Page 1of31 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/cncr.30817. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen prevention strategies for his entire family. entire family. his for strategies prevention primary malignancy. The majority of the men with ge with majority men of the The malignancy. primary D the in involved genes, predominantly predisposing Affiliations: Affiliations: Dayno, BSDayno, 84132 48109 77030 Email: [email protected] [email protected] Email: Lake 84112 UT Salt City, System Health Utah Universityof InternalMedicine Departmentof MD KathleenCooney A. Author: Corresponding Authors: Authors: Title: Running Cancers Additional 4 1 Funding Sources: Funding 801 581 7606 Phone: 801 581 5393 Fax: 3 2 Manuscript Title: Title: Manuscript
germline mutations on not only a proband’s own trea own only a not proband’s on mutations germline cancer, pa prostate genetictesting in criteriafor guidelin current genetictesting under for clinical Conflict of Interest of Disclosures: Conflict Cor Sequencing Center Cancer MichiganComprehensive (SPORE) Excellence Research of Program Specialized significant minority of a selected population of me selected population of a significantminority Precis for use in the Table of Contents: of Table the in use Precisfor University of Michigan Comprehensive Cancer Center, Cancer Comprehensive Universityof Michigan Utah of University Medicine, Internal Departmentof Mich of University Medicine, Internal Departmentof MD of Texas University of Cancer Medicine, Division
Patrick G. Pilié, MD Pilié, G. Patrick 2 ;
Accepted ArticleKapron,L.PhD Ashley Genetics of Men w/ PCa & Other Cancers Cancers & Other PCa w/ of Men Genetics Supported by a grant from the University of Michig Universityof the grantfrom a by Supported Germline Genetic Variants in Men with Prostate Canc Prostate with Men in Genetic Variants Germline
This article isprotected by copyright. All rights reserved. 1 ;
Anna M. MS AnnaM. Johnson, There are no conflict of interests from anyfrom of the of interests conflict no are There 3 ; Elena M. Stoffel, MD Stoffel, Elena M. ; In this study, pathogenic germline mutations in ca in mutations germline In pathogenic study, this Cancer rticularly given the impact of pathogenic of pathogenic given impact the rticularly
es, highlighting the need for expanded inclusion inclusion expanded for need the highlighting es, n with prostate cancer and at least one other least at and cancer prostate with n NA damage repair pathway, were found in a in found were pathway, repair NAdamage tment but also cancer screening and screening cancer also but tment School of Medicine, Salt Lake UT Salt City, of Medicine, School rmline mutations would not have qualified not would mutations rmline igan Medical School, Ann Arbor, Ann MI School, iganMedical 2 (P50 CA186786) and the University of University the of and CA186786) (P50 Anderson Cancer Center, Houston TX Houston Center, AndersonCancer ; Ann Arbor, MI 48109 48109 MI Arbor, Ann
Kristen Hanson, MS, CGC MS, Hanson, Kristen e. e. 2,4 ; Kathleen Cooney,A. ; MD an Prostate Cancer Cancer anProstate er and One or More and One or er
authors authors 2 ; Megan ; E. 3
ncer
project leading project publication.this to presentation of presentation the publishedwork from bythose th patients, laboratorysamples, animals, instrumentat published work,published specifically visualization/data pre of presentation the publishedwork, specifically wr performingexperiments, the data/evidence or collec computingor resources, other analysis tools. supportingalgorithms; testing existingcom of code programs;computer implementation of the computer c Programming, Software: development; design software models. of Methodology:design or Development methodology; of aims. and Conceptualization:Formulation of overarchingresea Fundingacquisition: Acquisition of the financials responsibility activity for the research planninga Project administration: Managementcoordination and to external the core team. activity research execution, planningand including Supervision:Oversight and leadership responsibilit Visualization:Preparation, and/or creation present – revision including pre post publication or stage group, specifically research review, critical comme Writingand review – editing: Preparation, creation draft:Writing original – Preparation, creation and itself) for initial use and laterre use. software code,where isit necessary forinterpreti data scrub metadata), and maintain data research (i curation: Data Management annotate activities to (p Provision Resources: study of materials, reagents, Research Investigation: and investigation process, synthesize data. study computational,or other formalto techniques analyz Formalanalysis: Application statistical, of mathem results/experiments other and research outputs. of separate, the overall replication/reproducibilit Validation:Verification, whether as part a of the Author Contributions: Contributions: Author initial draft initial (includingsubstantive translation). Accepted Article This article isprotected by copyright. All rights reserved.
