement. Criteria EZR ROS1 , yet each of the yetof the each , KIF5BRET FISH test. test. FISH RET

rearrangements have been identified in non in identified been have rearrangements ell lung carcinomas. Patients with with Patients lung carcinomas. ell RET ors has been published for for has been ors published , , rosine kinase that transduces signals for cell for signals transduces that kinase rosine e reported incidence of incidence ereported n ( n ROS1 angiocarcinomas, 0.5% (1/200) of ovarian (1/200) angiocarcinomas,0.5% CCDC6RET rt method is used to detect detect to used is method rt RET ] , 0.8% (2/236) of colorectal carcinomas, colorectalcarcinomas, of (2/236) 0.8% , tyrosine kinase gene were reportedwere gene tyrosine kinase , 2.9% (1/34) of angiosarcomas, and 5% angiosarcomas,and of (1/34) 2.9% ,

fusion products leads to constitutive constitutive to leads products fusion nonsmall cell lung carcinomas and carcinomas celllung nonsmall ) gene belongs to the cadherin cadherin the to ) gene belongs cinoma, and glioblastoma, but no no but glioblastoma, and cinoma, , , NCOA4RET ROS1 ROS1 ALK , and , ROS1 translocation is is translocation rearrangement fusion fusion TRIM33

Page 14of64 Page 15of64 positive patients, 9 (69%) 9 had patients, positive NCOA4RET histiocytoma ( histiocytoma g of the tumour sarcomalike cell clear observedin the the early lymph node metastasis. Drilon et al found found alet Drilon metastasis. earlylymphnode

should be noted that that benoted should Thymus and Heart, pulmonary myxoid sarcoma with with sarcoma myxoid pulmonary Thymusand Heart, Classif (WHO) Organization Health World In2015 the carcinoma, the carcinoma,the In a beneversmokers.[69] to likely aretheymore adenocarcinomas with with adenocarcinomas 5. displaying a distinct morphology, it bears a bears it morphology, a displaying distinct in cells or spindle round atypical cordsof mildly o consists The tumour youngfemales. frequentlyin m pulmonary Primary entity.[72] as a introduced new 4.1.4 and ple lungs the in disease decreasemeasurable in c therapy weeks and 12 4 of after imagingconducted adenocarcinoma; 2/24, 8.3% in adenosquamous cell ca cell adenosquamous in 8.3% 2/24, adenocarcinoma;

RET Chromosomal translocations Chromosomal mainly translocations k associated with

EWSR1-CREB1 kinase can be effectively inhibited by several sma byseveral inhibited effectively can kinase be fusion. Their tumours tended to be poorly differen be poorly to tended Their tumours fusion.

Table 1 Table Accepted Article RET

fusion gene was exclusively detected in 13 patient 13 in detected exclusively gene was fusion EWSR1CREB1 ) ) RET translocation in primary pulmonary myxoidsarcomas primary pulmonary in translocation This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch fusion tend to be younger than most patients with with patients youngermost bethan to tend fusion KIF5BRET translocation is not unique for this entity; ca for this unique it not is translocation , 3 (23%) had (23%) 3 , EWSR1CREB1

RET a prominent myxoid stroma. In addition to Into addition stroma. myxoid prominent a study of 936 patients with nonsmall celllung nonsmall with study patients of 936 astrointestinal tract and angiomatoid fibrous fibrous angiomatoid and tract astrointestinal ura. ura. f lobules with delicate, lacelike strands and strands delicate, lacelike with flobules fusions in 5 of 31 patients and showed that that and showed patients of 31 5 in fusions onfirmed a partial response with a 66% with response a partial onfirmed EWSR1CREB1 yxoid sarcoma is rare, and arises most and arises most yxoidrare, is sarcoma rcinoma).[70] Of the 13 13 Of the rcinoma).[70] ication of Tumours of the Lung, Pleura, of the of Tumours ication CCDC6RET ll molecule inhibitors.[71] Followup Followup inhibitors.[71] molecule ll translocation in 70% of cases.[73] It of cases.[73] 70% in translocation tiated carcinomas that exhibited exhibited that carcinomas tiated translocation was translocation , and 1 (7.6%) 1 had and , s (11/633, 1.7% in in 1.7% (11/633, s idney cancer idney lung cancer and lungcancer RET

n also be also n fusion NONO NONO partners for partnersfor and widely tested breakapart FISH assays, the the assays, FISH breakapart tested andwidely tu renal for enigmatic FISH of application clinical cell renal unclassified sevenincluding previously t(X;3)(p11.2;q23) and t(X;10)(11.2;q23). Different Different and t(X;10)(11.2;q23). t(X;3)(p11.2;q23) one signal diameter onesignal diameter of separation showed nuclei tumour of the when≥10% Seventeen cases showed showed Seventeencases Rao et al analyzed 24 poorly differentiated renal c renal differentiated poorly 24 analyzed alet Rao adver often less is evaluation, immunohistochemical as FISH and the cellcarcinoma, renal translocation 5.1 The mor different with associated be may cellcarcinoma in gene fusions of the gene fusions in translocati different several are carcinomas.There a and cellcarcinomas renal majorityof paediatric Orga Genital and Male System Urinary of the Tumours Wo 2016 the entity in adistinct as recognized were transl Xp11.2 with associated cellcarcinomas Renal

TFE3 TFE3 ( Fig.4 translocation translocation breakapart FISH assay has proven useful for detec assay provenuseful FISH has breakapart TFE3

Accepted Articlefusi unknown with Variant translocations 76] ).[75,

have been characterized, including including characterized, have been

(Fig. 5) (Fig. TFE3 TFE3 This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch . . gene with various activating partners. At least fi least At partners. activating various gene with rearrangement associated with Xp11.2 translocation Xp11.2 associatedwith rearrangement TFE3

tumours, supporting the diagnostic value and diagnosticvalue the supporting tumours, mours. On the basis of commercially available of commercially basis the On mours. ancers with breakapart breakapart with ancers ons involving chromosome Xp11.2, resulting Xp11.2, chromosome involving ons renal cell adult percentageof smaller say, in comparison with with comparison in say, rld Health Organization classification of classification Organization Health rld gene fusions in Xp11.2 translocation renal renal translocation Xp11.2 in genefusions ocation are uncommon renal tumours that that renal tumours are ocation uncommon phological features.[77, 78] 78] features.[77, phological sely affected by technical and fixation issues. issues. fixation and technical by affected sely splitsignal pattern was considered positive positive wasconsidered pattern splitsignal ASPSCR1, PRCC, SFPQ, CLTC SFPQ, PRCC, ASPSCR1, the two coloured signals by more than than bymore coloured signals two the ns.[74] These neoplasms comprise the the comprise These neoplasms ns.[74] ting ting on partners include include partners on TFE3 TFE3 gene fusions in Xp11.2 Xp11.2 in genefusions TFE3 ve different fusion fusion vedifferent FISH.[79] FISH.[79] by FISH, by , and , Page 16of64 Page 17of64 by translocation involving the transcription factor transcription the involving bytranslocation protein overexpression or t(6;11) translocation is is translocation t(6;11) or overexpression protein using FISH technology. All seven cases were were seven cases All usingFISH technology. 5.3 designs.[81] Rao et al reported seven patients with with patients seven reported alet Rao and appea tissues, paraffinembedded formalinfixed recently, a breakapart FISH assay to detect assay detect to FISH recently,a breakapart viable tumour cells for culture or flash frozen tis or frozen flash culture for cells tumour viable thes Unfortunately, translocation. this identifying chromosome 6q11 ( 6q11 chromosome TFEB r is carcinoma renal cell translocation Thet(6;11) 5.2 time of diagnosis. All five renal medullary carcino renal medullary five of All diagnosis. time presen who sicklecell trait with American patients re All carcinomas.[83] urothelial and2 carcinomas, t rhabdoid paediatric 2 carcinomas, renal medullary studied alet Cheng tumour. of this hallmark the is a to tum a aggressive rare, is carcinoma medullary Renal carcinoma. Cytogenetic karyotypic analysis and RTP and analysis karyotypic carcinoma.Cytogenetic

SMARCB1/SMARCB1 TFEB SMARCB1 and translocation MALAT1

AcceptedInactivationof tumou family.[82] tumour deficient Article

on chromosome 11q12, but rarely but 11q12, chromosome on Fig. 4B Fig.

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch genetic alterations and ALK translocation ALK translocation and geneticalterations ).[80] Renal cell carcinomas with t(6;11)(p21;q12) t(6;11)(p21;q12) with cellcarcinomas Renal ).[80] TFEB renal cell carcinoma confirmed diagnostically by by diagnostically confirmed cellcarcinoma renal TFEB TFEB TFEB

sue to quantitatively assay assay quantitatively to sue e methods are limited by the need for fresh fresh need for by are the limited methods e useful for the diagnosis of for useful diagnosis the are and usually bears a translocation between a translocation bears and usually are EB( a total of 19 renal cancers that included 5 5 included that cancers renal of 19 a total mas and two renal rhabdoid tumours showed showed tumours rhabdoid renal and two mas gene translocation has been validated on on validated has been genetranslocation ted with extensive extrarenal metastases at the the at metastases extrarenal extensive with ted nal medullary carcinomas were from African African from were carcinomas medullary nal umours of kidney, 10 high grade renal cell gradecell renal high of kidney, umours 10 positive by both fusion and splitapart probe probe and splitapart byfusion both positive our with a poor clinical outcome. It belongs outcome. a clinical poor with our rs to be superior to the TFEB IHCassay. TFEB the to besuperior rsto CR are common also CR TFEB TFEB ). Identification of either TFEB Identification ). may partner with with partner may r suppressor gene rsuppressor

TFEB methodologies for methodologies TFEB are characterized characterized are KHDRBS2 mRNA. More mRNA. renal cell renal cell SMARCB1 on on

protease, serine 2 ( 2 protease,serine partners including partnersincluding ALK of nephrectomy. time Incas both fusion.[87] STRNALK a harbouring novel More re carcinomas.[86] cell renal papillary two in specific early event in prostatic carcinogenesis th carcinogenesis prostatic in event specificearly to (ranging27% from tumours of 50% prostate about regulated gene regulated (21q22.2), (21q22.2), <1%. In a study including 534 adult renal cell carc cell renal adult 534 Inincluding <1%. a study renal all cellcarcin with associated rearrangement transcripts resulted from balanced translocations d balancedtranslocations from resulted transcripts in transcripts fusion identified further sequencing ofhemizy theseshowed Each sicklecell trait. with off each in 22q11 chromosome involving alterations study Another expression. of SMARCB1 loss complete twentysix transforming factor ( factor transforming twentysix invo carcinogenesis prostate event in Asignificant 6.

sicklecell trait to be associated with associatedwith be to sicklecelltrait

Chromosomal translocations Chromosomal mainly associated with translocation was also reported in renal medullary reported renal in was also translocation

ETV1 Accepted Article TMPRSS2

(7p21.2), or (7p21.2), CAPN2 TMPRSS2

This article isprotected by copyright. All rights reserved. and , , The JournalofPathology:ClinicalResearch RORA , 21q22.3) gene[8891]. The genes involved are the the are The genes involved gene[8891]. 21q22.3) , ETV4 ETS ETS , , transcription factor family members, including including members, family factor transcription MAML2 (17q21). (17q21). ) family of genes,including of )family VCLALK , and , TMPRSS2ERG translocation.[85] The incidence of translocation.[85]

MALAT1 at can be observed in high grade prostatic high in can beobserved at volving volving omas is low, with an overallof frequency with low, is omas isrupting isrupting inoma patients, patients, inoma lves gene fusion between members of the E of the members between gene lves fusion gous gous cently, Kusano et al reported 2 cases of RCC of RCC cases 2 reported alet Kusano cently, our renal medullary carcinomas associated associated carcinomas medullary renal our 79%). These fusions appear to represent a appear represent to fusions 79%).These es, the patients were in their 30s at the the at 30s their in were patients es,the carcinomas from young with patients from carcinomas by Calderaro et al found recurrent found al et Calderaro by SMARCB1 SMARCB1 . . SMARCB1 gene fusion has been identified in in beenidentified has genefusion ERG ALK deletion[84]. RNA deletion[84]. in these tumours. The tumours. these in , and the transmembrane transmembrane andthe , prostate cancer and fusing it to various various to fusingit and rearrangements occurred rearrangements androgen ERG ALK

Page 18of64 Page 19of64 protein with potent transforming capability. The fu The capability. transforming potent with protein

colour split apart probe or by tricolour probes ( probes byapart probetricolour or split colour indicated that functionally important fusion events fusion important functionally that indicated translocation between ETS variant 6 ( variant 6 ETS between translocation c breast cancer, secretory breast Ararevariant of 7. The neoplasia.[90] intraepithelial Recurrent w cancers colorectal nine genomesof the correlated cance colorectal gene in fusion recurrent Thefirst 8. and the andthe The biological consequence of this translocation is translocation of this consequence The biological readily fo that cells transformed in resulted cells of secretory breast cancer. Retroviral transfer of transfer Retroviral cancer. breast ofsecretory appea translocation This 96] t(12;15)(p13;q25).[95, assay strategy. using cells either beensee have patterns signal Positive FISHdesign. cancer.[97] The cancer.[97] an init is oncogene of the expression consequential

Chromosomal translocations Chromosomal mainly translocations b associated with Chromosomal translocations Chromosomal mainly translocations c associated with PIK3CA/AKT1

VTI1ATCF7L2 Accepted Article ETV6NTRK3 pathways.[96] The occurrence of the The occurrence of the pathways.[96] This article isprotected by copyright. All rights reserved. fusion was identified in 3% of colorectal cancers. of3% colorectal in was identified fusion The JournalofPathology:ClinicalResearch translocation is demonstrated either by breakapar either by demonstrated is translocation TMPRSS2 ETV6 ) and neurotrophic tyrosine kinase type 3 (type 3 kinase tyrosine )and neurotrophic ERG rearrangement can be identified by both dual bydual both identified can be rearrangement ERG Fig.6

rmed tumours in nude mice. mice. nude in tumours rmed ETV6NTRK3 ETV6NTRK3 ancer, has a characteristic recurrent acharacteristic has ancer, r was reported in 2011.[98] Bass alet 2011.[98] in was reported r also occur in colorectal cancers, but the the cancers, but occur colorectal also in expression of a chimeric tyrosine kinase kinase tyrosine of a chimeric expression sion protein strongly activates the the strongly activates protein sion iating event in the genesis of secretory breast breast of secretory genesis the iatingevent in rs to be the initial hit required for formation for formation required hit initial be the rsto n in most secretory breast carcinoma tumour carcinoma tumour secretory breast most in n ith paired nonneoplastic tissue controls. controls. tissue pairednonneoplastic ith ).[9294] ).[9294] ETV6NTRK3 into murine mammary epithelial murine epithelial mammaryinto olorectal cancerolorectal reast cancer translocation and translocation [98] Their findings [98] t or by fusion fusion or by t MAPK1 NTRK3

), proliferation of follicular cells. cells. of follicular proliferation (30%) in follicular thyroid carcinoma.[106] The fus carcinoma.[106] thyroid follicular (30%) in ( thyroiof the fusion translocation, t(2;3)(q13;p25) approxima accounts for carcinoma Follicularthyroid kinase.[105] protein fusion STRNALK patients. targetfor these evidenc initial provide and cancer typesof thyroid involving Rspondin family members members family Rspondin involving colore in transcripts fusion multiple identified al yetelucidated. be to of theseis impact clinical More than 10 rearrangements involving involving rearrangements 10 Morethan 9. Kelly et al reported that that reported alet Kelly