y of nd execution. execution. nd activity or ngthe data Cancer /or s. s. upport for the sentation. ationthe of materials, specifically ion, iting the ncluding and/or atical, atical, mentorship ntary or yforthe ponents. ponents. e or or e e original e roduce roduce tion. tion. 2 2 rch goals
ode and ode ing creation Kathleen A. Cooney Kathleen n/a Elena Stoffel M. Elena Hanson, Kristen E. Megan Dayno, Anna PatrickG. Pilié, M. Johnson, Kathleen A. Cooney Kathleen Kathleen Stoffel, A. Cooney AshleyL.Kapron, Elena M. Hanson, Kristen E. Megan Dayno, Anna PatrickG. Pilié, M. Johnson, Cooney Stoffel, M. Elena Kathleen A. Anna PatrickG. Pilié, M. Johnson, Cooney Stoffel, M. Elena Kathleen A. AshleyL.Kapron Hanson, Kristen E. Megan Dayno, Anna PatrickG. Pilié, M. Johnson, Cooney AshleyL.Kapron, KathleenA. Anna PatrickG. Pilié, M. Johnson, Cooney E.Dayno, Megan Kathleen A. M. Anna Johnson, Kristen Hanson, Cooney Stoffel, M. Elena Kathleen A. AshleyL.Kapron Anna PatrickG. Pilié, M. Johnson, Kathleen A. Cooney Kathleen Elena Stoffel, Kapron, M. E.Dayno, Megan Ashley L. M. Anna Johnson, Kristen Hanson, PatrickG. Pilié Page 2of31 Page 3of31 predisposing genes. The majority of these men (64%) men majorityof these genes.The predisposing
Background Abstract were found across six genes including six across found were Methods pr one additional least at and cancer prostate with vari germline pathogenic of describe prevalence the the genes can increase certain in variants germline Likely pathogenic missense variants were identified were variants missense Likely pathogenic testing, genetesting, panel germline testing germline (10.8%) subjects were found to have pathogenic or l have or pathogenic to found were (10.8%)subjects Conclusions Keywords: Keywords: mee not do most but and treatment, cancer prognosis a in mutation deleterious germline a forharboring Results for testing criteria established met patient the if reviewed independently were data clinicopathologic more primary 3) three or and/or tumor, ofa common maligna first of diagnosis at age55 ≤ criteria:1) w cancer primary one additional least at cancerand : Sequencing identified ~3500 variants. Nine protein Nine variants. ~3500 identified Sequencing : : Using a multi gene panel, we sequenced germline D germline we sequenced panel, Using : a multi gene prostate cancer, germline variants, multiple primar multiple germlinevariants, cancer, prostate : Men with prostate cancer and at least one additio andleast at with Men cancer : prostate Accepted Article compo heritable a significant : cancer has Prostate .
This article isprotected by copyright. All rights reserved. BRCA2 Cancer , , for a hereditary cancer syndrome. syndrome. cancer a hereditary for ATM, MLH1ATM, 3 3 ncy, 2) rare tumor type or atypical presentation presentation atypical or type raretumor ncy,2) imary cancer. cancer. imary risk of prostate cancer. Our aim was to was to aim Our cancer. of prostate risk cancer predisposing gene that may impact may that impact gene cancer predisposing ho also met one or more of the following following of the one or more met also ho ants in cancer predisposing genes in men men genesin cancer predisposing in ants in in ikely pathogenic mutations in cancer in mutations ikely pathogenic by a clinical genetic counselor to determine to geneticcounselor aclinical by t current criteria for clinical genetic testing. genetic testing. clinical for criteria current t malignancies. Cancer family history and familyhistory Cancer malignancies. did not meet current clinical criteria for criteria clinical current meet not did CHEK2 , , truncating deleterious mutations mutations deleterious truncating BRIP1 y malignant neoplasms, genetic neoplasms, y malignant NA from 102 men with prostate prostate with men 102 NAfrom and nal primary cancer are enriched cancer enriched are primary nal nent, and rare deleterious deleterious and rare nent, HOXB13 , , PALB2 , and , . In . 11/102 total, FGFR3.
rsns s utpe niiul i a aiy presen family a in individuals multiple as presents predisposition genes that have been definitively sh definitively been have that genes predisposition prostate cancer in men of European descent. European of men in cancer prostate ahgnc r iey ahgnc ains n N dam DNA in variants pathogenic likely or pathogenic prostate cancer plus an additional primary cancer. primary anadditional cancer prostate plus hog lnae analysis. linkage through germline mutations in mismatch repair genes. mismatchrepair in mutations germline and endometrial, bowel, small colorectal, including found prostate cancer is increased in individuals w individuals in increased is cancer prostate found 02 or aoaoy dniid rcret mutatio recurrent a identified laboratory our 2012, hereditary prostate cancer has proven challenging. challenging. proven has cancer prostate hereditary identifica however, patterns; inheritance Mendelian
Introduction Introduction uain nrae te ik f te cnes n is and cancers other of risk the increases mutation osset ih fudr lee n acut fr a for accounts and allele founder a with consistent neetd o fml hsoy ae hw a signific a shown have history family for unselected clinically aggressive phenotype. aggressive clinically m are and cancer prostate of risk increased an have eeeiu mttos n N dmg rpi gns i genes, repair damage DNA in canc mutations deleterious ovarian and breast hereditary with families in genesand repair DNA damage homologous in mutations rsae acr s ptnil hntpc manifesta phenotypic potential a is cancer Prostate Accepted Article her strong a have to shown been has cancer Prostate This article isprotected by copyright. All rights reserved. 1 The 6 8 HOXB13 Multiple recent studies of men with metastatic pro metastatic with men of studies recent Multiple G84E mutation is typically on a common haplotype haplotype common a on typically is mutation G84E 2 Cancer 12,13 Some studies have found evidence that this G84E G84E this that evidence found have studies Some 4 4
3 5 own to increase the risk of prostate cancer. In cancer. prostate of risk the increase to own To date, there are a limited number of cancer cancer of number limited a are there date, To tion of highly penetrant genes accounting for for accounting genes penetrant highly of tion
ith Lynch Syndrome (LS), which classically classically which (LS), Syndrome Lynch ith n in the the in n pproximately 5% of all cases of hereditary hereditary of cases all of 5% pproximately en oe rqety n niiul with individuals in frequently more seen ore likely to have prostate cancer with a a with cancer prostate have to likely ore ting with one or more primary cancers cancers primary more or one with ting ant minority of these individuals harbor harbor individuals these of minority ant bladder/ureteral cancers and is due to to due is and cancers bladder/ureteral ncluding er (HBOC) syndrome and who carry carry who and syndrome (HBOC) er individuals with Lynch Syndrome. Men Men Syndrome. Lynch with individuals g rpi genes. repair age HOXB13 tion in individuals with germline germline with individuals in tion BRCA2 tbe opnn ad exhibit and component itable gene on chromosome 17 17 chromosome on gene , have been observed to to observed been have , 9 11 Studies have also also have Studies state cancer cancer state Page 4of31 Page 5of31 be heterogeneous in their presentation, pathology, pathology, presentation, their in heterogeneous be penetrance genes explain only a fraction of heritab of fraction a only explain genes penetrance phenotype. reportedly comprising 6.3% of tumor registry cases. registry of tumor 6.3% comprising reportedly in locations anatomic distinct in arising histology and early detecti goalaof prevention historywith p is genes cancer susceptibility of testing genetic n/rmlil rmr mlgace.Hwvr here However, malignancies. primary multiple and/or multi age of onset, early include: syndromes cancer referrals in these persons with multiple primaryca multiple with thesereferrals persons in geneticasse for referred MPMNs with ofindividuals refe for indication one as considered is individual
and that those germline carriers in the study were were study the in carriers germline those that and high a have overall populations sarcoma that shown u of study a example, For MPMNs. developing of risk (LF), Li Fraumeni as such syndromes, cancer certain most frequently mutated. frequently most genes, predisposition cancer more or one in variant genetic clinical for referred were who malignancies h sm tm, r eahoos ocrig rae t greater occurring metachronous, or time, same the Mlil piay ainn nolss MMs (defi (MPMNs) neoplasms malignant primary Multiple nw cne ssetblt snrms o nme >1 number now syndromes susceptibility cancer Known 17,18
Accepted individuals of study retrospective a addition, In Article This article isprotected by copyright. All rights reserved. 19 While the presence of certain constellations of MP of constellations certain of presence the While Cancer 5 5 on of cancers in these high risk populations. populations. thesehigh risk of cancers in on rral for genetic risk assessment, the percentage percentage the assessment, risk genetic for rral ncers has not been extensively described. described. extensively ncers been not has rimarily based on family and personal cancer cancer personal and family on based rimarily with DNA mismatch repair genes among the the among genes repair mismatch DNA with 15 le cancers. le incidence of pathogenic germline mutations, mutations, germline pathogenic of incidence ssment and the outcomes of clinical genetics clinical of outcomes and the ssment are well known to carry a particularly high high particularly a carry to known well are and outcomes. Identifying individuals for for individuals Identifying outcomes. and MPMNs may be synchronous, occurring at occurring may besynchronous, MPMNs ple affected generations, rare tumor types types tumor rare generations, affected ple a single individual) are relatively rare, rare, relatively are individual) single a significantly more likely to have MPMN MPMN have to likely more significantly testing found 44/111 (39.6%) carried a a carried (39.6%) 44/111 found testing a sx ots apart. months six han iay acr,lk soai acr, can cancers, sporadic like cancers, ditary nselected individuals with sarcoma has has sarcoma with individuals nselected 14 Common features of hereditary hereditary of features Common 0 tog mttos n high in mutations though 00, ned as tumors of different different of tumors as ned ih utpe primary multiple with 16 Individuals with with Individuals MNs in a single single a in MNs
prostate cancer before age 55 (more than 4,000 cons 4,000 than (more 55 age before cancer prostate been diagnosed with at least one additional primary additional one least at with diagnosed been Patient Selection Selection Patient
registries identified 414 men diagnosed with early with diagnosed men 414 identified registries 3800 from individuals consented 5000 (approximately hi family or personal with patients recruits CGC UM iig is o scn dge rltv wt prostat with relative degree second or first living with men enrolls PCGP UM The participant. each from Institutional local the by approved are Both Mich CGC). of University the Michigan’s from of University selected the were and Subjects PCGP) (UM Project & Methods Patients s generation next via genes simultaneously multiple opport the provides which approach panel multi gene ri cancer confer and on passed be to able are which in those detecting of likelihood the increase would M an including definition clinical rigorous a using pr additional one least at and cancer prostate with determ to out set we cancer, prostate to contribute 1) early age of onset of first malignancy (<55 year (<55 malignancy first of onset of age early 1) cr following the used we cases, these From cancer). Accepted Article mutations deleterious rare that evidence the Given This article isprotected by copyright. All rights reserved. Cancer 6 6 ine the frequency of germline mutations in men in mutations germline of frequency the ine dividuals with deleterious germline mutations, mutations, germline deleterious with dividuals onset and/or familial prostate cancer who had had who cancer prostate familial and/or onset PMN phenotype and early onset cancers, we we cancers, early onset and phenotype PMN equencing. equencing. e cancer, and/or who were diagnosed with with diagnosed were who and/or cancer, e iteria to further select patients for this study: this for patients select further to iteria s old), 2) diagnosed with rare cancers (e.g., (e.g., cancers rare with diagnosed 2) old), s malignancy (excluding non melanoma skin skin non melanoma (excluding malignancy Review Board and obtain informed consent consent informed obtain and Board Review imary neoplasm. We hypothesized that by by that hypothesized We neoplasm. imary ented individuals from 1792 families). The The families). 1792 from individuals ented k o usqet eeain. e sd a used We generations. subsequent to sk story suggestive of hereditary cancer risk risk cancer hereditary of suggestive story nt t sqec te oig ein of regions coding the sequence to unity families). Initial queries of these two two these of queries Initial families). prostate cancer who have at least one one least at have who cancer prostate Cancer Genetics Clinic registry (UM (UM registry Clinic Genetics Cancer igan’s Prostate Cancer Genetics Genetics Cancer Prostate igan’s n acr rdsoiin genes predisposition cancer in Page 6of31 Page 7of31 ahgnc emie uain ascae wt hered with associated mutations germline pathogenic was which history, cancer family a provided patient acetc acr tsiua cne, acm, brai sarcoma, cancer, testicular cancer, pancreatic which included 160 genes. The remaining samples (8) samples remaining The genes. 160 included which Q the using typed were (94) samples of majority The p of carcinogenesis in involved pathways in mutated heredi penetrance moderate and high with associated re exonic the of >95% amplify which sets primer PCR Pan extra Cancer DNA on performed Comprehensive was profiling DNAseq mutation Gene GeneRead Qiagen the Analysis Gene Mutational Polyp Adenomatous or Familial (PHTS) Syndrome Tumor Sy Lynch (LFS), Syndrome Fraumeni Li (HBOC), Cancer gui 2015 using NCCN or Network Cancer Comprehensive ge clinical for criteria published met they whether suggestiv were these whether determine to counselor diagnosis PSA >10ng/mL, N1 or M1 at diagnosis. diagnosis. at M1 >10ng/mL, or N1 diagnosisPSA PSA>15 pre diagnosis tumor, T4 or T3b stage >7, sum exhibi they if aggressive clinically as categorized diagn cancer prostate to pertaining records Medical Indi pedigree. generation 3 a construct to used and lymphoma) and/or 3) three or more primary malignanc primary more or three 3) and/or lymphoma)