104]. The fusion genes code for constitutively acti for constitutively genes code The fusion 104]. frequent were exclusiv almost identified have been rearrangements years include cancers.[ colorectal in 10% of frequency cumulative formed by fusion of the RET tyrosine kinase domain domain tyrosine kinase RET of the fusion formed by PAX8

Chromosomal translocations Chromosomal mainly translocations t associated with ) with peroxisome proliferator activated receptor receptor activated proliferator peroxisome )with

EML4ALK, C2orf44ALK EML4ALK, AcceptedRETCCDC6 Article

STRNALK This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch (60%), fusion occurs in a subset of patients with highly with of patients occursa subset in fusion RETNCOA4 EIF3ERSPO2 RET , , SLC34A2ROS1 have been reported; all of the rearrangements are are rearrangements of the all beenreported; have RNAsequencing studies reported by Seshagiri et byreported Seshagiri studies RNAsequencing

ctal cancer, including recurrent gene fusions fusions gene recurrent ctalcancer, including (20%) and d transcription factor, paired box gene 8 box paired factor, transcription d vated proteins driving uncontrolled driving uncontrolled vated proteins e suggesting that it may represent a therapeutic a therapeutic represent may it that esuggesting ion product acts as an oncogene by by acts as product an oncogene ion leads to constitutive activation of ALK activation constitutive leadsto 99] Other translocations reported in recent reported recent in Other translocations 99] ely in papillary thyroid carcinomas; most carcinomas; most elythyroid papillary in tely 20% of all thyroid malignancies. The malignancies. thyroid all telyof 20% and with a fusion partner gene[100103]. partner a fusion with γ( PTPRKRSPO3 , and , PPARG RET NAV2TCF7L1

PRKAR1A PRKAR1A ) is most commonly observed observed commonly most )is hyroid cancer that occurred with a occurredwith that (512%)[67, 68, 68, (512%)[67, .[66] .[66] aggressive RET

Page 20of64 Page 21of64 been identified in benign thyroid adenomas with a b a with thyroidadenomas benign in beenidentified diagnostic, therapeutic, and prognosticimplication and diagnostic,therapeutic, translocation chromosomal recurrenttumourspecific fusion in hyalinizing clear cell carcinoma ( cellcarcinoma clear hyalinizing in fusion the the and causing loss of contact inhibition. It notew is inhibition. of contact loss andcausing apopt downregulating growth, cellular accelerating half di of the almost represents [t(3;8)(p21;q12)], rearrangements with Ofcases cases(30%). unchanged transloc otherrecurring (8%), (39%), 12q1315 8q12 categories cytogenetic four are There of cases. 70% recu and a highlyspecific with presents Thetumour glandtumo salivary a benign adenoma is Pleomorphic adenoma Pleomorphic 10.1 malignan in translocations recurrent aremajor four harbour glandtumours of salivary Approximately20% 10. fusion in adenoid cystic carcinoma, the the carcinoma, cystic adenoid in fusion 108] 6%.[107,

ETV6NTRK3 tumours Chromosomal mainly translocations s associated with

Accepted Article fusion in mammary analogue secretory carcinoma, an carcinoma, analoguesecretory fusion mammary in

orthy that rearrangement of these genes has also genesalso has these of rearrangement that orthy agnostic translocations found. found. translocations agnostic s. )[96, 97, 110, 111]. The identification of 111]. 110, 97, )[96, t salivary gland tumours: the the tumours: gland salivary t of pleomorphic adenoma. These involve These involve adenoma. of pleomorphic osis, promoting anchorageindependence, anchorageindependence, promoting osis, rrent pattern of chromosome abnormalities in in abnormalities chromosome of rrent pattern reakapart frequency between 3% and and 3% between frequency reakapart

ations (23%), and cytogenetically andcytogenetically (23%), ations s and novel fusion oncogenes has oncogenes fusion and novel s ur most often arising in the parotid gland. parotid the in oftenarising urmost , the 8q12 rearrangement rearrangement 8q12 the , chromosomal translocation.[109] There translocation.[109] chromosomal fusion in mucoepidermoid carcinoma, carcinoma, mucoepidermoid in fusion alivary gland d the the d EWSR1ATF1 MYBNFIB

NOTCH signaling coactivator ( coactivator signaling NOTCH tumors. tumors. and differentiation.[114] West et al used FISH to i FISH used alet to West anddifferentiation.[114] i participates that 6q2224 at factor transcription adenoid cyst carcinomas lacks any detectable lacksany detectable carcinomas cyst adenoid gland or nonsalivary glandtumours othersalivary role in a significant subset of these tumours. Ther of thesetumours. subset a significant role in t carcinoma cystic adenoid indicates in fusion this the the ad in translocation Recurrentt(6;9)(q22–23;p23–24) cystic carcinoma Adenoid 10.3 tumours.[112] fusionnegative with whencompared marke present,this When carcinomas. mucoepidermoid "intermediate" cells. The cells. "intermediate" squamous proportions: varying in cellularelements type a distinct represents carcinoma Mucoepidermoid carcinoma Mucoepidermoid 10.2 AMP response element protein related transcription related transcription response protein element AMP chromo from derived oncogene fusion carcinomas.The 10.4 Mammary analogue secretory carcinoma secretory Mammary 10.4 analogue f may prognosis the improve targets transcriptional MYB MYBNFIB

Acceptedgenefactor transcription with protooncogene Article

translocation was present in 49% of adenoid cystic of adenoid 49% in was present translocation

), t(11;19)(q12;p13) is aetiological for some aetiological is ),t(11;19)(q12;p13) fusion is present in 55% of mucoepidermoid of mucoepidermoid 55% presentin is fusion MYB

n the regulation of cell proliferation, apoptosis, apoptosis, proliferation, of cell regulation the n

apies directed against against directed apies hat the transcript may play a developmental adevelopmental play may transcript the hat nvestigate gene fusion.[116, 117] The high frequency of frequency The high 117] gene fusion.[116, or this chemoresistant neoplasm. neoplasm. chemoresistant orthis neoplasms.[115] Asubset of 20% of about neoplasms.[115] cells, mucussecreting cells, and cells, mucussecreting cells, cofactor 1 (cofactor 1 enoid cystic carcinoma results in a fusion of a fusion in results carcinoma cystic enoid of polymorphous tumour, containing three containing three tumour, polymorphous of somal translocation that binds cyclic binds that translocation somal NFIB r confers a favourable survival outcome outcome survival a favourable confers r MYB [113]. [113]. CRTC1 translocation in 37 of these 37 in translocation MYB carcinomas but not in in not but carcinomas MYBNFIB MYBNFIB ) with mastermindlike 2 2 mastermindlike )with is aleucine zipper Page 22of64 Page 23of64 gene.[119] Histologically, conventional MASC displa MASC conventional Histologically, gene.[119] ( family member twentysix (p13;q25) harbours MASC a t(12;15) breast.[118] the and histologically, immunohistochemically, is that a re is (MASC) carcinoma secretory analogue Mammary clear cell sarcomalike tumor from the GI the from tract.[51 tumor cellsarcomalike clear g of parotid the angiosarcoma histiocytoma, fibrous oth in befound also could translocation EWSR1ATF1 hyaliniz finding in consistent a generelatively is (region 1 Ewing breakpoint sarcoma hyaliniz with cells clear glycogenrich of composed a recent is (HCCC) cellcarcinoma clearHyalinizing clear cellcarcinoma Hyalinizing 10.5 MASC. mimic morphologically that 121] mortality.[118, metast lymphnode recurrence, 15–20% with carcinoma where nuclei in the for the probe breakapart adualcolour analysis, and bythe FISH, MASC secretio homogenous or bubbly eosinophilic abundant structu and solid tubular, of microcystic, composed

Accepted Article

ETV6 ETV6 gene participates in translocation. MASC behaves a behaves MASC translocation. in gene participates ETV6NTRK3 This article isprotected by copyright. All rights reserved. FISH is useful to diagnose difficult cases and to and to cases difficult diagnose to useful FISH is The JournalofPathology:ClinicalResearch ETV6 ) and the neurotrophic tyrosine kinase receptor typ receptor kinase tyrosine neurotrophic the )and EWSR1 rearrangement was identified in six cases.[120] Fo cases.[120] six in was identified rearrangement ) and the activating transcription factor ( 1 transcription activating the and )

ing clear cell carcinoma.[122] However, ingcellcarcinoma.[122] clear ETV6 , 123126] In the one 123126] study, , genetically similar to secretory carcinoma of carcinoma secretory to similar genetically res. Between epithelial structures, one finds finds one structures, epithelial res.Between land, clear cell sarcoma of soft tissue, and tissue, ofsoft cellsarcoma clear land, ed or myxoid stroma. Gene fusion between Gene between fusion edorstroma. myxoid ly described minor salivary gland tumour salivary minor ly described translocation resulting in fusion of anE of fusion in resulting translocation ys a lobulated growth pattern of a tumour patternof a growthtumour ys a lobulated ns. Majewska et al investigated seven seven Majewska investigated alet ns. gene exhibits a “split” fluorescent signal a signal “split” fluorescent gene exhibits er types of tumour including angiomatoid angiomatoid including erof tumour types ases in 15–20% of cases, and occasional cases,and occasional of 15–20% asesin cently recognized salivary gland tumour salivary recognized cently exclude the tumours tumours the exclude s a lowgrade a s lowgrade ATF1 e( 3 gene ATF1 NTRK3 rFISH ) ) BRAF diagnosisof amthe in ancillarytool beas anused constitutiv are The chimeric proteins pattern.[127] 11. diagnosis.[109] differential the in othertumours clear of hyalinizing 82% in was found translocation inhibition. MEK ren pathway MAPK of the This activation 132]. [131, involving usually translocations found contain not nevi Spitz ar melanomas in seen commonly Molecularalterations excision.[1 require wide not anddo are nevi benign 16/73), (75%). The kin tumours Spitz atypical of 8 6 within pr were fusions kinase that colleaguesdemonstrated Inastud tumorigenesis. the and initiate signaling (17%), Spitzoid typically absent. are associatedoncogenes are nevi poorly of Spitz Thegenetic underpinnings

melanoma Chromosomal translocations Chromosomal mainly associated with fusion genes characteristically activate the MAPK MAPK activatethe genes characteristically fusion NTRK1 ALK BRAF

(11%, 8/75), (11%, 8/75),

Accepted Article(16%), and MET MET ALK This article isprotected by copyright. All rights reserved. NTRK1 genes have been recently reported in melanoma patie melanoma in reported recently genes been have The JournalofPathology:ClinicalResearch (10%), (11%, 8/75), (11%, 8/75), BRAF (5%), and and (5%), BRAF

y of 140 spitzoid neoplasms, Wiesner et al andalet neoplasms, Wiesner yspitzoid of 140 biguous melanocyte neoplasms, since Spitz sinceSpitz neoplasms, melanocyte biguous ely activated, which stimulate oncogenic stimulate activated,which ely in melanoma[91, 128130]. Translocations Translocations 128130]. melanoma[91, in neoplasms harbour kinase fusions of fusions harbour kinase neoplasms 27] understood, and alterations in melanoma in and alterations understood, cell carcinoma cases, but in none of none the in but cases, cellcarcinoma ase gene fusions involved involved genefusions ase esent in 18 of 30 Spitz (60%) nevi and Spitz of 30 18 esentin RET (5%, 4/75), and (5%, 4/75), ders the tumours potentially sensitive to to sensitive potentially derstumours the e typically absent from Spitz nevi and nevi Spitz from absent etypically (3%) in a mutually exclusive exclusive (3%) a mutually in pathway with transformation abilities abilities transformation pathwaywith Spitz nevi and Spitzand nevi RET (3%, 2/75). FISH can FISH (3%, 2/75). ROS1 nts ( nts (26%, Table 2 Table ROS1 ).

Page 24of64 Page 25of64 DCTN1MET MET lesions and blue nevi. The patients’ tumours were t were tumours patients’ The nevi. and blue lesions convent nevi, Spitz melanoma, representingspitzoid e 1202 Yeh analyzed alet and invasion.[133] growth wit receptor kinase tyrosine a highaffinity is MET oligoastrocytomas[140143]. Deletions of 1p and 19q of 1p Deletions oligoastrocytomas[140143]. 70 to up in beenobserved has of 1p/19q Codeletion found. also were pathways signaling glioblastoma s containing transcripts fusion otherrare Fourteen transcripts: fusion threerecurrent andidentified byseq RNA gliomas investigated272 frequently recurring most the it rendering cohorts, 2 occur approximate in genefusions and glioblastomas More t classification.[135] of molecular importance centr of the of tumours classification 2016 TheWHO 12. control. without MET express genes: ).[136139] ).[136139]

nervous systemnervous Chromosomal translocations Chromosomal mainly translocations t associated with translocations were found in six melanocytic tumou melanocytic six in found were translocations TRIM4MET, ZKSCAN1MET, PPFIBP1MET LRRFIP1MET, EP LRRFIP1MET, PPFIBP1MET ZKSCAN1MET, TRIM4MET, .[134]

AcceptedPTPRZ1MET Article

MET

fusion genes are driven by the promoter of par the by promoter the driven genes are fusion This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch translocation was detected in 15% of glioblastomas of 15% in was detected translocation FGFR3TACC3

, , equences of genes involved in the canonical canonical the in genesinvolved of equences transcript in glioblastoma. Recently, Bao et al Baoet Recently, glioblastoma. in transcript h functions in angiogenesis, cellular motility, angiogenesis, in functions h ested by comparative genomic hybridization. hybridization. genomic comparative ested by RNF213SLC26A11 han 10 translocations have been reported in in beenreported have translocations han10 ional nevi, deep penetrating nevuslike nevuslike deep nevi, penetrating ional % of oligodendrogliomas and 50% of mixed ofand mixed 50% %of oligodendrogliomas quivocal pigmented skin lesions lesions skin pigmented quivocal 67 inframe fusion transcripts, including transcripts, fusion inframe 67 ly 3050% of glioblastoma patients ( patients glioblastoma of ly3050% al nervous system emphasizes the the emphasizes system nervous al have been associated with prolongedwith associated have been rs resulting in the following fusion followingfusion the rsresulting in umours the of central ,and S15MET tner geneand tner PTPRZ1MET in independent independent in , and , Table Table .[139] .[139] patients.[146] Parker et al showed that more than t morethan that showed Parkeral et patients.[146] KIAA1549BRAF a has which preval t(1;19)(q10;p10), translocation deleti and 19q of 1p majority the that hypothesized mi and oligodendrogliomas with patients in survival widespread. Common FISHdetected alterations are ch are alterations FISHdetected widespread.Common demand of FISH, results the incorporate algorithms pathologypr and surgical medicine genomic areas in ha analysis of neoplasms FISH Overdecade, past the 13. treatment. effective biology the for understanding only significantnot activates protein fusion A( homolog avian between translocations chromosomal contained disea for this treatments major the are irradiation of b the cells ependymal the arisesfrom Ependymoma harbour of tumours majority sincethe astrocytomas suggested that revelations newmolecular sequencing bywholegenome was found translocation

Conclusions

AcceptedRELA Article

translocations are characteristic of pilocytic ast of pilocytic characteristic are translocations ) and chromosome 11 open reading frame 95( frame reading open 11 andchromosome ) NFκB This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch target genes, transforming the cells.[148] This fi cells.[148] the genes,transforming target BRAF

targeted therapy may be applicable in pilocytic in applicable be may therapy targeted se since chemotherapy is ineffective in most most in ineffective is sincechemotherapy se of the tumour but also affords potential for an potential affords also but tumour of the wothirds of supratentorial ependymomas ependymomas of supratentorial wothirds ence of 81% in all 1p/19q deletion cases.[144] cases.[144] deletion 1p/19q all in enceof 81% ons in gliomas were derived from afrom weregliomas in ons derived for the technology will becomemore will fortechnology the xed oligoastrocytomas. Jenkins et alet Jenkins oligoastrocytomas. xed KIAA1549BRAF actice. As more diagnostic and treatment and treatment morediagnostic As actice. s become one of the most rapidly growingrapidly most of the becomes one reticuloendotheliosis viral oncogene viral reticuloendotheliosis rain and spinal cord. Surgery and Surgery cord. rainand spinal romosome deletions, gains, translocations, gains, translocations, deletions, romosome of 96 pilocytic astrocytomas.[145] These astrocytomas.[145] pilocytic of96 C11orf95 rocytoma.[138, 145] The 145] rocytoma.[138, fusions ( fusions ).[147] The resulting ).[147] Table 2 Table nding is ndingis ). Page 26of64 Page 27of64 pathologists and the clinicians and patients they s they and patients clinicians and the pathologists the decisions involved in choice of cancer therapy cancertherapy choice ofin involved decisions the Itsclari rolein technology. evolving continuously FISHassessme partners. fusion the distance between genes with and fusion fusions ofdiscovery cryptic mapping precise the simultaneously, genemutations mol current superiorto is RNAseq identification. a empowered has technology (RNAseq) sequencing RNA transcription the at both genes of fusion detection Nex challenges. medicine these precision overcoming challenges many technical poses decisions treatment Int types. many for tumour therapeuticimplications alte chromosome These and polysomy. amplifications,

Accepted Article

erve. erve. al and genomic levels. The rapidly emerging emerging rapidly The levels. and genomic al fying cancer diagnoses and its contributions to to contributions its and diagnoses fyingcancer ecular test methods in its capacity to detect capacitydetect to its in ecularmethods test will become ever more important to surgical surgical to moreimportant become ever will unknown partners or with short physicalshort with partnersor unknown egrating genomic testing into cancer into testing genomic egrating , but rapid progress is being made in in beingis made rapid progress but , nt of chromosomal changes is a is changes of chromosomal nt of breakpoint and joint sequences, and the andthe sequences, and joint of breakpoint t generation sequencing platforms allow allow generation platforms sequencing t rations may have diagnostic and diagnostic have may rations n increasing pace of fusion gene of fusion pace increasing n and approved and the final manuscript. GTM, DDD) and GTM, participateddata in acquisition and LC,SZ, were conception LW involvedin and and desi Contributions: Author authors wouldThe like to thankGibson for Natasha Acknowledgments:

Accepted Article

excellent editorial assistance. analysis,writing and All the article. the authors gn of the paper.gnAllthe the authors of SZ, (LC, LW, read Page 28of64 Page 29of64 ALK beauty of this design is that it detects chromosoma it design that is of beauty this originally juxtapo the sites, between probe two the closely approximated or fused signals (A). When tra (A). When or fused signals approximated closely wi The configuration. type wild their in chromosome specific probes of two composed is set apart probe Figure1 test uses dual colour labeled probes covering the the covering probes labeled colour dual uses test into distinct yellowcommercial (in signals andred distinct into Figure2 new the partnersin fusion as serve genes which may Itw determine not does original location. its from ident only probe breakapart the However, involved. Figure3 fu definitive with genefusion a of directevidence approximat a closely to move probes occurs,two the sep from physically resulting signals separated two chrom different or on chromosome same the eitheron iden probes The fusion or diseases. certaintumours co different labeled with locusspecific probes two (red). When translocation occurs, the normal close normal occurs, the (red). translocation When Breakapart probe design for translocations with m with for translocations design Breakapart probe Fusion design for translocation between specific p between translocation for design Fusion

AcceptedThe com probes. of ALK splitapart patterns Signal Article

ALK ALK hich chromosome receives the fragment the or receives chromosome hich sion partners identified. partnersidentified. sion l translocation regardless of the fusion partner partner fusion of the regardless translocation l apart The (B). split signals) (fusion loci sed lours targeting the genes known to fuse in fuse in to genesknown targeting lours the FISH ALK translocation kits Green and Red kits FISH ALK translocation arated chromosome loci (A). When fusion fusion (A). When loci chromosome arated for loci physically close to each other on the each to the otheron close physically forloci tify chromosomal loci far from each other other each from far loci tifychromosomal nslocation occurs involving a breakpoint a breakpoint involving occurs nslocation ifies the breaking away of a gene fragment genefragment of a breakingthe away ifies location. location. ed position (fusion signal, B). This provides B). provides signal,This (fusion ed position ld type signal pattern shows 2 pairs of pairs 2 shows type pattern ld signal osomes. The wild type configuration shows shows configuration type The wild osomes. gene (yellow) and 3’ flanking region of region flanking geneand 3’ (yellow) ly approximated signal pattern separates separates signal pattern approximated ly artners. A fusion probe set contains contains probe set fusion A artners. ultiple fusion partners.fusion A break ultiple monly used monlyused ALK splitapart FISH splitapart t(X;19)(p11.2;q13.1) [ t(X;19)(p11.2;q13.1) (B) patients. A positive result in a female in patient result A positive (B) patients. renal cell carcinoma are shown in B, in t(6;11)(p21;q1 shown are carcinoma renalcell t(X;17)(p11.2;q23) [ t(X;17)(p11.2;q23) [ design ensures that the probe set will uncover will set probe the that designensures Figure 5 TFE3 TFE3 tran different several involve translocation Xp11.2 (yellow) and downstream (red) to (yellow)and downstream translocation renal cell carcinomas are shown in A, in shown are cellcarcinomas renal translocation tra The chromosomal each in translocation. involved conne a line with shown is Aspecific translocation tra chromosomal visualize to used is representation c size proportionate in chromosomes of all composed i genomic between relationships displaying ideogram Figure 4 partners. fusion t(X;3)(p11.2;q23) [ t(X;3)(p11.2;q23) signals may be used). Since Since signals beused). may (Red), t(X;1)(p11.2;p34) [ (Red),t(X;1)(p11.2;p34) ASPSCR1TFEB gene with various fusion partners. The breakapart partners.The breakapart fusion various genewith Signal patterns of patterns Signal

Accepted ArticleCi by presented relationships translocation Genomic

] (Red). ] unknownTFE3 CLTCTFE3 unknownTFE3 This article isprotected by copyright. All rights reserved. PSFTEF3 The JournalofPathology:ClinicalResearch TFE3 ALK translocations involve multiple fusion partners,a fusion multiple involve translocations ] (Magenta), t(X;17)(p11.2;q25) [ (Magenta), t(X;17)(p11.2;q25) ] splitapart probes. Renal cell carcinomas associat cellcarcinomas Renal probes. splitapart TFE3 ] (Black), t(X;10)(p11.2;q23) [ (Black), ] t(X;10)(p11.2;q23) ] (Gray), ] ] (Purple). Translocations involved in in involved Translocations (Purple). ] showing different signal patterns in female (A) anfemale (A) in patterns signal different showing

ALK t(X;1)(p11.2;q21) [ t(X;1)(p11.2;q21)

shows a fused or closely approximated normal normal approximated closely a fused or shows slocations resulting in gene fusions of the genefusions resulting in slocations translocations with most of the possible of possible the most with translocations cting the two chromosome partner loci partnerloci chromosome two ctingthe including inv(X)(p11.2;q12) [ inv(X)(p11.2;q12) including entity. a clinical with associated nslocations 3)[ nslocations that may be involved in Xp11 Xp11 in involved be may that nslocations lockwise from 1 to Y. This graphic This Y. to 1 from lockwise ntervals. The Circos plot is a ring is plot The Circos ntervals. MALAT1TFEB FISH assay uses probes both upstream upstream both probes uses FISHassay rcos plot. Circos applies a circular a circular applies Circos rcos plot. unknownTFE3 PRCCTFE3 ASPLTFE3 ] (Blue), ] t(6;17)(p21;q25) TFEB ] (Blue), ] ] (Green), ] ] (Yellow), ] NonOTFE3 translocation translocation splitapart splitapart ed with edwith d male male d ] ] Page 30of64 Page 31of64 ERG endof localized redyelloworange pattern (A). (A). redyelloworange pattern localized Figure6 yellowdu red signal aor single or of redsignals, con a patient male in result a positive chromosome, truncati section due to yellowredsignal orsingle an Xchromosome) (uninvolved pair yellowredsignal respectively. The probes hybridizing to the wild ty wild the hybridizingto probes respectively.The TMPRSS2 TMPRSS2 TMPRSS2ERG si the with asshown entirely (B), deleted in or be and TMPRSS2 Signal patterns of patterns Signal TMPRSS2 Acceptedsignal.The Article tricolour fused probe uses 3 different colour procolour different 3 uses fused probe tricolour

(orange), and both up and down stream ends of of ends stream andup down and both (orange),

genes leads to a redorange fusion of fusion a redorange leadsto genes ERG This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch upstream signal may either split from the downst the from either split may upstreamsignal TMPRSS2ERG TMPRSS2/ERG translocation by tricolour splitapart probes. Th probes. splitapart bytricolour translocation

e to section truncation. truncation. section to e gnal pattern shown in (C). (C). in patternshown gnal on artifact. Because males have only one X have only Becausemales artifact. on pe sists either of a pair of splitapart yellowand either of a pairof splitapart sists TMPRSS2/ERG d either a pair of splitapart signals or a signals of splitapart a pair either d loci rearrangement via breaks in both breaks both via in rearrangement loci ERG downstream signal to the the signal to downstream bes recognizing the upstream the recognizing bes ERG loci show the normal co normal the show loci (yellow, red), (yellow, ream sequence as ream sequence e 6. Cheng L,Cheng JN. 6. Eble 8. Lin C, Yang L, Tanasa B LinL,YangTanasa 8. C, 7. Mitelman F, Johansson B, Mertens F. Fusion ge Fusion F. B, Mertens F, Johansson Mitelman 7. 11. Martin CL, Warburton D. Detection of Detection D.chromos CL, Martin Warburton 11. 1. BuongiornoNardelli M, Amaldi F. Autoradiogra Amaldi M, BuongiornoNardelli 1. 2. John HA, Birnstiel ML, Jones KW. RNADNA hybr RNADNA KW. ML, HA, Birnstiel Jones John 2. 10. Mertens F, Johansson B, Fioretos T B, Fioretos MertensF, Johansson 10. 9. Doroshow JH, Kummar S. Translational research Translational S. Kummar JH, Doroshow 9. 3. Gall JG, Pardue ML. Formation and detection o and detection Formation Pardue ML. JG, Gall 3. 5. Cheng L, Zhang DY, Eble JN. Eble DY, Zhang L,Cheng 5. 4. Katsanis SH, Katsanis N. Molecular geneticte Molecular N. Katsanis SH, Katsanis 4. breaks underlie specific translocations in cancer. in translocations specific breaksunderlie between RNA and DNA in tissue sections. sections. tissue in andDNA between RNA Rev Genet RevGenet preparations. preparations. of chromosome aberrations in cancer. in aberrations ofchromosome Springer, 2013. Springer,2013. karyotype to genome sequence. genomesequence. karyotypeto cancer. future prospects. future prospects. 1969; 223

Accepted RevCancer Nat Article :582587. :582587.

2013;

Proc Natl Acad Sci U S A A US Sci Acad Natl Proc

14 Molecular Surgical Pathology. 1 Pathology. MolecularSurgical Nat Rev Clin Oncol Oncol Clin Rev Nat This article isprotected by copyright. All rights reserved. :415426. :415426. The JournalofPathology:ClinicalResearch , et al.et , 2015;

Molecular Genetic Pathology. 2 Pathology. MolecularGenetic Nuclear receptorinduced chromosomal proximity and proximity chromosomal receptorinduced Nuclear 15 Annu Rev Genomics Hum Genet Genet Hum Genomics Rev Annu :371381. :371381. , et al.et , References: 2014; Nat Genet Nat 1969; The emerging complexity of gene fusions in in ofgene fusions complexity emerging The 32 32 11 Nature Nature sting and the future of clinical genomics. clinical futureof sting and the 63 f RNADNA hybrid molecules in cytological cytological in molecules fRNADNA hybrid :649662. nes and rearranged genes as a linear function function genesas a linear and rearranged nes phic detection of molecular hybrids of hybrids molecular detection phic omal aberrations in clinical practice: from practice:from clinical aberrations in omal in oncology10 yearsand of progress oncology10 in :378383. :378383.

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16 13

:293300. :293300. Accepted :443454. Article Nat Rev Genet RevGenet Nat 2013; This article isprotected by copyright. All rights reserved. 21 The JournalofPathology:ClinicalResearch :3147. :3147. 2005; Nat RevGenet Nat Front Cell Dev Biol Dev Biol Cell Front , et al.et , 6 :782792. :782792. , et al.et , Nat Rev Cancer RevCancer Nat , et al.et , Highresolution array CGH and gene expression genearrayexpression and CGH Highresolution Clin Cancer Res Cancer Clin Precision medicine for cancer with next with for medicine cancer Precision Genome Med Genome Laserassisted microdissection in translational translational in Laserassistedmicrodissection 2016; 33 33 ridization: CellBased Genetic Diagnostic ridization: osome translocations. translocations. osome slocations and cancer. and cancer. slocations Mol Cytogenet Cytogenet Mol 17 : blurring the boundaries with molecular with blurring: boundaries the DM erphase chromosomes: a review of a review erphasechromosomes: 2016; n AM. Landscape of gene fusions in in gene Landscapefusions of AM. n nges. nges. :333351. :333351. ure applications. ureapplications. 2015; , et al.et , of age: ten years of nextgeneration yearsof nextgeneration of age: ten 4 2015; Nat Rev Genet Genet Rev Nat :89. :89. 2014; 15 Translating RNA sequencing sequencing RNA Translating :747756. :747756. 7 :129. :129. 2010; 20 :15211530. :15211530. Appl Immunohistochem Immunohistochem Appl 3 Nat Cell Biol Biol Cell Nat Nat Rev Cancer Nat :1. :1. 2016; 17 :257271. :257271. 2. Nielsen TO, Poulin NM, Ladanyi M. Synovial s LadanyiSynovial M. NM, Poulin TO, Nielsen 2. 5. Latysheva NS, Babu MM. Discovering and under and Discovering MM. Babu Latysheva NS, 5. 7. Mertens F, Antonescu CR, Mitelman F. Gene fu F. Gene Mitelman CR, Antonescu MertensF, 7. 6. Ozsolak F, Milos PM. RNA sequencing: advance sequencing: PM. RNA F, Milos Ozsolak 6. 3. Martin JA, Wang Z. Nextgeneration transcrip Wang Nextgeneration Z. JA, Martin 3. 4. Yoshihara K, Wang Q, TorresGarcia W TorresGarcia Q, Yoshihara Wang K, 4. 1. Grunewald TG, Bernard V, GilardiHebenstreit V, Bernard TG, Grunewald 1. 0. Thway K, Fisher C. Tumors with EWSR1CREB1 a EWSR1CREB1 with Tumors FisherC. Thway K, 0. 9. Fletcher CD. The evolving classification of classification The evolving CD. Fletcher 9. 8. Flechter CDM, Bridge JA, Hogendoom PCW Hogendoom Bridge JA, CDM, Flechter 8. to new avenues for therapy. for therapy. new avenues to data intensive computational approaches. approaches. computational dataintensive 2015; Genet the Ewing sarcoma susceptibility gene EGR2 via a GG a via geneEGR2 Ewingsusceptibility the sarcoma 682. 682. status. status. cancerassociated transcript fusions. fusions. transcript cancerassociated new 2013 WHO classification. classification. WHO new2013 overlapping pathogenetic themes. themes. pathogenetic overlapping 2013. 2013. tissue and bone. Lyon, France International Agency International Lyon, France and bone. tissue 47 2011; Am J Surg Pathol Pathol JAm Surg