Accepted re was subject each for history family and Personal Article This article isprotected by copyright. All rights reserved. Cancer 7 7 ted one of more the following features: Gleason features: following the more of one ted oses were reviewed and prostate cancers were were cancers prostate and reviewed were oses n cancer, parathyroid cancer, Hodgkin’s Hodgkin’s cancer, parathyroid cancer, n netic testing (as defined by the National National the by defined (as testing netic rostate cancer and additional tumor types. tumor additional and cancer rostate pathologically confirmed when possible; possible; when confirmed pathologically iagen GeneRead DNAseq CCP version 2, 2, version CCP DNAseq GeneRead iagen gions of a panel of genes including genes genes including genes of panel a of gions ies in a single individual. Each individual individual Each individual. single a in ies ay acr ydoe a wl a genes as well as syndromes cancer tary were typed using the Qiagen GeneRead GeneRead Qiagen the using typed were o a eeiay acr ydoe and syndrome cancer hereditary a of e itary cancer syndromes were excluded. excluded. were syndromes cancer itary viduals who were known carriers of of carriers known were who viduals osis (FAP). (FAP). osis delines for Hereditary Breast Ovarian Ovarian Breast Hereditary for delines gm, lao soe7 n pre and score=7 Gleason ng/mL, ndrome (LS), PTEN Hamartoma Hamartoma PTEN (LS), ndrome el (CCP) consisting of multiplex multiplex of consisting (CCP) el cted from peripheral blood using blood peripheral from cted viewed by a certified genetic genetic certified a by viewed
rsne f o mr piay ainnis whether malignancies, primary more or 3 of presence non carri and carriers mutation germline pathogenic Statistical Analysis Analysis Statistical Patients ahgnct uig h pbial aalbe databa available publically the using pathogenicity whom DNA was available, as available, DNA was whom igoi o pott cne, S a pott cance prostate at at PSA age cancer, including prostate characteristics Clinicopathogical of diagnosis Sanger sequencing. via Results Results we <0.05 values P test. exact Fisher’s compared via cl of presence the and kind, any of testing genetic sequencing for the the for sequencing established consensus guidelines. consensus established nlss otl (http://ngsdataanalysis.sabioscienc Portal Analysis T GeneRead the using performed was data of analysis Sequencing 1. Table Information Supporting in found l A genes. 124 included which 1, version CCP DNAseq netosdltos slc vrat. l deleteri All variants. splice insertions/deletions, importance functional putative with identified were hts/wwnb.l.i.o/lna/ ad I (ht BIC and (https://www.ncbi.nlm.nih.gov/clinvar/) Called variants were annotated with Annovar. with annotated were variants Called Accepted Article HOXB13 This article isprotected by copyright. All rights reserved. 8E lee a promd n 312 ujcs n th in subjects 93/102 on performed was allele G84E HOXB13 21 23 Pathogenic and likely pathogenic variants were con were variants pathogenic likely and Pathogenic was not included in either Qiagen gene panel. gene panel. either Qiagen in included wasnot Cancer 8 8 ous and missense variants were referenced for for referenced were variants missense and ous edee infcnl ifrn. different. significantly redeemed ers via two sided T test. Gleason score, race, race, score, Gleason test. T two sided via ers preferentially given to stop/loss, frameshift frameshift stop/loss, to given preferentially was performed on an Illumina HiSeq, and and HiSeq, Illumina an on performed was 20 es.com/NGS2/). In addition, Sanger Sanger addition, In es.com/NGS2/). inically aggressive prostate cancer were were cancer prostate aggressive inically Deleterious, protein truncating variants variants protein truncating Deleterious, r o ptet e NC ciei for criteria NCCN met patient not or r diagnosis were compared between between compared were diagnosis r tps://research.nhgri.nih.gov/bic/), and and tps://research.nhgri.nih.gov/bic/), argeted Exon Enrichment Panel Data Data Panel Enrichment Exon argeted ist of genes included in each panel is is panel each in included genes of ist igoi o frt rmr, g at age primary, first of diagnosis ses, ClinVar ClinVar ses, s oot for cohort is firmed Page 8of31 Page 9of31 MLH1 MLH1 profiling (Figure 1). The clinical characteristics characteristics clinical The 1). (Figure profiling bladder cancer). Review of 525 missense mutations u mutations missense 525 of Review cancer). bladder missense variant in in variant missense men two in mutations missense pathogenic likely two gene in 93/102 men identified two carriers of the k the of carriers two identified men 93/102 in gene (1),
variants in one of six cancer predisposition genes: predisposition cancer six of one in variants found were men Eight genes. cancer predisposing in harbore study this in men (10.8%) 102 of out Eleven among identified were variants insertion 3500 coding over in frame total, 5 In frameshift, 7 nonsense, Events Mutational Germline criteria meeting (38/40) most with familyhistory, o testing genetic clinical for criteria met cohort) >7 prostate cancer, and 30% had clinically aggressi had clinically and 30% >7cancer, prostate T Information (Supporting cancer primary additional ca primary four had 4 and cancers primary three had (76/102 majority The years. 53 was diagnosis cancer w cancer primary first of diagnosis at age mean The least at cancer, prostate with men 102 c of inclusion additional total three A of more or one meeting PALB2 PALB2 (Table 2). This man had three primary malignancies malignancies primary three had man This 2). (Table
Acceptedand (1), Article CHEK2 FGFR3 FGFR3 This article isprotected by copyright. All rights reserved. . Additional sequencing of the the of sequencing Additional . (1), with one man harboring deleterious variants in variants deleterious harboring man one with (1), Cancer 9 9 of this study population are described in Table 1. 1. Table in described are population study this of f any syndrome based on review of personal and personal of review on based syndrome any f for HBOC. forHBOC.