Accepted :10731078. Article

12 :8798. :8798. This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch 2012; Cancer Discov Cancer 36 Histopathology Histopathology :e1e11. :e1e11. Genes Chromosomes Cancer Cancer GenesChromosomes Oncogene , et al.et , 34 34 Nucleic Acids Res Acids Nucleic soft tissue tumours an the update based on tumours tissue soft 2015; , et al. al. et , tome assembly. tome The landscape and therapeutic relevance of relevance and therapeutic The landscape P arcoma: Recent discoveries as a roadmap as a discoveries arcoma:Recent sions in soft tissue tumors: Recurrent and tumors: tissue soft in sions 2014; 2015; s, challenges and opportunities. andopportunities. challenges s, , et al.et , standing oncogenic gene fusions through through gene fusions oncogenic standing 5 :124134. :124134. nd EWSR1ATF1 fusions: The current The current fusions: EWSR1ATF1 nd WHO Classification of tumours of soft of soft of tumours Classification WHO for Research on Cancer (IARC) Press Press (IARC) Cancer on Research for 64 34 Chimeric EWSR1FLI1 regulates regulates EWSR1FLI1 Chimeric AA microsatellite. AAmicrosatellite. :211. :211. :48454854. :48454854. 2016. 2016. Nat Rev Genet Rev Nat 2016; 55 :291310. :291310. Nat Genet Nat 2011; Nat Rev Nat 12 :671 Page 34of64 Page 35of64 6. Kouba E, Simper NB, Chen S Chen NB, Simper KoubaE, 6. 4. Chmielecki J, Crago M Rosenberg AM, J, Chmielecki 4. 3. Svejstrup JQ. Synovial sarcoma mechanisms: A sarcoma Synovial mechanisms: JQ. Svejstrup 3. 5. Robinson DR, Wu YM, KalyanaSundaram S KalyanaSundaram Wu YM, DR, Robinson 5. 7. Mohajeri A, Tayebwa J, Collin A Collin J, Tayebwa A, Mohajeri 7. 9. Choi EY, Thomas DG, McHugh JB DG, McHugh Thomas EY, Choi 9. 0. Choi E, Williamson SR, Montironi R Montironi SR, Williamson E, Choi 0. 8. Gambarotti M, Benini S, Gamberi G S, Benini M, Gambarotti 8. pathognomonic NAB2/STAT6 fusion gene, nonrandom sec gene, nonrandom fusion NAB2/STAT6 pathognomonic 2013; 2013; recurrent NAB2STAT6 fusion in solitary fibrous tum solitary fibrous in fusion recurrent NAB2STAT6 STAT6 gene fusions in solitary fibrous tumor by int by solitarytumor fibrous in gene fusions STAT6 gene. ass andtheir cases of 11 study clinicopathological and a characteristic gene expression profile in sol in profile expression gene anda characteristic distinctive histopathology. distinctive highly a novel fusion: CICDUX4 t(4;19)(q35;q13.1) urinary bladder: the role of immunoglobulin G4 and and G4 ofimmunoglobulin role the urinary bladder: Cancer Cancer of 7 cases. of7 a single bone: institut and tissue sarcomasof soft 45 153 J Clin Pathol Pathol JClin 2013; Accepted Article :180185. :1112. :1112.

Histopathology Histopathology

52 :873886. :873886. This article isprotected by copyright. All rights reserved. 2016. 2016. The JournalofPathology:ClinicalResearch Am J Surg Pathol Pathol JSurg Am 2016. 2016. , et al.et , , et al.et , , et al.et , Solitary fibrous tumour of the genitourinarytract of the tumour fibrous Solitary , et al.et , , et al.et , Comprehensive genetic analysis identifies a identifies geneticanalysis Comprehensive , et al.et , Undifferentiated small round cell sarcoma with with cellsarcoma round small Undifferentiated 35 35 CICDUX4 Fusionpositive round cell round Fusionpositive CICDUX4 Inflammatory myofibroblastic tumour of the tumour Inflammatory myofibroblastic , et al.et , Wholeexome sequencing identifies a sequencing identifies Wholeexome 2013; series of unfortunate events. events. series of unfortunate ion morphologic and molecular analysis analysis morphologicand molecular ion itary fibrous tumor. itarytumor. fibrous ociation with the NAB2STAT6 fusion fusion NAB2STAT6 the with ociation Identification of recurrent NAB2 Identificationof 37 egrative sequencing. egrativesequencing. the comparison of two of two comparison the :13791386. :13791386. aggressive soft tissue tumor with with tumor tissue soft aggressive ors. ors. Nat Genet Nat ondary genomic imbalances, imbalances, genomic ondary 2013; Genes Chromosomes Chromosomes Genes Nat Genet Nat 45 Cell Cell :131132. :131132. : a : 4. Gaudichon J, JeannePasquier C, Deparis M Deparis JeannePasquier C, J, Gaudichon 4. 2. Hallberg B, Palmer RH. Mechanistic insight i insight Mechanistic RH. B,Palmer Hallberg 2. 3. Butrynski JE, D'Adamo DR, HornickJL DR, D'Adamo JE, Butrynski 3. 1. Mano H. ALKoma: a cancer subtype with a shar a with a cancer subtype ALKoma: H. Mano 1. 5. Yamamoto H, Yoshida A, Taguchi K Taguchi A, Yoshida H, Yamamoto 5. 6. Antonescu CR, Suurmeijer AJ, Zhang L Zhang AJ, Suurmeijer CR, Antonescu 6. 8. Brown RE, Buryanek J, Katz AM Katz J, Buryanek Brown 8. RE, 7. Hodge JC, Pearce KE, Wang KE, Pearce X HodgeJC, 7. cancer biology. of anaplastic lymphoma kinase alterations. alterations. kinase oflymphoma anaplastic in and fluorescence antibodies immunohistochemical and clinical experience with 75 cases. 75 with experience andclinical al and carcinoma renal Xp11.2 cell in rearrangement girl. myofibroblas inflammatory ALKrearranged metastatic myofibroblastic tumor. tumor. myofibroblastic in inflammatory myofibroblastic tumours. tumours. inflammatory myofibroblastic in rearrangement. rearrangement. g ROS1 and frequent ALK with tumors myofibroblastic subtype and provide targeted therapeutic options. options. therapeutic targeted provide subtypeand define further grafttesting tumor and personalized

Accepted Oncol Hematol J Pediatr Article Am J Surg Pathol Pathol JAm Surg Nat Rev Cancer Cancer Rev Nat This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch N Engl J Med Engl N , et al.et , 2016; 2013; , et al.et , 2015; 38 , et al.et , Molecular cytogenetic analysis for TFE3 analysis Molecular cytogenetic 2010; 13 Mod Pathol Pathol Mod :308311. :308311. Alveolar rhabdomyosarcoma: morphoproteomics morphoproteomics Alveolar rhabdomyosarcoma: , et al.et , , et al.et , 39 :685700. :685700. 36 36 :957967. :957967. Histopathology Histopathology ALK, ROS1 and NTRK3 gene rearrangements gene rearrangements and NTRK3 ALK,ROS1 , et al.et , Histopathology Histopathology 363 nto ALK receptor tyrosine kinase in human human in kinase tyrosine ALK nto receptor Molecular characterization of inflammatory Molecular characterization Crizotinib in ALKrearranged inflammatory ALKrearranged in inflammatory Crizotinib :17271733. :17271733. ed target. edtarget. Complete and repeated response ofa responseand repeated Complete Oncotarget Oncotarget the biology of PAX3FKHR(FOXO1) of PAX3FKHR(FOXO1) biology the 2014; veolar soft part sarcoma: validation validation sarcoma: veolar part soft situ hybridization for detection the hybridization situ tic tumor to Crizotinib in a teenage in Crizotinib to tumor tic ene fusions and rare novel RET RET and rarenovel fusions ene 27 Cancer Discov Discov Cancer 2016; :113127. :113127. 2015; 2016; 69 67 :7283. :7283. :2038. :2038. 7 :4626346272. :4626346272. 2012; 2 :495502. :495502. Page 36of64 Page 37of64 9. Thway K, Rockcliffe S, Gonzalez D Gonzalez S, Thway Rockcliffe K, 9. 6. Alkan A, Koksoy EB, Utkan G. Firstline criz Firstline G. Utkan EB, Koksoy A, Alkan 6. 0. Wang WL, Mayordomo E, Zhang E, W Wang WL, 0. Mayordomo 7. Shen L, Ji HF. Ceritinib in ALKrearranged n ALKrearranged in L,HF. Ceritinib Shen 7. Ji 2. Shaw AT, Engelman JA. ALK in lung cancer: Pa ALK cancer: lung in JA. Engelman AT, Shaw 2. 1. Hisaoka M, Ishida T, Kuo TT Kuo T, Ishida HisaokaM, 1. 4. Swanton C, Govindan R. Clinical implications Clinical R. Govindan C, Swanton 4. 5. Hirsch FR, Scagliotti GV, Mulshine JL GV, Mulshine HirschScagliotti FR, 5. 3. Cheng L, Alexander RE, Maclennan GT Maclennan RE, L,Cheng 3. Alexander Med personalized medicine. medicine. personalized Engl J MedEngl in paraffinembedded material for routine diagnosis for routine material paraffinembedded in 2010; of soft parts). ofsoft in chimeric transcripts and EWSR1/CREB1 EWSR1/ATF1 2008; immunohistochemical, and molecular analysis of 33 c 33 of and analysis molecular immunohistochemical, targeted treatments. targetedtreatments. 2014; 2013; 2015; 63 32 370 31

:508512. :508512. :452460. :452460. Accepted :11051111. Article :2537. :2537.

372 2016; Mod Pathol Pathol Mod :781782. :781782. 374 This article isprotected by copyright. All rights reserved. Lancet Lancet The JournalofPathology:ClinicalResearch :18641873. :18641873. Mod Pathol Pathol Mod 2009; 2016. 2016. , et al.et , 22 :12011209. :12011209. Clear cell sarcoma of soft tissue: Aclinicopathol tissue: sarcoma of soft Clear cell , et al.et , , et al.et , 2012; , et al.et , , et al.et , 37 37 Utility of sarcomaspecific fusion gene analysis gene analysis fusion Utility of sarcomaspecific 25 Detection and characterization of characterization and Detection :347369. :347369. Lung cancer: Current therapies andnew Lungtherapies Current cancer: onsmallcell lung cancer. cancer. lung onsmallcell otinib in ALKpositive in cancer. lung otinib of genomic discoveries in lung cancer.in discoveries of genomic Molecular pathology of lung cancer: Key to Key to oflung cancer: Molecular pathology st, present, and future. present,and future. st, at a specialist centre. centre. aat specialist ases. Am J Surg Pathol Pathol JSurg Am clear cell sarcoma (melanoma (melanoma cellsarcoma clear J Clin Oncol Oncol JClin N Engl J Med Engl N J Clin Pathol Pathol Clin J N Engl J Engl N ogic, ogic, N N 1. Takeuchi K, Soda M, Togashi M, Y Takeuchi Soda K, 1. 0. Uguen A, De Braekeleer M. ROS1 fusions in ca in fusions ROS1 BraekeleerM. UguenDeA, 0. 8. Morton MJ, Zhang S, LopezBeltranZhang A S, MJ, Morton 8. 9. Bergethon K, Shaw AT, Ou SH Ou AT, Shaw K, Bergethon 9. 2. Charest A, Lane K, McMahon K McMahon LaneK, A, Charest 2. 6. Aisner DL, Nguyen TT, Paskulin DD Paskulin TT, Aisner Nguyen DL, 6. 7. Mulligan LM. RET revisited: Expanding the on the Expanding revisited: LM.RET Mulligan 7. 3. Davies KD, Doebele RC. Molecular pathways: R Molecular pathways: RC. Davies KD, Doebele 3. 5. Lee J, LeeLeeKang SY SE, 5. J, 4. Gu TL, Deng X, Huang F DengHuangX,TL, Gu 4. Med 2016; abnormalities in intestinal metaplasia of the urina of the metaplasia intestinal in abnormalities 2007; class of lung cancers. ofclass lung in a glioblastoma with an interstitial del(6)(q21q2 interstitial an with a glioblastoma in 2014; 2014; mol for heterogeneity evidence ofwith intratumoral 2003; adenocarcinoma. adenocarcinoma. fusions in human cholangiocarcinoma. human in fusions Cancer Res Cancer 2012; 12 13 14 12 37 :19111928. :19111928. :62326236. :62326236. :173186. :173186. :111118. :111118. Accepted :5871. Article

2013; :378381. :378381. Cancer Cancer 19 This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch :40404045. :40404045. J Clin Oncol Oncol JClin , et al.et , , et al.et , 2013; Identification of ROS1 rearrangement in gastric in rearrangement of ROS1 Identification , et al.et , Survey of tyrosine kinase signaling reveals ROS ki revealsROS signaling tyrosine kinase of Survey 119 , et al.et , , et al.et , :16271635. :16271635. 2012; , et al.et , ROS1 rearrangements define a unique molecular unique a define rearrangements ROS1 RET, ROS1 and ALK fusions in lung cancer.in and ALK fusions ROS1 RET, , et al.et , Fusion of FIG to the receptor tyrosine kinase ROS ROS tyrosinekinase receptor of FIG the to Fusion PLoS One One PLoS 30 38 38 ROS1 and ALK fusions in colorectal cancer, colorectal in and ALK fusions ROS1 :863870. :863870. Telomere shortening and chromosomal chromosomal and Telomere shortening cogenic portfolio. cogenic portfolio. ncer: A review. Areview. ncer: OS1 fusion proteins in cancer. in proteins fusion OS1 ry bladder. rybladder. 1). 2011; ecular drivers. eculardrivers. Genes Chromosomes Cancer Cancer GenesChromosomes 6 :e15640. :e15640. Clin Cancer Res Res Cancer Clin Future Oncol Oncol Future Nat Rev Cancer Nat Mol Cancer Res Cancer Mol Clin Clin nase Nat Nat Page 38of64 Page 39of64 3. Thway K, Nicholson AG, LawsonAG,K Thway K, Nicholson 3. 4. Moch H, Humphrey PA, Ulbright TM Ulbright PA, HumphreyH, Moch 4. 0. Wang R, Hu H, Pan Y Pan H, Hu Wang R, 0. 9. Vargas AJ, Harris CC. Biomarker development Biomarker development CC. Harris Vargas 9. AJ, 5. Smith NE, IlleiAllafM NE, PB, Smith 5. 8. Shaw AT, Hsu PP, Awad MM PP, Hsu AT, Shaw 8. 6. Kauffman EC, Ricketts CJ, RaisBahramiS CJ, Ricketts EC, Kauffman 6. 7. Argani P. MiT family translocation renal celrenal family translocation MiT Argani P. 7. 1. Drilon A, Wang L, HasanovicL,A WangA, Drilon 1. 2. Travis WD, Brambilla E, Burke A Burke E, Brambilla WD, Travis 2. pleura, thymus and heart. 4 andheart. pleura, thymus as a case study. asstudy. a case Cancer (IARC) Press, 2015. 2015. Press, Cancer(IARC) 113. 113. EWSR1CREB1 fusion: fusion: entity. anew tumor EWSR1CREB1 System and Male Genital Organ. 4 Genital and Male System genetically confirmed cases. cases. confirmed genetically m RCC novel emphasizing profile immunohistochemical malignancies. malignancies. on Cancer (IARC) Press, 2016. 2016. Press, Cancer on (IARC) of TFE3 and TFEB fusion kidney cancers. kidney andfusion TFEB ofTFE3 subtype of nonsmallcell lung cancer. lung cancer. subtypeof nonsmallcell