BRCA2 BRCA2 ve prostate cancer. Forty patients (39% of this of this (39% Forty patients vecancer. prostate nown prostate cancer risk associated G84E G84E associated cancer risk prostate nown d pathogenic or likely pathogenic mutations mutations pathogenic likely or pathogenic d riteria were selected for germline mutation mutation germline for selected were riteria sing Clinvar resulted in the identification of identification the in resulted Clinvar sing s or deletions, and 525 missense variants. variants. missense 525 and deletions, or s able 2). Over half of the men had Gleason Gleason had men the of half Over 2). able ) of patients had two primary cancers, 22 22 cancers, primary two had patients of ) as 51 years and the mean age at prostate prostate at age mean the and years 51 as cr. eaoa a te ot common most the was Melanoma ncers. who had the same likely pathogenic pathogenic likely same the had who to harbor protein truncating germline germline truncating protein harbor to HOXB13 (3 cases), (3 102 individuals tested, including 2 2 including tested, individuals 102 (prostate cancer, kidney cancer, and and cancer, kidney cancer, (prostate one additional primary cancer and and cancer primary additional one prostate cancer predisposing predisposing cancer prostate ATM ATM (2) , MLH1 MLH1 , both BRCA2 (1), BRIP1 BRIP1 and
PALB2 both both population. Protein truncating variants were found found were variants truncating Protein population. increased risk for multiple cancers in a single ind single a in cancers multiple for risk increased associated ( repair damage DNA for important is function whose with genes, cancer selected 160 of panel multi gene Discussion Discussion carrier with prostate cancer, liver cancer, and bla cancer,cancer, liver prostate carrierwith
for HBOC testing and harbored pathogenic variants i variants pathogenic harbored and testing HBOC for histo family and/or personal their on based testing w and syndrome cancer hereditary a for criteria met of the (36%) only 4/11 guidelines, genetics cancer r expert on Based 3). Table Information (Supporting germl pathogenic or deleterious a have to found not p tumor or malignancies, primary of number history, the fourth individual met criteria for HBOC and LS and HBOC for criteria met individual fourth the lee Oe f hs G4 crir as hroe a harbored also carriers G84E these of One allele. dniid eeeiu o lkl ptoei germlin pathogenic likely or deleterious identified three primary malignancies: prostate cancer, liver liver cancer, prostate threemalignancies: primary BRCA2 , and , mn mn ih rsae acr n oe r oe addi more or one and cancer prostate with men Among Men who harbored a germline mutation did not differ not did mutation germline a harbored who Men HOXB13 and AcceptedFGFR3) Article MLH1 8E lee wih a rcnl be son o e a be to shown been recently has which allele, G84E and a likely pathogenic missense mutation in one ge one in mutation missense pathogenic likely a and . The aforementioned aforementioned The . This article isprotected by copyright. All rights reserved. Cancer 10 10 HOXB13 dder cancer did not meet any criteria for testing. for any criteria meet not did cancer dder cancer, and bladder cancer. cancer,and bladder ry. Three of these four individuals met criteria criteria met individuals four these of Three ry. individuals with a pathogenic germline variant germlinevariant a pathogenic with individuals ividual, was found in two individuals with a with individuals two in found was ividual, the majority of these variants found in genes genes in found variants these of majority the in six genes ( genes six in henotypes compared to those men who were were who men those to compared henotypes testing and harbored a pathogenic variant in in variant pathogenic a harbored and testing pathogenic pathogenic DDR). In addition, the prostate cancer risk cancer prostate the addition, In DDR). n n e mutations in 10.8% of this selected selected this of 10.8% in mutations e ould have qualified for clinical genetic genetic clinical for qualified have ould eview of pedigrees using 2015 NCCN NCCN 2015 using pedigrees of eview n mtto fo or ae o genes of panel our from mutation ine ATM, BRIP1, BRIP1, ATM, G84E allele and and allele G84E with respect to age of onset, family onset, of age to respect with BRCA2 BRCA2, ATM, MLH1 ATM, BRCA2, tional primary cancers, we we cancers, primary tional and splice variant and had had and variant splice CHEK2 CHEK2 BRCA2 ne ( ne
scae wt an with ssociated CHEK2 splice variant splice respectively; , , )
BRIP1 from a from
, , Page 10of31 Page 11of31 been identified as at risk for a hereditary cancer cancer hereditary a for risk at as identified been BRCA2 and uain i mn ih eattc rsae acr un cancer prostate metastatic with men in mutations studie recent in found 8 17% of rates to similar is difference in age of onset in carriers versus non c carriers non versus in of onset age difference in crit inclusion the of one as malignancy of onset of cancer. prostate of onset of age or aggressiveness, in carriers non versus carrier in difference no was variants did not meet current criteria for clinical for criteria current meet not did variants cancer patients found 6/50 subjects harbored delete harbored subjects 6/50 found patients cancer olaparib of study II phase A inhibitors. PARP and sens tumors’ deficient DDR given treatment for also now is mutations DDR with men these Identifying 2). metas of regardless genes DDR in in mutations germline at be may cancer prostate including malignancies suggest carriers, mutation in disease aggressive or wasno there that is population study our to Unique
similarly, the majority of deleterious variants in in variants deleterious of majority the similarly, h ery dniiain f DR emie mutation germline DDR a of identification early the PN phenotype. MPMN BRCA2 Prevalence of germline mutations in this selected p selected this in mutations germline of Prevalence . The majority (7/11) of the individuals with path with individuals the of (7/11) majority The .
, with all six showing response to PARP inhibition. PARP to response showing six all with , Accepted Article 4 h ms feunl mttd ee n u suy was study our in gene mutated frequently most The This article isprotected by copyright. All rights reserved. Cancer 11 11 arriers from the study population. study the population. from arriers genetic testing and thus would likely not have have not likely would thus and testing genetic syndrome otherwise. In this pilot study, there there study, pilot this In otherwise. syndrome u suy ee n D ptwy genes. pathway DDR in were study our However, as this study selected for early age age early for selected study this as However, statistical difference in presence of metastatic metastatic of presence in difference statistical rious variants in the DDR related genes, DDR related the in variants rious terms of prostate cancer metastatic disease, disease, metastatic cancer prostate of terms s focusing on the identification of germline germline of identification the on focusing s itivity to platinum based chemotherapeutics chemotherapeutics platinum based to itivity not only important for risk assessment but but assessment risk for important only not n e wt pott cne ad MPMN and cancer prostate with men in ing that patients with multiple primary primary multiple with patients that ing tatic disease or gleason score (e.g., Figure Figure (e.g., score gleason or disease tatic ra i wud e ifcl t acran a ascertain to difficult be would it eria, in previously treated metastatic prostate prostate metastatic treated previously in eetd o fml history family for selected creased risk of harboring deleterious deleterious harboring of risk creased opulation of men with prostate cancer cancer prostate with men of opulation ogenic or likely pathogenic germline germline pathogenic likely or ogenic 9 In the era of targeted therapies, therapies, targeted of era the In h HO gene, HBOC the 9 11,24 Also . 9 11,24 ATM
BRCA2 hntp cud infcnl atr h tetet c treatment the alter significantly could phenotype deleterious deleterious c prostate with patient a 2, Figure in pedigree the heredit for testing genetic clinical for guidelines mut the of majority a that finding the and mutated, population this in useful particularly be may tests udln rcmedtos o pott cne scree cancer prostate for recommendations guideline grsie lncl phenotypes. clinical aggressive d typically and cancer, prostate for risk increased relatives, not only for prostate cancer but also ot also cancer but for prostate only not relatives, treatment and screening cancer for recommendations aberrations are in general more frequent than previ than frequent more general in are aberrations sequencing germline of studies recent multiple with are significance undetermined of variants germline comprehensiv most at ubiquitous becoming quickly is found to have this same deleterious deleterious same this have to found testing, subsequent Upon testing. genetic germline
cancer prevention. For example, men with with men example, For prevention. cancer regards in members family patient’s that for impact multiple cancers. multiple uain ares Or urn suy lo suggests also study current Our carriers. mutation Large scale tumor sequencing via comprehensive pane comprehensive via sequencing tumor scale Large h ietfcto o a ik lee ihn n indiv an within allele risk a of identification The
AcceptedBRCA2 Article uain hwvr ti poad i nt et curre meet not did proband this however, mutation; This article isprotected by copyright. All rights reserved. 6,7,25,26 These high risk prostate cancer features have led led have features cancer prostate high risk These BRCA2 Cancer BRCA2 12 12 her HBOC associated malignancies. malignancies. HBOC associated her mutation. This exemplary finding will alter alter will finding exemplary This mutation. ary cancer syndromes. For example, as seen in in seen as example, For syndromes. cancer ary sly n ale ae f ne o dsae and disease of onset of age earlier an isplay ne ad eaoa a fud o abr a harbor to found was melanoma and ancer ie te aid uo peoye, genes phenotypes, tumor varied the given ously thought and can be found in patients patients in found be can and thought ously an increasing concern. Our study is in line line in is study Our concern. increasing an to crir dd o me cret NCCN current meet not did carriers ation to risk assessment, cancer screening, and and screening, cancer assessment, risk to this patient’s unaffected brother was also also was brother unaffected patient’s this emie uain ae nw t b at be to known are mutations germline ourse and outcomes for these patients’ patients’ these for outcomes and ourse e cancer centers, and the identification of identification the and centers, cancer e ning beginning at age 40 in unaffected unaffected in 40 age at beginning ning for the proband, but also for his at risk at risk his for also but proband, the for in cancer patients showing germline germline showing patients cancer in idual with cancer also has enormous enormous has also cancer with idual ht s o mliee ae genetic panel multigene of use that ls focused on actionable mutations mutations actionable on focused ls nt clinical criteria for for criteria clinical nt to to Page 12of31 Page 13of31 pathogenic or likely pathogenic mutations in the pa the in mutations pathogenic likely or pathogenic rvlne n hs ouain a b underestimated be may population this in prevalence pat our Clinvar, in pathogenic likely or pathogenic oeta sotoig i cret lncl genetic clinical current in shortcomings potential that the vast majority of this selected patient pop patient selected this of majority vast the that n genes in harbored variants pathogenic any reflect isne ains o ny hs rfrne wt sup with referenced those only to variants missense deleteriou for selecting used we criteria stringent of variants missense including significance unknown studie sequencing whole exome panel large most with Clinvar and thus was not included in our pathogenic our in included not was thus and Clinvar cance prostate in pathogenicity its cancer, ovarian incre to shown been has variant this while however,