Accepted Article lung adenocarcinomas. fusionpositive Nat Rev Cancer RevCancer Nat Nat Rev Cancer Cancer Rev Nat This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch , et al.et , , et al.et , th RET fusions define a unique molecular andclinicop define molecular a unique fusions RET ed. Lyon, France: Internationalfor Researc Agency ed. Lyon, France: Am J Surg Pathol Pathol JAm Surg , et al.et , 2013; , et al.et , 2016; , et al. al. et , t(6;11) renal cell carcinoma (RCC): Expanded Expanded (RCC): cellcarcinoma renal t(6;11) th , et al.et , Tyrosine kinase gene rearrangements in epithelial epithelial in generearrangements kinase Tyrosine ed. Lyon, France: International Agency for Researc for Agency International Lyon,France: ed. 13 , et al. al. et , Response to Cabozantinib in patients with RET RET patientswith in Cabozantinib to Response 16 J Clin Oncol Oncol JClin :772787. :772787. Cancer Discov Discov Cancer WHO classification of tumours of the lung, lung, of the of tumours classification WHO :525537. :525537. 39 39 Primary pulmonary myxoid sarcoma with sarcoma with myxoid pulmonary Primary , et al.et , Nat Rev Urol Urol Rev Nat l carcinoma. l WHO Classification of Tumors of the Uronary Uronary of the of Tumors Classification WHO Am J Surg Pathol Pathol Surg J Am in the precision medicine era: lung cancer cancer era: lung medicine precision the in 2014; Molecular genetics and cellular features features andcellular genetics Molecular 2012; 38 2013; :604614. :604614. Semin Diagn Pathol Pathol Diagn Semin 2014; arkers and report of 10 newarkers of 10 and report 30 3 :43524359. :43524359. :630635. :630635. 11 2011; :465475. :465475. 35 :17221732. 2015; athologic athologic h on on h 32 :103 h h 8. Argani P, Zhong M, Reuter VEReuter Zhong Argani M, P, 8. 0. Malouf GG, Su X, YaoH X, GG, Su Malouf 0. 1. Rao Q, Liu B, Cheng L LiuB, Q,Cheng Rao 1. 9. Rao Q, Williamson SR, Zhang S SR, Williamson Q, Rao 9. 4. Calderaro J, MasliahPlanchon J, Richer W Richer J, MasliahPlanchon Calderaro 4. J, 3. Cheng JX, Tretiakova M, Gong C Gong M, Tretiakova Cheng 3. JX, 2. LopezBeltran A, Cheng L, Raspollini MR L,LopezBeltranChengA, Raspollini 2. Pathol Pathol point, immunobiomarkers, and ultrastructural featur and ultrastructural immunobiomarkers, point, clinicopathologic associations among transloca Xp11 associations clinicopathologic remodeling genes. remodeling f and splicing partners RNA novel reveals carcinoma 2016; immunohistochemical staining alone: Expanding the m the Expanding staining alone: immunohistochemical cellcarcinom renal translocationassociated Xp11.2 Urol Urol geneticalterations recurrent are hallmark SMARCB1 2008; and the absence of INI1 expression as markers of ag as markers of INI1expression of absence andthe renal medullary carcinomas. carcinomas. renal medullary fusion by fluorescence in situ hybridization. hybridization. situ in byfusion fluorescence clinicopathologic study emphasizing unusual morphol unusual emphasizing study clinicopathologic 2016; 40 21 2013; :723737. :723737. Accepted :647652. Article

37 :10551061. :10551061. :804815. :804815. This article isprotected by copyright. All rights reserved. Clin Cancer Res Cancer Clin The JournalofPathology:ClinicalResearch , et al.et , , et al.et , Renal cell carcinomas with t(6;11)(p21;q12): A t(6;11)(p21;q12): with cellcarcinomas Renal Eur Urol Urol Eur , et al.et , Nextgeneration sequencing of translocation renal of sequencing translocation Nextgeneration , et al.et , , et al.et , 2014; TFE3fusion variant analysis defines specific defines variant analysis TFE3fusion TFE3 greakapart FISH has a higher sensitivity for higher a sensitivity FISHhas greakapart TFE3 2016; Renal medullary carcinoma: Rhabdoid features Rhabdoid carcinoma: medullary Renal 40 40 20 , et al.et , , , al.et :41294140. :41294140. 69 Am J Surg Pathol Pathol JAm Surg :10621064. :10621064. SMARCB1/INI1 genetic alterations in in geneticalterations SMARCB1/INI1 Balanced translocations disrupting disrupting Balanced translocations a compared with TFE3 or cathepsin Kor cathepsin TFE3 with acompared es, as well as detection of the geneof the as detection es,as well gressive behavior. gressive behavior. requent mutations of chromatin requentmutations tion cancers. tion in renal medullary carcinomas. renalcarcinomas. in medullary ogy, novel alphaTFEB gene fusion genefusion ogy,alphaTFEB novel orphologic spectrum. orphologicspectrum. 2012; Am J Surg Pathol Pathol JSurg Am 36 Mod Pathol Pathol Mod :13271338. Am J Surg JAm Surg cell cell Eur Eur

Page 40of64 Page 41of64 5. MarinoEnriquez A, Ou WB, Weldon CB Weldon WB, Ou A, MarinoEnriquez 5. 4. Williamson SR, Zhang JL SR, Yao S, Williamson 4. 8. Tomlins SA, Rhodes DR, Perner Rhodes S DR, SA, Tomlins 8. 7. Kusano H, Togashi Y, Akiba J Akiba Y, Togashi H, Kusano 7. 9. Tomlins SA, Laxman B, Dhanasekaran SM B,Laxman Dhanasekaran SA, Tomlins 9. 3. Fisher KW, Zhang S, Wang M S, Zhang Fisher 3. KW, 2. Yoshimoto M, Joshua AM, ChiltonMacneill S M, ChiltonMacneill AM, Joshua Yoshimoto 2. 0. Tomlins SA, Bjartell A, ChinnaiyanA, AM Bjartell SA, Tomlins 0. 6. Sukov WR, Hodge JC, Lohse Hodge JC, CM WR, Sukov 6. 1. Palanisamy N, Ateeq B, KalyanaSundaram S B, KalyanaSundaram Ateeq Palanisamy N, 1. pathway in prostate cancer, gastric cancer andmela cancergastric cancer, prostate pathwayin associated renal medullary carcinoma. carcinoma. medullary associatedrenal concurrent prostatic adenocarcinoma and prostatic s and prostatic adenocarcinoma prostatic concurrent transcription factor genes in prostate cancer. prostate genesin factor transcription rearrangements create oncogenic ETS gene fusions in genefusions ETS create oncogenic rearrangements STRNALK fusion gene. gene. fusion STRNALK PTEN deletions in stage T1a prostate cancer. stageT1a cancer. prostate in deletions PTEN chromosome 21 is associated with rearrangement. rearrangement. with associated is 21 chromosome th cancer prostate fusions indicates in TMPRSS2/ERG 2007; treated patients. treated patients. frequency, clinicopathologic features and outcome i and outcome features clinicopathologic frequency, discovery to daily clinical practice. clinical daily to discovery

Accepted448 Article :595599. :595599. Mod Pathol Pathol Mod This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Am J Surg Pathol Pathol JAm Surg 2012; , et al.et , , et al.et , , et al.et , , et al.et , , et al.et , 25 Eur Urol Urol Eur TMPRSS2ERG gene fusion is rare compared to to rarecompared is gene fusion TMPRSS2ERG Two cases of renal cell carcinoma harboring aharboring nove carcinoma cases cell Two of renal :15161525. :15161525. ERGTMPRSS2 rearrangement is shared rearrangement is by ERGTMPRSS2 Genes Chromosomes Cancer Cancer GenesChromosomes ALK alterations in adult renal cell carcinoma: cellcarcinoma: renal adult in alterations ALK , et al.et , Recurrent fusion of TMPRSS2 and ETS and ETS TMPRSS2 of fusion Recurrent , et al.et , 41 41 , et al.et , 2016; Science Science , et al.et , 2009; Mol Carcinog Carcinog Mol ETS gene fusions in prostate cancer: from cancer: prostate in gene fusions ETS , et al.et , ALK rearrangement in sickle celltrait sickle in ALK rearrangement Distinct classes of chromosomal classes of chromosomal Distinct 40 Neoplasia Neoplasia 56 Rearrangements of the RAF kinase RAFof kinase the Rearrangements noma. noma. n a large series of consecutively of consecutively a n large series mall cell carcinoma and absent in in absent and cellcarcinoma mall :761769. :761769. Threecolor FISH analysis of analysis FISH Threecolor 2005; :275286. :275286. prostate cancer. prostate at genomic microdeletion of microdeletion genomic at Nat Med Nat 310 2016. 2016. 2006; :644648. :644648. 8 2010; :465469. :465469. 2011; Nature Nature 16 50 :793798. :793798. :146153. :146153. l l 03. Nikiforov YE, Nikiforova MN. Molecular gene Molecular MN. YE, Nikiforova Nikiforov 03. 02. Cancer Genome Atlas Research Network. Integ Network. Research Atlas Cancer 02. Genome 01. Cabanillas ME, McFadden DG, Durante C. Thyr C. DG, Durante McFadden ME, Cabanillas 01. 00. Xing M. Molecular pathogenesis and mechanis pathogenesis Xing Molecular 00. M. 9. Seshagiri S, Stawiski EW, DurinckS EW, Stawiski Seshagiri 9. S, 6. Del Castillo M, Chibon F, Arnould L F, Chibon Arnould M, Del Castillo 6. 5. Li Z, Tognon CE, Godinho FJ Godinho Li Z,CE, 5. Tognon 8. Bass AJ, Lawrence MS, Brace LEBrace Lawrence MS, Bass 8. AJ, 7. Tognon C, Knezevich SR, Huntsman D Huntsman SR, Knezevich Tognon 7. C, Rev Endocrinol Rev Endocrinol papillary thyroid carcinoma. carcinoma. papillarythyroid Nature Nature Pathol Pathol 2013; small cell carcinoma of the urinary bladder: eviden urinary bladder: the cellcarcinoma of small 2007; 968. 968. from committed mammary progenitors via activation o activation via mammary progenitors committed from adenocarcinomas identifies a recurrent VTI1ATCF7L2 a recurrent identifies adenocarcinomas as a primary event in human secretory breast carcin breast secretory human eventin asa primary and genomic spectrum characterized by a joint speci a by joint characterized spectrum andgenomic Surg Pathol Pathol Surg 13 12 2011; 2012; :184199. :184199. Accepted Article :542558.

2015; 24 488 :11201127. :11201127. 2011; :660664. :660664. 39 This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch :14581467. 7 :569580. :569580. Cell Cell , et al.et , , et al.et , 2014; ETV6NTRK3 fusion oncogene initiates breastcancer initiates oncogene fusion ETV6NTRK3 , et al.et , , et al.et , , et al.et , Genomic sequencing of colorectal colorectal of sequencing Genomic 159 42 42 Recurrent Rspondin fusions in colon cancer. colon in fusions Recurrent Rspondin Secretory breast carcinoma: A histopathologic Ahistopathologic carcinoma: Secretory breast :676690. :676690. Expression of the ETV6NTRK3 gene fusion genefusion ETV6NTRK3 of the Expression ms of thyroid cancer. of thyroid cancer. ms tics and diagnosis of thyroid cancer. thyroid cancer. of and diagnosis tics rated genomic characterization of characterization genomic rated oid cancer. oid ce supporting monoclonal origin. monoclonal cesupporting oma. oma. fic ETV6NTRK3 gene fusion. genefusion. ficETV6NTRK3 f AP1 complex. complex. fAP1 fusion. fusion. Cancer Cell Cell Cancer Lancet Lancet Nat Genet Nat 2016. 2016. Nat Rev Cancer Nat 2002; Cancer Cell 2011; 2 :367376. :367376. 43 :964 Am JAm Nat Nat Mod Mod

Page 42of64 Page 43of64 08. Sharifah NA, Zakaria Z, Chia WK. FISH analy FISH Z,WK. Chia Zakaria Sharifah NA, 08. 07. Caria P, Frau DV, Dettori T Dettori DV, Frau Caria P, 07. 05. Kelly LM, Barila G, LiuG, P Barila LM,Kelly 05. 09. Weinreb I. Translocationassociated salivar I. Translocationassociated Weinreb 09. 06. Raman P, Koenig RJ. Pax8PPARgamma fusion Pax8PPARgamma RJ. Koenig P, Raman 06. 04. Romei C, Ciampi R, Elisei R. Acomprehensiv R. Elisei R, Ciampi C, Romei 04. 10. Amelio AL, Fallahi M, Schaub FX Schaub M, Fallahi AL, Amelio 10. 11. Tonon G, Modi S, Wu L Wu S, Modi G, Tonon 11. Endocrinol Endocrinol Mol Biol Biol Mol Pathol Pathol Proc Natl Acad Sci U S A A US Sci Acad Natl Proc Cytopathol Cytopathol rearrangements in thyroid neoplastic cells using a a using cells neoplastic thyroid in rearrangements U S A A US a potential therapeutic target in the aggressive fo aggressive the target in therapeutic a potential oncogene in thyroid carcinoma. carcinoma. thyroid oncogene in detection of PAX8PPAR gamma translocation in folli in gamma translocation of PAX8PPAR detection with MYC create a gene signature predictive of canc geneof predictive signature create a MYC with Genet disru that product fusion acreates novel carcinoma 2014; 2003;

Accepted2013; Article 2013;

2014; 2014; 111 33 20 :208213. :208213. 952 :367377. :367377. :42334238. :42334238. 122 10 This article isprotected by copyright. All rights reserved. :187196. :187196. :616623. :616623. The JournalofPathology:ClinicalResearch :377385. , et al.et , 2014; , et al.et , , et al.et , t(11;19)(q21;p13) translocation in mucoepidermoid mucoepidermoid in translocation t(11;19)(q21;p13) 111 Nat Rev Endocrinol Rev Endocrinol Nat Identification of the transforming STRNALK fusion STRNALK transforming of the Identification Optimizing detection of RET and PPARg PPARg and of RET detection Optimizing , et al.et , :E32603268. :E32603268. 43 43 CRTC1/MAML2 gainoffunction interactions interactions gainoffunction CRTC1/MAML2 y gland tumors: a review and update. review ya glandtumors: e overview of the role of the RET proto RET of the role the eoverview of sis using PPAR gammaspecific probes for for gammaspecific probes PPAR using sis rms of thyroid cancer. of thyroid cancer. rms homebrew tetracolor probe. probe. homebrewtetracolor protein in thyroid carcinoma. thyroid in protein pts a notch signaling pathway. pathway. signaling a notch pts ers with CREBMYC involvement. involvement. CREBMYC erswith 2016; cular thyroid neoplasms. neoplasms. cularthyroid 12 :192202. :192202. Proc Natl Acad Sci Sci Acad Natl Proc Cancer Cancer Methods Methods Nat Rev Rev Nat Adv Anat Anat Adv Nat Nat as 19. Skalova A, Weinreb I,M Hyrcza Weinreb A, Skalova 19. 17. North JP, Garrido MC, Kolaitis NA Kolaitis Garrido MC, JP, North 17. 18. Skalova A, Vanecek T, Sima R Sima T, Vanecek A, Skalova 18. 16. Stenman G, Persson F, Andersson MK. Diagnos MK. F, Andersson Persson G, Stenman 16. 15. West RB, Kong C, Clarke N RB, Kong C, West 15. 14. Ramsay RG, Gonda TJ. MYB function in normal in MYB function TJ. Ramsay Gonda 14. RG, 12. Anzick SL, Chen WD, Park Y Park WD, SL, Chen Anzick 12. 13. Wysocki PT, IzumchenkoJ Meir E, PT, Wysocki 13. Pathol Pathol carcinomas with prominent clear cell component. component. clear cell prominent with carcinomas analy Molecular rearrangement: EWSR1 glandsshowing cases. of melano ambiguous diagnosis the in ancillarytool tumor entity. tumor gene:Ahi fusion ETV6NTRK3 the glands,containing molecular biomarkers in salivary gland cancers. glandcancers. salivary in molecular biomarkers carcinomas and other salivary gland tumors with cli with glandtumors andothersalivary carcinomas 2008; 2010; deletions. CDKN2A with tumors mucoepidermoid translocations and gene fusions. genefusions. and translocations 8 49 Am J Surg Pathol Pathol JSurg Am :523534. :523534. 2011;

Accepted Article :5969.