For example, a K3326X stop gain variant in in variant gain stop K3326X a example, For whic impact, pathogenic clinical its determining in m germline a on rely We phenotype. tumor(s)’ the on a there novel, are study our findings of the While b to sequencing somatic paired of lack the and size algorithm decision the to add to beneficial may be dise of age early cancers, primary multiple as such Additional testing. mutation germline pursue should canc family and personal specific of constellations cos g gop ad uo tps eades f fam of regardless types tumor and groups age across Accepted Article This article isprotected by copyright. All rights reserved. Cancer BRCA2 BRCA2 13 13 ulation in the study (~90%) were negative for for negative were (~90%) study the in ulation for germline testing in prostate cancer. cancer. prostate in germlinefortesting r is less clear and is categorized as benign in in benign as categorized is and clear less is r hogenic or likely pathogenic germline variant variant germline pathogenic likely or hogenic er histories to decide whether or not a patient patient a not or whether decide to histories er ot tested in this panel. It should also be noted noted be also should It panel. this in tested ot etter determine a pathogenic variant’s impact impact variant’s pathogenic a determine etter s functional mutations, including restricting restricting including mutations, functional s h does not always align across tumor types. types. tumor across align always not does h ase onset, and/or rare/aggressive histologies histologies rare/aggressive and/or onset, ase nel of cancer associated genes; in addition, addition, in genes; associated cancer of nel carrier rate for this study. this for rate carrier testing practices, which rely primarily on on primarily rely which practices, testing parameters independent of family history, history, family of independent parameters was found in two individuals in this study; this in individuals two in found was utation’s putative functional changes to aid aid to changes functional putative utation’s l history. ily ase the risk of developing breast and/or and/or breast developing of risk the ase . The reported prevalence also does not not does also prevalence reported The . re limitations including the small sample sample small the including limitations re nnw ciia ipc. ie the Given impact. clinical unknown porting evidence as cancer associated cancer associated as evidence porting , hr i a ih ae f ains of variants of rate high a is there s, 17,27 30 hs suis highlight studies These 31 In addition, as addition, In
ahgnss f ifrn tmr ye, lo fr ta for allow types, tumor mo different of underlying pathogenesis the of understanding better a provide eern gns Hwvr tee niiul ad the and individuals these However, genes. penetrant does not typically cover genetic testing for patien for testing genetic cover typically not does ca hereditary for criteria clinical current meeting warrant andthus variants germline for enriched are an cancer, early onset phenotype, MPMN a with those show have studies, germline recent other with along ear from benefit would that groups high risk define currently recommended in the general US population US general the in recommended currently unaffected in screening prostate prompt could that fa their and patients cancer prostate for important
germline variants is warranted. warranted. is variants germline prostat with of men population this in andoutcomes variants in unique subgroups of men with prostate c prostate with men of subgroups unique in variants there were individuals who were discovered to have have to discovered were who individuals were there oeua ptooy ad scooil ae o disc tests. genetic these interpreting for care psychosocial and pathology, incor molecular that patients cancer in testing and screening nec the highlight and risk cancer of families their ethic and clinical potential the highlight findings wa and cancers other or prostate for risk increased Accepted penet Article and prevalence the qualifying and Quantifying This article isprotected by copyright. All rights reserved. Cancer 14 14 al dilemmas for how to best inform patients and patients inform best to how for dilemmas al essity of a multidisciplinary approach to genetic genetic to approach multidisciplinary a of essity ts outside of guideline criteria. It is particularl is It criteria. guideline of outside ts milies to identify heritable pathogenic variants variants pathogenic heritable identify to milies consideration for genetic testing regardless of of regardless testing genetic for consideration ncer syndromes. However, health insurance insurance health However, syndromes. ncer ancer and multiple primary malignancies will will malignancies primary multiple and ancer e cancer and MPMNs who harbor deleterious harbor who deleterious and MPMNs ecancer novel mutations or mutations in moderately in mutations or mutations novel 32 rn lniuia cne sreig These screening. cancer longitudinal rrant rgeted therapeutic approaches, and better better and approaches, therapeutic rgeted ta cran lncl ouain sc as such populations clinical certain that n ly screening and intervention. Our study, study, Our intervention. and screening ly carriers screening that is otherwise not not otherwise is that screening carriers . Future larger studies to better define risk risk define better to studies larger Future . d/or metastatic/aggressive prostate cancer cancer prostate metastatic/aggressive d/or porates genetic counselors, physicians, physicians, counselors, genetic porates ir family members may still have an an have still may members family ir ussing, consenting, performing, and and performing, consenting, ussing, eua aertos novd n the in involved aberrations lecular rance of pathogenic germline germline pathogenic of rance y Page 14of31 Page 15of31