35 Am J Surg Pathol Pathol JAm Surg :9299. :9299. This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch 2014; , et al.et , 38 , et al.et , , et al.et , 2010; Oncotarget Oncotarget :824831. :824831. , et al.et , MYB expression and translocation in adenoid cystic adenoid in and translocation expression MYB , et al.et , , et al.et , Unfavorable prognosis of CRTC1MAML2 positive positive of CRTC1MAML2 prognosis Unfavorable 34 Mammary analogue secretory carcinoma of salivary salivary carcinomaof analoguesecretory Mammary Clear cell myoepithelial carcinoma of salivary carcinoma Clear cellmyoepithelial :599608. :599608. 44 44 Fluorescence in situ hybridization as an hybridization Fluorescence situ in Adenoid cystic carcinoma: emerging role ofemerging carcinoma: cystic Adenoid 2016. 2016. Oral Oncol Oncol Oral tic and therapeutic implications of new implications andtherapeutic tic and cancer cells. cells. and cancer Am J Surg Pathol Pathol JAm Surg Genes Chromosomes Cancer Cancer GenesChromosomes cytic neoplasms: a review of 804 of 804 a review cyticneoplasms: nicopathologic correlation. nicopathologiccorrelation. therto undescribed salivary gland salivary undescribed therto sis of 94 salivary gland salivary of 94 sis 2014; 50 Nat Rev Cancer Nat 2015; :683690. :683690. 39 :338348. :338348. Am J Surg JAm Surg

Page 44of64 Page 45of64 23. Kao YC, Lan J, Tai HC Tai Lan J, Kao YC, 23. 24. Gru AA, Becker N, Pfeifer JD. Angiosarcoma Angiosarcoma Pfeifer N, BeckerJD. Gru AA, 24. 27. Wiesner T, He J, Yelensky R Yelensky He T, J, Wiesner 27. 22. Antonescu CR, Katabi N, Zhang L Zhang Katabi N, CR, Antonescu 22. 21. Connor A, PerezOrdonez B, Shago M B, Shago PerezOrdonez A, Connor 21. 26. Wang J, Thway K. Clear cell sarcomalike tu Clear cellsarcomalike Thway K. Wang J, 26. 25. Hallor KH, Mertens F, Jin Y F, Jin KH, Mertens Hallor 25. 20. Majewska H, Skalova A, Stodulski D Stodulski A, Majewska Skalova H, 20. finding in hyalinizing clearcell carcinoma of sali carcinoma clearcell hyalinizing findingin molecular characterisation with emphasis on variant on emphasis with characterisation molecular 2011; 2014; spitzoid melanomas. spitzoid entity. 2012; 2015; translocation creating a EWSR1ATF1 fusion: Adiagn fusion: a EWSR1ATF1 creating translocation and immunohistochemical spectrum of a recently desc recently of a spectrum andimmunohistochemical generearrangem ETV6 the glandwith origin salivary expression of the MITFM transcript in angiomatoid angiomatoid in transcript MITFM of the expression Chromosomes Cancer Cancer Chromosomes 2013; salivary glands: A new entity associated with ETV6 ETV6 with associated entity glands:Anew salivary

50 67 36 466 66

Arch Pathol Lab Med Lab Pathol Arch :559570. :559570. :210215. :210215. :2734. :2734. Accepted :452454. Article :245254. :245254.

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Nat Commun Commun Nat 2005; , et al.et , 44 , et al.et , 2015; , et al.et , Angiomatoid fibrous histiocytoma: Clinicopathologi histiocytoma: fibrous Angiomatoid :97102. :97102. 139 , et al.et , 2014; Fusion of the EWSR1 and ATF1 genes without genes without and ATF1 EWSR1 of the Fusion Kinase fusions are frequent in Spitz tumours and tumours Spitz are in fusions frequent Kinase , et al.et , :407412. :407412. , et al.et , 5 45 45 EWSR1ATF1 fusion is a novel and consistent and aconsistent novel is fusion EWSR1ATF1 :3116. :3116. Mammary analogue secretory carcinoma of carcinoma secretory analogue Mammary Mammary analog secretory carcinoma of carcinoma secretory analog Mammary mor of the gastrointestinal tract: An evolving evolving An tract: gastrointestinal of the mor of the parotid gland with a t(12;22) a t(12;22) with gland of parotid the vary gland. vary histomorphology. histomorphology. gene rearrangement. generearrangement. fibrous histiocytoma. histiocytoma. fibrous ent by FISH: Expanded morphologic FISH:Expanded byent ribed entity. ribed ostic dilemma. dilemma. ostic Genes Chromosomes Cancer Cancer Chromosomes Genes Am J Surg Pathol Pathol JSurg Am J Clin Pathol Pathol JClin J Clin Pathol Pathol JClin Virchows Arch Arch Virchows Genes caland 33. Bottaro DP, Rubin JS, Faletto DL JS, Rubin Bottaro DP, 33. 34. Yeh I, Botton T, Talevich E T, I,Botton Yeh 34. 35. Louis D, Ohgaki H, Wiestler O LouisWiestler H, Ohgaki D, 35. 32. Ross JS, Wang K, Chmielecki J Wang Chmielecki K, Ross JS, 32. 29. Cancer Genome Atlas Research Network. Genom Network. Research Atlas Cancer 29. Genome 37. Frattini V, Trifonov V, Chan JM Chan V, Trifonov V, Frattini 37. 36. Shah N, Lankerovich M, LeeLankerovich M, H N, Shah 36. 28. Bradish JR, Cheng L. Molecular pathology of L. pathology Cheng Molecular Bradish 28. JR, 31. Hutchinson KE, Lipson D, Stephens PJ Stephens D, Lipson KE, Hutchinson 31. 30. Shain AH, Bastian BC. From melanocytes to m to BC. From melanocytes AH, Bastian Shain 30. practice paradigm toward a personalized approach. approach. a personalized toward practice paradigm Nervous System. 4th ed. Lyon, France: Inernational Inernational France: Lyon, ed. 4th NervousSystem. receptor as the cmet protooncogene product. product. protooncogene cmet as the receptor and Spitz tumours. tumours. andSpitz 2013; tumors and response to targeted therapy. therapy. targeted and response to tumors 2013; alterations in glioblastoma. glioblastoma. in alterations subset of melanomas with potential sensitivity to M sensitivity to potential with of melanomas subset (IARC), 2016. 2016. (IARC), glioblastoma using transcriptome sequencing and cop and sequencing using transcriptome glioblastoma 358. 358. Cell Cell 2015;

19 14

:66966702. :66966702. :818. :818. Accepted Article 161 :16811696. :16811696. This article isprotected by copyright. All rights reserved. Nat Commun Nat The JournalofPathology:ClinicalResearch Nat Genet Nat , et al.et , , et al. al. et , , et al.et , , et al.et , , et al.et , 2015; , et al.et , Activating MET kinase rearrangements in melanoma melanoma in rearrangements kinase MET Activating Exploration of the gene fusion landscape of landscape of genefusion of the Exploration The distribution of BRAF gene fusions in solid solid in geneof BRAFfusions The distribution WHO Classification of Tumours of the Central Central of the of Tumours Classification WHO 2013; 6 The integrated landscape of driver genomic of driver The landscape integrated , et , al. :7174. :7174. Identification of the hepatocyte growth factor factor growth hepatocyteof the Identification Int J Cancer JInt Cancer 46 46 45 BRAF fusions define a distinct molecular adistinct BRAFdefine fusions malignant melanoma: changing the clinical clinical the changing malignant melanoma: Science Science :11411149. :11411149. elanomas. elanomas. ic classification of cutaneous melanoma. of cutaneousmelanoma. classification ic Hum Pathol Hum Pathol EK inhibition. inhibition. EK Agency for Research on Cancer on Research Agencyfor ydata. number 2016; 1991; Nat Rev Cancer RevCancer Nat 138 251 :881890. :881890. 2014; :802804. :802804. Clin Cancer Clin Res BMC Genomics BMC 45 :13151326. :13151326. 2016; 16 :345 Page 46of64 Page 47of64 45. Jones DT, Hutter B, N Hutter DT, Jager Jones 45. 44. Jenkins RB, Blair BallmanH, KV Jenkins 44. 46. Merchant TE, Li C, Xiong X C, Li Merchant TE, 46. 43. Rodriguez FJ, Vizcaino MA, Lin MT. Recent a LinRecent MT. MA, Vizcaino FJ, Rodriguez 43. 47. Parker M, Mohankumar KM, Punchihewa C Punchihewa KM, Parker Mohankumar 47. M, 40. EckelPassow JE, Lachance DH, Molinaro AM Lachance DH, Molinaro JE, EckelPassow 40. 42. Wesseling P, van den Bent M, Perry A. Oligo A. denBent Perry M, van P, Wesseling 42. 41. Mur P, Mollejo M, HernandezIglesias T M, HernandezIglesias Mollejo P, Mur 41. 39. Bao ZS, Chen HM, Yang MY ZS,HM, Bao Chen 39. 38. Ceccarelli M, Barthel FP, Malta TM Malta FP, Barthel M, Ceccarelli 38. Exp Neurol Exp Neurol irrespective gliomagroups distinct prognostically oligodendroglioma. oligodendroglioma. progn a predicts better and and 19q of 1p deletions ependymoma: a prospective study. a prospective ependymoma: in pilocytic astrocytoma. pilocyticastrocytoma. in glial neoplasms in children and adults. and adults. children in glialneoplasms oncogenic NFkappaB signalling in ependymoma. ependymoma. in signalling oncogenic NFkappaB mechanisms and markers. and markers. mechanisms 1773. 1773. IDH, and TERT promoter mutations in tumors. tumors. in mutations promoter IDH,and TERT PTPRZ1MET fusion transcript in secondary glioblast secondary in transcript fusion PTPRZ1MET

Accepted Article dif in of progression and pathways discretesubsets

2015;

74 This article isprotected by copyright. All rights reserved. Cancer Res Cancer :241249. :241249. The JournalofPathology:ClinicalResearch Nat Genet Nat Acta Neuropathol Neuropathol Acta , et al.et , , et al. et , , et al.et , 2006; , et al.et , Recurrent somatic alterations of FGFR1 and NTRK2 and NTRK2 FGFR1 of alterations somatic Recurrent Lancet Oncol Oncol Lancet Conformal radiotherapy after surgery for paediatri afterfor radiotherapy surgery Conformal 2013; RNAseq of 272 gliomas revealed a novel, recurrent a novel, revealed gliomas of 272 RNAseq , et al.et , 66 J Mol Diagn Diagn J Mol A t(1;19)(q10;p10) mediates the combined combined the mediates t(1;19)(q10;p10) A :98529861. :98529861. 47 47 , et al. et , 45 Molecular profiling reveals biologically biologically reveals Molecular profiling :927932. :927932. , et al.et , 2015; dendroglioma: Pathology, molecular molecular Pathology, dendroglioma: Molecular classification defines 4 Molecular classification dvances on the molecular pathology of pathologyof dvancesmolecular the on , et al.et , N JN MedEngl 2009; of diagnosis and grade. and ofdiagnosis 129 osis of patients with with of patients osis fuse glioma. fuse Nature Nature C11orf95RELA fusions drive fusions C11orf95RELA 2016; Glioma groups based on 1p/19q, 1p/19q, basedon groups Glioma omas. omas. :809827. :809827. 10 :258266. :258266. 18 2014; :620634. :620634. Genome Res Genome Res 2015; Cell Cell 506 372 :451455. :451455. 2016; :24992508. :24992508. J Neuropathol Neuropathol J 2014; 164 :550563. :550563. 24 :1765 c

148. Versteeg R. Cancer: Tumours outside the mut the outside Tumours Versteeg Cancer: 148. R. Supplementary Material - None - None Material Supplementary

Accepted Article

ation box. box. ation Nature Nature 2014; 506 :438439. :438439. Page 48of64 Page 49of64 Nodular fasciitis t(17;22)(p13;q13) t(17;22)(p13;q13) fasciitis Nodular protuberans lsoirm apX(1-2) - t(17;22)(q22;q13) Dermatofibrosarcoma del(13)(q14) fibroblastoma cell Giant tumour cell giant Tenosynovial myofibroblastoma amp(X)(q12-q22) Mammary-type t(2;11)(q31;q12) angiofibroma Cellular t(2;11)(q31;q12) fibroblastoma Desmoplastic sheath tendon of Fibroma Elastofibroma t(12;16)(q13;p11) del(11)(q13-21) liposarcoma Myxoid liposarcoma differentiated tumour/well t(2;8)(q31;q12) lipomatous Atypical Hibernoma t(3;12)(q27;q14) lipoma pleomorphic cell/ Spindle t(11;16)(q13;p13) Lipoblastoma Translocation Chromosomal Lipoma lipoma Chondroid Type Tumour u and mesenchymal in alterations Chromosome 1 Table EDITED HERRINGTON

Accepted Article

Supernumerary ring ring Supernumerary t(17;22)(q22;q13) t(9;11)(p24;q13) t(9;11)(p24;q13) t(1;2)(p13;q37) t(1;2)(p13;q37) del(13)(q14) del(13)(q14) t(11;17)(q12;p11) t(12;22;20)(q13;q12;q11) t(12;22)(q13;q12) del(10)(q23) ring Supernumerary amp(12)(q14-15) del(16)(q13) -13/del(13)(q14) t(8;14)(q12;q24) t(7;8)(q21;q12) t(8;8)(q24;q12) t(Y;12)(q12;q14) t(3;13)(q27;q14) t(12;13)(q13;q14) This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Fibroblastic/myofibroblastic tumours Fibroblastic/myofibroblastic Adipocytic tumours Adipocytic

RB1, FOXO1 FOXO1 RB1, EWSR1DDIT3 EWSR1DDIT3 PTEN FUSDDIT3 MDM2 RB1 LPPLHFP HMGA2LHFP HMGA2LPP RB1, FOXO1 FOXO1 RB1, MEN1 MYH9USP6 MYH9USP6 RAD51BPLAG1 RAD51BPLAG1 HAS2PLAG1 COL1A1PDGFB - - CSF1COL6A3 CSF1COL6A3 - ?HMGA2 COL1A1PDGFB COL1A1PDGFB C11orf95MKL2 Involved Genes - - COL1A2PLAG1 COL3A1PLAG1

ncertain derivation solid tumours solid derivation ncertain

50–65 50–65 74–90 50–80 50–80 75–90 75–90 80–90 * * * 20–25 80–92 80–92 75-85 % 70-92 70-92 * * 7–12 90–95 54–80 54–80 66–80 90–92 90–92 * * * * 50-75 # # # 40–50 40–50 40–48 # # # 16–30 16–30 Epithelioid haemangioma t(1;3)(p36;q25) t(1;3)(p36;q25) haemangioma Epithelioid t(7;12)(p22;q13) t(2;13)(q35;q14) rhabdomyosarcoma Alveolar t(12;14)(q14;q22) rhabdomyosarcoma Embryonal Myopericytoma leiomyoma Uterine leiomyoma metastasizing Benign t(2;10)(q22;p22) t(1;2)(p11;q35-36) histiocytoma fibrous Epithelioid tumour cell giant Tenosynovial t(12;15)(p13;q25) inv(12)(q13q13) fibrosarcoma (p13;q25) ;15) t(12 epithelioid Sclerosing fibrosarcoma Congenital tumour fibrous Solitary fibrosarcoma Infantile sarcoma fibroblastic Myoinflammatory sarcoma fibromyxoid grade Low tumour myofibroblastic Inflammatory

Accepted Article

t(19;1)(q13;q22) t(19;1)(q13;q22) t(19;19)(q13;q13) t(X;11)(p11;q22) amp(2)(p24) amp(12)(q13-15) t(2;8)(q35;q13) t(2;2)(q35;p23) t(1;13)(p36;q14) del(11)(p15.5) - del(22)(q12) del(19)(q13.3), t(2;5)(p23;q35) t(11;16)(P13;p11) t(7;16)(q33;p11) t(12;16)(q13;p11) t(11;22)(p11;q12) amp(3)(p12) t(1;10)(p22;q24) ring Supernumerary t(11;16)(p11;p11) t(7;16)(q33;p11) t(5;12)(q32;q13) t(6;17)(q22;p13) t(6;3)(q22;q12) t(2;2)(p23;q13) t(2;19)(p21;p13) t(2;1)(p21;q21) t(2;2)(p21;p23) t(2;5)(p23;q35) t(2;12)(p23;p12) t(2;4)(p23;q27) inv(2)(p23q35) (p23;p15) t(2;11) t(2;17)(p23;q23) t(2;19)(p23;p13) t(1;2)(q21;p23) This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch So-called Fibrohistiocytic tumours Fibrohistiocytic So-called Pericytic (perivascular) tumour (perivascular) Pericytic Skeletal muscle tumours muscle Skeletal Smooth muscle tumours muscle Smooth Vascular tumours Vascular

MYCN MYCN PAX3NCOA2 PAX3NCOA1 PAX7FOXO1 PAX3FOXO1 HOTS CDKN1C, H19, IGF2, FUSCREB3L1 FUSCREB3L2 DDIT3FUS EWSR1CREB3L1 FUSCREB3L1 FUSCREB3L2 ACTBGLI1 ACTBGLI1 HMGA2ALDH2 ETV6NTRK3 NAB2STAT6 ETV6NTRK3 FOSLMNA FOSLMNA ZFP36FOSB NAB2PDGFRB RANBP2ALK EML4ALK NPM1ALK PPFIBP1ALK ATICALK GLI1, CDK4, MDM2 MDM2 CDK4, GLI1, CSF1COL6A3 CSF1COL6A3 YAP1TFE3 YAP1TFE3 WWTR1CAMTA1 SQSTM1ALK VCLALK VGLL3 TGFBR3MGEA5 YWHAEROS1 TFGROS1 TPM4ALK TPM3ALK SEC31AALK CARSALK CLTCALK TPM4ALK TPM3ALK

25-42 25-42 3-6 60-80 50-64 50-64 16-50 16-50 22-56 * 10-18 15-20 60-85 35-45 * * 10-20 80-90 * * 80-88 37-50 62-80 # # 17-20 90-99 44-55 75-90 * * * * 70-90 * 6-10 10-20 25-30 # # Page 50of64 Page 51of64 chondrosarcoma chondrosarcoma myxoid Extraskeletal tumour fibrolipomatous Hemosiderotic chondrosarcoma myxoid Extraskeletal histiocytoma fibrous Angiomatoid t(11;22)(q24;q12) -22/del(22)(q12) sarcoma Ewing del(2)(p16)/amp(2)(p16) Schwannoma Perineurioma schwannoma Melanotic del(8)(q13;q21)/t(8;8)(q chondrosarcoma Mesenchymal inv(6)(p25q13) fibroma Chondromyxoid hemangioendothelioma Epithelioid haemangioendothelioma Pseudomyogenic

Accepted Article

t(19;10)(q13;p13) t(19;10)(q13;p13) - 22q -22q t(9;17)(q22;q11) t(9;17)(q22;q11) t(9;15)(q22;q21) t(9;17)q22;q11) t(9;22)(q22;q12) t(1;10)(p22;q24) t(12;22)(q13;q21) t(9;22)(q22;q15) t(9;15)(q22;q21) t(9;17)(q22;q11) t(9;22)(q22;q11) t(9;15)(q22;q21) t(9;17)q22;q11) t(9;22)(q22;q12) t(12;16)(q13;p11) t(12;22)(q13;q12) t(2;22)(q33;q12) t(X;X)(p11;p11) t(4;19)(q35;q13) del(9)(p21) t(2;16)(q35;p11) t(16;21)(p11;q22) t(1;22)(p36;q12) t(2;22)(q31;q12) t(6;22)(p21;q12) t(4;22)(q31;q12) inv(22)(q12q12) t(20;22)(q13;q12) t(2;22)(q35;q12) t(17;22)(q21;q12) t(7;22)(p2;q12) t(21;22)(q22;q12) ring Supernumerary t(6;9)(q25;q22) t(6;17)(q23;p13) del(6)(q24) t(1;3)(p36;q23) t(11;X)(q22;p11) t(7;19)(q22;q13) This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Tumours of uncertain differentiation uncertain of Tumours Chondro-osseous tumours Chondro-osseous Nerve sheath tumour sheath Nerve Ewing sarcoma Ewing 21;q13) 21;q13)

FOSVIM FOSVIM NF2, SMARCB1 SMARCB1 NF2, EWSR1NR4A3 EWSR1NR4A3 EWSR1CHOP EWSR1NR4A3 EWSR1NR4A3 FUSATF1 EWSR1ATF1 EWSR1CREB1 BCORCCNB3 FUSFEV FUSERG EWSR1PATZ EWSR1SP3 EWSR1POU5F1 EWSR1SMARCA5 EWSR1ZFG EWSR1NFATC2 EWSR1FEV EWSR1ETV1 EWSR1ERG EWSR1FLI1 NF2 BCLAF1RAP1GAP2 BCLAF1RAP1GAP2 HEY1NCOA2 HEY1NCOA2 TAF15NR4A3 TAF15NR4A3 TFC12NR4A3 TAF2NNR4A3 TFGNR4A3 TCFI2NR4A3 TAF15NR4A3 TFC12NR4A3 TAF2NNR4A3 CICDUX4 CDKN2A WESR1ETV4 CNC2 CNC2 TGFBR3MGEA5 TGFBR3MGEA5 COL12A1? - - WWTR1CAMTA1 YAP1TFE3 SERPINE1FOSB

* * 40 40 * * * 15-20 50-75 75-80 70-80 70-80 * * * * * * * 15-20 50-75 * 10-14 75-85 * * * * * * * * * * * * * 5-10 12-15 80-90 70-85 70-85 6-20 15-20 20-40 75-80 77-85 80-94 20-30 70-80 70-80 spindle cell sarcomas sarcomas cell spindle t(X;18)(p11;q11) and round Undifferentiated t(X;17)(p11;p13) Sarcoma Synovial amp(12)(q13-14) PEComa sarcoma myxoid pulmonary Primary sarcoma Intimal t(11;22)(q24;q12) sarcoma Ewing Extraskeletal tumour cell round small Desmoplastic tract GI of tumour like sarcoma cell Clear t(10;17)(q22;p13) kidney the of sarcoma cell Clear t(12;22)(q13;q12) tissue soft of sarcoma cell Clear t(5;8)(p15;q13) t(6;12)(p21;q24) tumour fibromyxoid Ossifying angiofibroma tissue Soft t(X;17)(p11;q25) tumour carcinoma/mixed Myoepithelioma/myoepithelial sarcoma softpart Alveolar

Accepted Article

t(12;16)(q13;p11) t(12;16)(q13;p11) t(2;22)(p13;q12) t(12;22)(q13;q21) t(12;22)(q13;q21) t(9;22)(q22;q15) inv(X)(p11.2p11.4) inv(X)(p11.2p11.4) t(4;19)(q35;q13.1) t(X;20)(p11;q13) t(X;18)(p11;q13) t(X;18)(p11;q11) t(x;14)(q12;q24.1) t(3;3)(p21;p13) t(5;8)(q32;q24) inv(X)(p11.2q12) 1)(p11;p34) t(X; t(2;22)(q33;q12) t(2;16)(q36;p11) t(16;21)(p11;q22) t(2;22)(q36;q12) t(7;22)(q22;q12) t(21;22)(q22;q12) t(17;22)(q12;q12) t(21;22)(q22;q12) t(11;22)(p13;q12) t(2:22)(q33:q12) t(12;22)(q13;q12) t(X;22)(p11;q13) t(6;10)(p21;p11) t(1;6)(p34;p21) t(12;22)(q13;q12) t(19;22)(q13;q12) t(9;22)(q33;q21) t(1;16)(p34;p11) t(1;22)(q23;q12) t(6;22)(p21;q12) This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Undifferentiated/unclassified sarcoma Undifferentiated/unclassified

FUSATF1 FUSATF1 EWSR1CREB1 EWSR1ATF1 EWSR1CHOP EWSR1CHOP RAD51BRRAGB RAD51BRRAGB RASSF1PDZRN3 HTR4ST3GAL1 NONOTFE3 DVL2TFE3 EWSR1CREB1 FUSFEV FUSERG EWSR1FEV EWSR1ETV1 EWSR1ERG EWSR1EIAF EWSR1FLI1 EWSR1ERG EWSR1WT1 EWSR1CREB1 EWSR1ATF1 ZC3H7BBCOR EPC1PHF1 MEAF6PHF1 EP400PHF1 EWSR1ATF1 EWSR1ZNF444 EWSR1PBX3 FUSKLF17 EWSR1PBX1 EWSR1POU5F1 AHRRNCOA2 AHRRNCOA2 ASPSCR1TFE3 MDM2, GLI GLI MDM2, BCORCCNB3 BCORCCNB3 TFGNR4A3 TFGNR4A3 SFPQTFE3 CDK4, TSPAN31, TSPAN31, CDK4, YWHAENUTM2E CICDUX4 CICDUX4 SS18L1SSX1 SYTSSX4 SYTSSX2 SYTSSX1

* * 6-13 50-75 70-90 70-90 * * * 13-25 13-25 * * * * 90-100 * * * * * 5-10 80-90 * 90-99 6-20 85-90 * 50-80 * * 8 9 16 23 * * * 31-35 65-80 30-50 30-50 80-95 75-100 75-100 3-12 3-12 28-30 Page 52of64 Page 53of64 Aneurysmal bone cyst t(16;17)(q22;p13) t(16;17)(q22;p13) cyst bone Aneurysmal t(4;19)(q35;q13) sarcoma Ewing-like cell Round www.tumorfusions.org. www.tumorfusions.org. http://atlasgeneticsoncology.org; http://cgap.nci.n http://atlasgeneticsoncology.org;

infrequent *Too to estimate percentage,limited r # ht http://cancer.sanger.ac.uk/cosmic; Sources: Data

Accepted Article

t(12;15)(p13;q25) t(12;15)(p13;q25) inv(X)(p11.4p11.22) t(20;16)(q13;p11) t(16;21)(p11;q22) t(X;19)(q13;q13) t(10;19)(q26;q13) t(2;22)(q31;q12) t(1;22)(p36;q12) t(4;22)(q31;q12) inv(22)(q12q12) t(4;22)(q31;q12) t(6;22)(p21;q12) t(20;22)(q13;q12) This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Tumour of undefined neoplastic nature nature neoplastic undefined of Tumour ih.gov/chromosomes; http://www.genecards.org; ih.gov/chromosomes; tps://www.mycancergenome.org; http://www.genenames. tps://www.mycancergenome.org; eports

ETV6NTRK3 ETV6NTRK3 BCORCCNB3 FUSNCATc2 FUSERG EWSR1SP3 ZSG EWSR1 EWSR1SMARCA5 EWSR1PATZ1 EWSR1SMARCA5 EWSR1POU5F1 EWSR1NFATc2 CDH11USP6 CDH11USP6 CICFOXO4 CICDUX10 CICDUX4 66-72 66-72 * * * * * * * * * * * * * * 60-75

org; org; NUT midline carcinoma t(15;19)(q13;p13) t(15;19)(q13;p13) carcinoma midline NUT Tumour Type Chromosome alteration Gene Involved % % Involved Gene alteration Chromosome t(3;8)(p21;q12) adenoma Pleomorphic Type Tumour Follicular thyroid carcinoma t(2;3)(q13;p25) t(2;3)(q13;p25) carcinoma thyroid Follicular inv(10)(q11q21) t(6;12)(q23;q23) carcinoma thyroid Papillary del(10)(q23) neck and head the of carcinoma cell Squamous cylindroma dermal Solitary carcinoma duct Salivary carcinoma t(11;19)(q21;p13) secretory analogue Mammary t(6;9)(q22;p23) t(22;12)(q12;q13) t(22;12)(q12;q13) carcinoma Mucoepidermoid carcinoma cell clear Hyalinizing carcinomas odontogenic cell Clear carcinoma cystic Adenoid Table 2 Chromosome alterations in solid tumours of tumours of solid in alterations Chromosome 2 Table

Accepted Article

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch Head and Neck/Salivary gland Neck/Salivary and Head t(3;12)(p14;q14) t(3;12)(p14;q14) t(9;12)(p22;q14) t(8;8)(q24;q12) t(7;8)(q21;q12) t(8;8)(q11;q12) t(8;8)(q12;q12) r(8)(p12q12) t(5:8)(p13;q12) t(7;7)(q21;q34) t(7;7)(q21;q34) t(2;2)(p22;p23) t(10;18)(q11;q21) t(10;12)(q11;p13) t(8;10)(p11;q11) t(6;10)(p21;q11) t(8;10)(p21;q11) t(10;14)(q11;q22) t(1;10)(p13;q11) t(10;14)(q11;q32) t(7;10)(q32;q11) t(10;14)(q11;q32) t(12;15)(p13;q25) t(10;17)(q11;q23) t(1;15)(q21;q25) inv(10)(q11q10) Amp(8)(p11) t(12;8)(q14;q12) t(12;15)(p13;q25) t(6;22)(p21;q12) t(1;11)(q21;q21) t(15;11)(q26;q21) t(15;9)(q13;q34) t(15;9)(q13;q34) Thyroid gland Thyroid

epithelial origin. epithelial

EWSR1ATF1 EWSR1ATF1 PAX8PPARγ PAX8PPARγ MYB–NFIB EWSR1ATF1 MYBNFIB ETV6NTRK3 PRKAR1A(PTC2) RET NTRK1TPM3 RETNCOA4(PTC3) RETCCDC6(PTC1) FGFR1 HMGA2PLAG1 PTEN ETV6NTRK3 BRD3NUTM1 BRD3NUTM1 BRD4–NUTM1 HMGA2NFIB HMGA2NFIB HAS2PLAG1 FGFR1PLAG1 LFIRPLAG1 EWSR1POU5F1 EWSR1POU5F1 RET AKAP9BRAF AKAP9BRAF RETMBD1 RETERC1 RETHOOK3 RETTRIM27 RETPCM1 RETKTN1 RETTRIM33 RETTRIM27 RETTRIM24

HMGA2FHIT HMGA2FHIT COL1A2PLAG1 TCEA1PLAG1 CHCHD7PLAG1 CTNNB1PLAG1 CRTC2MAML2 CRTC2MAML2 CRTC3MAML2 CRTC1MAML2

STRNALK STRNALK

GOLGA5 GOLGA5 a a 63–82 63–82 * * * * * * * * * * * * * 2-14 5-11 12 30-35 30-35 60–80 60–85 30–50 5-8 30–40 9–15 9–15 22-50 40–50 85–94 10–15 10–15 70–80 * * * 2–6 50–70 22-30 60-70 a a a a Page 54of64 Page 55of64 Lung adenocarcinoma inv(2)(p21p23) inv(2)(p21p23) t(10;17)(q11;p13) adenocarcinoma Lung carcinoma thyroid Medullary t(7;17)(p15;q11) t(1;1)(q23;q25) sarcoma stromal Endometrial t(3;8)(p14.2;q24) cholangiocarcinoma Intrahepatic carcinoma hepatocellular Fibrolamellar adenocarcinoma Esophageal t(14;22)(q23;q12) t(6;6)(q22;q22) carcinoma Colorectal Mesothelioma t(2;22)(q33;q12) sarcoma myxoid pulmonary Primary

Accepted Article

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch t(9;7)(q21;q33) t(9;7)(q21;q33) t(1;10)(p13;q11) t(10;10)(q11;q11) t(10;10)(q11;q21) t(10;10)(q11;p11) inv(1)(q23q21) t(1;5)(q23;q33) t(1;17)(q23;p11) t(4;6)(p15;q22) t(6;1)(q22;q21) t(6;6)(q22;q25) t(6;19)(q22;q13) t(6;5)(q22;q32) t(6;20)(q22;q13) t(6;12)(q22;q14) t(6;7)(q22;p22) t(6;10)(q22;q21) t(2;7)(p23;q11) t(2;4)(p23;q21) t(2;2)(p23;p22) t(2;9)(p23;q31) t(2;14)(p23;q32) t(2;10)(p23;p11) t(2;3)(p23;q12) t(6;7)(p21;p15) t(6;7)(p21;p15) t(1;6)(p34;p21) t(7;10)(p13;q23) t(7;10)(p13;q23) t(19;19)(p13.1;p13.2) t(1;1)(q21;q23) t(8;8)(q23;q23) t(10;10)(q25;q25) t(4;6)(p15;q22) inv(2)(p21p23) t(2;2)(p23;p23) t(11;2)(p15;p11) Pleura and peritoneum and Pleura Gastrointestinal tract Gastrointestinal Gynaecological tract Gynaecological Lung

RABGAP1LNTRK1 RABGAP1LNTRK1 FHITRNF139 EWSR1YY1 EWSR1CREB1 NCOA4RET NCOA4RET KIF5BRET MPRIPNTRK1 EZRROS1 FIGROS1 LRIG3ROS1 KDELR2ROS1 HIP1ALK PTPN3ALK KLC1ALK KIF5BALK EML4ALK RETMYH13 JAZF1PHF1 JAZF1PHF1 MEAF6PHF1 JAZF1SUZ12 DNAJB1PRKACA NTRK1TPM3 NAV2TCF7L1 EML4ALK EIF3ERSPO2 PTPRKRSPO3 TRIM24NTRK2 TRIM24NTRK2 TRIM33RET CCDC6RET TPM3NTRK1 CD74NTRK1 SLC34A2ROS1 TPM3ROS1 CD74ROS1 SDC5ROS1 CCDC6ROS1 SEC31AALK STRNALK TFGALK NUTM2B YWHAE YWHAENUTM2A VTI1ATCF7L2 SLC34A2ROS1 WDCPALK # # 1 1-3 2-3 1-2 3-7 * * * * 0.4-0.8 2-5 * * # * 70-90 # # 6–10 6–10 20-30 40-50 92–100 3-4 5-8 ALK ALK carcinoma carcinoma Oncocytoma t(5;11)(q35;q13) t(5;11)(q35;q13) t(1;1)(p13;q44) Oncocytoma carcinoma breast Triple-negative t(12;15)(p13;q25) carcinoma breast Secretory cystadenocarcinoma papillary Ovarian Urothelial carcinoma Polysomy 3 3 Polysomy i(17)(q10) t(10;17)(q22;p13) carcinoma Urothelial kidney the of sarcoma cell Clear tumour Wilms t(1;22)(q41;q11) carcinoma medullary Renal -1 carcinoma cell renal Chromophobe translocations t(6;11) with associated carcinoma cell Renal translocations 7 Xp11.2 + with associated carcinomas Renal carcinoma cell renal Papillary del(3)(p11-pter) t(1;22)(q22;q13) carcinoma cell renal cell Clear adenoma Metanephric translocation associate renal cell cell renal associate translocation b

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This article isprotected by copyright. All rights reserved. The urinary system and male genital organs genital male and system urinary The The JournalofPathology:ClinicalResearch t(2;10)(p23;q22) t(2;10)(p23;q22) t(2;1)(p23;q21) t(6;9)(p12;p24) t(6;9)(p12;p24) dic(8;11)(p12;q14) t(3;6)(q26;q25) t(8;11)(p12;q14) - t(6;14)(q21;q24) del(9)(p21) del(9)(p21) 17 Polysomy 7 Polysomy i(7)(q10) t(11;22)(q13;q11) t(11;22)(q21;q11) t(15;22)(q22;q11) -21 -17 -13 -10 -6 -2 t(6;6)(p21;q11) t(6;11)(p21;q12) t(X;19)(p11.2;p13.3) t(X;17)(p11.2;q21.3) t(X;17)(p11.2;q23) inv(X)(p11.2q12) t(X;17)(p11.2;q25) t(X;1)(p11.2;p34) t(X;1)(p11.2;q21) -Y 17 + del(14)(q23) t(15;16)(q21;p13) t(1;22)(q22;q13) inv(12)(q13q15) t(9;15)(p24;q24) t(15;16)(q21;p13) t(6;10)(p21;p11) t(6;10)(p21;p11) Breast

MAGI3–AKT3 MAGI3–AKT3 ETV6NTRK3 ETV6NTRK3 KHDRBS2TFEB KHDRBS2TFEB MALAT1TFEB KHSRPTFE3 LUC7L3TFE3 NONO–TFE3 ASPSCR1–TFE3 PRCC–TFE3 MET EWSR1PBX1 EPC1PHF1 EPC1PHF1 HIF1A HIF1A VCLALK VCLALK TPM3ALK TENM4NRG1 TENM4NRG1 TBL1XR1RGS17 TENM4NRG1 CLTC–TFE3 CLTC–TFE3 SFPQ–TFE3 - - - - - YWHAENUTM2E YWHAENUTM2E - - CDKN2A CDKN2A SMARCB1MALAT1 SMARCB1MAML2 SMARCB1RORA SMARCB1CAPN2 SETD2 BAP1, PBRM1, VHL,

32-40 32-40 # # 100 # # # # # * * * * * * 56–100 70 70 85 80 # # #

1 1 13-25 13-25 80–94 # * # # # # 70–90 # # 90–100 * * * * 5-7 10-20 60-70

35–40 35–40 70–90 c Page 56of64 Page 57of64 Prostatic adenocarcinoma t(21;21)(q22;q22) t(21;21)(q22;q22) adenocarcinoma Prostatic t(5;6)(q33;q22) i(12p) nevi Spitz tumour cell germ Testicular

Accepted Article

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch del(10)(q23) del(10)(q23) t(7;1)(q34;q32) t(3;8)(p25;q22) t(17;19)(q21;q13) t(3;1)(q27;q32) t(3;21)(q27;q22) t(17;17)(q21;q25) t(17;21)(q21;q22) t(1;1)(q32;q32) t(7;17)(p21;p13) t(7;14)(p21;q13) t(7;11)(p21;p15) t(7;7)(p21;q15) t(7;15)(p21;q21) t(7;1)(p21;q32) t(7;21)(p21;q22) t(17;22)(q21;q22) t(7;22)(p21;q22) t(21;8)(q22;q24) t(21;1)(q22;q32) t(21;16)(q22;q13) t(2;7)(q37;q31) t(2;7)(q37;q31) t(7;19)(q34;q13) t(7;19)(q34;q13) t(10;10)(q11;p11) t(10;14)(q11;q32) t(1;1)(q23;q22) t(1;17)(q23;p13) t(1;2)(q23;p23) t(2;2)(p23;p23) t(3;6)(q12;q22) t(6;10)(q22;q25) t(6;12)(q22;q24) t(6;12)(q22;q24) t(6;12)(q22;p13) t(6;15)(q22;q21) t(6;12)(q22;p11) t(6;6)(p22;q22) t(12;16)(q13;p13) t(12;16)(q13;p13) t(4;4)(p16;p16) t(4;7)(p16;q22) Skin

LRRFIP1MET LRRFIP1MET LSM14ABRAF KIF5BRET LMNANTRK1 DCTN1ALK ZCCHC8ROS1 ERC1ROS1 MYO5AROS1 PPFIBP1ROS1 HLAAROS1 PWWP2AROS1 PTEN PTEN ESRP1RAF1 KLK2ETV4 HERVK17ETV1 EST14ETV1 ASCL3ETV1 HNRPA2B1ETV1 ETV4ERG ETV1ERG NDRG1ERG HERPUD1ERG FGFR3TACC3 FGFR3TACC3 FGFR3BAIAP2L1 CEP89BRAF GOLGA5RET TP53NTRK1 TPM3ALK TFGROS1 SHTN1ROS1 CLIP1ROS1 SLC45A3BRAF SLC45A3ELK4 SLC45A3ETV5 TMPRSS2ETV5 CANT1ETV4 TMPRSS2ETV4 C15orf21ETV1 SLC45A3ETV1 TMPRSS2ETV1 SLC45A3ERG TMPRSS2ERG SCN8AGRIN2A SCN8AGRIN2A 67–83 67–83 * * * * 3 7–16 11–15 15–20 # # 3-6 5-9 40-70 40-70 * * * * * * * * 7–10 * * 47–79 CCND1 (11q13) genes and of centromere 6 in melanocy in 6 centromere of genes and (11q13) CCND1 * Too infrequent to estimate percentage, # limited limited # percentage, estimate infrequentto *Too www.tumorfusions.org. http://atlasgeneticsoncology.org; http://cgap.nci.n http://atlasgeneticsoncology.org; Melanoma amp(11)(q13) amp(11)(q13) Melanoma t designed is Kit Probe FISH Melanoma Vysis The d: in locus 9p21 the of loss and 17, 7, 3, chromosomes Kit (UroVysion Kit Cancer Bladder UroVysion The c: -del(22)(q11) t(9;17)(q31;q24) t(1;19)(q10;p10) ht http://cancer.sanger.ac.uk/cosmic; Sources: Data del(22)(q12) tumour glioneuronal Papillary neurocytoma Extraventricular Ependymoma t(7;7)(q34;q34) t(6;6)(q23;q26) Meningioma Medulloblastoma del(10)(q23) astrocytoma Pilocytic glioma Angiocentric del(19)(q13) del(1)(p36), Glioblastomas Oligodendrogliomas b: 50% with sickle-cell trait trait sickle-cell with 50% b: ca thyroid induced inradiation incidence Higher a:

Accepted Article

This article isprotected by copyright. All rights reserved. The JournalofPathology:ClinicalResearch t(3;8)(p25;q22) t(3;8)(p25;q22) t(7;7)(q22;q31) t(7;7)(q22;q31) t(7;19)(q34;p13) t(7;7)(q22;q34) t(7;11)(q34;p15) t(7;7)(p13;q34) t(7;7)(q11;q34) t(7;7)(p22;q34) t(7;7)(q34;q34) t(7;7)(q33;q34) t(4;7)(q25;q34) t(1;7)(q32;q34) amp(6)(q23) amp(6)(p25) del(2)(p16p23) del(2)(p16p23) t(2;14)(p23;q22) t(11;11)(q13;q13) t(1;19)(q21;q13.3) t(12;22)(p13;q12) t(9;6)(q21;q26) t(7;5)(q34;q35) t(7;7)(p11;p12) t(3;?)(p27;?) t(4;8)(p16;p11) t(4;4)(p16;p16) t(7;7)(q31;q31) t(1;19)(q10;p10) t(1;19)(q23;p13) t(1;19)(q23;p13) i(17q) Nervous system Nervous ih.gov/chromosomes; http://www.genecards.org; ih.gov/chromosomes; report ncers ncers tps://www.mycancergenome.org; http://www.genenames. tps://www.mycancergenome.org; urothelial tumours. tumours. urothelial o detect copy number of the RREB1 (6p25), MYB (6q23 MYB (6p25), RREB1 the of number copy detect o ) is FDA approved and designed to detect aneuploidy detect to designed and approved FDA is )

tic lesions. lesions. tic

MYBQKI MYBQKI MN1ETV6 MN1ETV6 NF2 RNF130BRAF KIAA1549BRAF LANCL2 FGFR1TACC3 FGFR3TACC3 PTPRZ1MET PTEN ESRP1RAF1 ESRP1RAF1 ZKSCAN1MET PLIN3BRAF ZKSCAN5BRAF NUDCD3BRAF KCTD7BRAF MAD1L1BRAF AGKBRAF PAPSS1BRAF MYB RREB1 KTN1ALK KTN1ALK E2APBX1 E2APBX1 QKINTRK2 ?BCL6 SLC44A1PRKCA SLC44A1PRKCA TRIM4MET SOX6BRAF TRIM24BRAF SLC45A3BRAF CCND1 CCDC88AALK CCDC88AALK C11orf95RELA

SEPT14 SEPT14 * * 5 5-8 15-35 43 # # # 50-60 * * 64–73 * * * * * * * * * * * * * * # # 17-20 80 # # # 71–80 20–30 # 77-92 54–82 # # 30–50

d for for org; org; ), ), Page 58of64 Page 59of64

Accepted Article

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Accepted Article

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Accepted Article

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