1. Ewing CM, Ray AM, Lange EM, et al. Germline muta Germline al. et Lange AM, EM, Ray EwingCM, 1. References 2. Xu J, Lange EM, Lu L, et al. HOXB13 al. a suscept is et L,LuLange J, Xu EM, 2. 3. Beebe Dimmer JL, Hathcock M, Yee C, et al. The H The al. et C, Yee M, Hathcock Beebe DimmerJL, 3. 4. Hoffmann TJ, Sakoda LC, Shen L,Imputatio Shen al. et LC, Sakoda HoffmannTJ, 4. 5. Laitinen VH, Wahlfors T, Saaristo L,HOXB al. et Saaristo T, Wahlfors LaitinenVH, 5. 8. Gleicher S, Kauffman EC, Kotula L,G Bratslavsky Kotula EC, Kauffman GleicherS, 8. 6. Castro E, Goh C, Leongamornlert D, et al. Effect al. etD, Leongamornlert C, Goh E, Castro 6. 7. Castro E, Goh C, Olmos D, et al. Germline BRCA m BRCA Germline al. etD, Olmos C, Goh E, Castro 7. Epidemiol Biomarkers Prev. Prev. Biomarkers Epidemiol population based analysis of prostate, breast, and breast, of prostate, analysis population based Epidemiol Biomarkers Prev. Prev. Biomarkers Epidemiol cancer risk. cancerrisk. 2013;132(1):5 14. 2013;132(1):5 14. from the International Consortium for Prostate Canc for Prostate Consortium International the from and cancer risk in a large population based cohort. population based a large in risk andcancer Associated with an Increased Risk for Prostate Canc for Prostate IncreasedRisk an with Associated Rates of Metastatic Prostate Cancer in BRCA2 Mutati BRCA2 in Cancer Prostate of Metastatic Rates cancer. and metastasis, distant involvement, of nodal risk 2016;76(13):1135 1145. 2016;76(13):1135 1145. AcceptedCancer. T After Radical Survival and Cause specific Relapse Article J Clin Oncol. Oncol. JClin Eur Urol. Urol. Eur N Engl J Med. J Med. Engl N This article isprotected by copyright. All rights reserved. 2015;68(2):186 193. 2015;68(2):186 193. 2013;31(14):1748 1757. 2013;31(14):1748 1757. 2012;366(2):141 149. 2012;366(2):141 149. 2015;24(9):1366 1372. 2015;24(9):1366 1372. 2013;22(3):452 460. 2013;22(3):452 460. Cancer 15 15 of BRCA Mutations on Metastatic Metastatic on Mutations ofBRCA colorectal cancer risk. cancerrisk. colorectal poor survival outcomes in prostate prostate in outcomes survival poor
13 G84E mutation in Finland: Finland: in mutation G84E 13 n of the rare HOXB13 G84E mutation mutation G84E rareofHOXB13 the n ibility gene for prostate cancer: results cancer:results genefor ibility prostate PLoS Genet. PLoS , Vourganti S. Implications of HighImplications S. Vourganti , er Genetics (ICPCG). (ICPCG). erGenetics er and Other Malignancies. OtherMalignancies. erand OXB13 G84E Mutation Is Mutation G84E OXB13 reatment for Localised Prostate Prostate Localised reatmentfor utations are associated with higher with are associated utations on Carriers. on tions in HOXB13 and prostate HOXB13 in and tions 2015;11(1):e1004930. 2015;11(1):e1004930. Prostate. Prostate. Cancer Cancer Hum Genet.Hum Cancer Cancer
. Mateo J, Carreira S, Sandhu S, et al. DNA Repair al. et S, Carreira Sandhu S, J, Mateo . 0. Pritchard CC, Mateo J, Walsh MF, et al. InheritMF, al. et Walsh J, Mateo CC, Pritchard 0. 5. Rosso S, De Angelis R, Ciccolallo L,Mul al. et Ciccolallo De Angelis S, R, Rosso 5. 1. Robinson D, Van Allen EM, Wu YM, et al. Integra al. et YM, Wu EM, VanD, Allen Robinson 1. 6. Xu LL, Gu KS. Clinical retrospective analysis o analysis retrospective LL,Clinical KS. Gu Xu 6. 4. Stadler ZK, Schrader KA, Vijai J, Robson Of ME, Robson J, Vijai KA, Schrader ZK, Stadler 4. 9. Whitworth J, Hoffman J, Chapman C, et al. Acli al. et C, Chapman Hoffman J, J, Whitworth 9. 7. Mitchell G, Ballinger ML, Wong S, et al. High f High al. et S, Wong BallingerG, ML, Mitchell 7. 3. Haraldsdottir S, Hampel H, Wei L, Prosta Wei H, al. et Hampel S, Haraldsdottir 3. 2. Raymond VM, Mukherjee B, Wang F,Elevate al. et B, Wang Mukherjee RaymondVM, 2. 8. Ballinger ML, Goode DL, Ray Coquard I,M al. et Ray Coquard DL, Goode Ballinger ML, 8. prostate cancer. prostate primary cancer referrals to genetics services. services. genetics to referrals cancer primary Prostate Cancer. Prostate with Metastatic Prostate Cancer. Prostate Metastatic with Cancer. Cancer. neoplasms. neoplasms. risk. risk. syndrome. a prospective adult onset sarcoma cohort. cohort. sarcoma adult onset a prospective with Lynch with syndrome. of sarcoma risk: an international genetic study. genetic study. an international risk: ofsarcoma
Accepted Oncol. JClin Article 2009;45(6):1080 1094. 2009;45(6):1080 1094. Genet Med. Genet Genet Mol Res. Genet Res. Mol Cell. Cell. N Engl J Med. Engl N This article isprotected by copyright. All rights reserved. 2014;32(7):687 698. 2014;32(7):687 698. 2015;161(5):1215 1228. 2015;161(5):1215 1228. J Clin Oncol. Oncol. Clin J 2014;16(7):553 557. 2014;16(7):553 557. 2014;13(4):9271 9284. 2014;13(4):9271 9284. 2015;373(18):1697 1708. 2015;373(18):1697 1708. N Engl J Med. J Med. Engl N 2013;31(14):1713 1718. 2013;31(14):1713 1718. Cancer 16 16 PLoS One. One. PLoS Eur J Hum Genet. Hum J Eur te cancer incidence in males with Lynch with males in cancerincidence te Lancet Oncol. Oncol. Lancet tiple tumours in survival estimates. estimates. survival in tumours tiple ed DNA Repair Gene Mutations in Men Men in Mutations Gene DNA Repair ed f cases with multiple primary malignant primarymalignant multiple with fcases 2016. 2016. requency of germline TP53 mutations in in mutations TP53 germline of requency nical and genetic analysis of multiple multiple of geneticanalysis and nical Defects and Olaparib in Metastatic Metastatic in and Olaparib Defects fit K. Cancer genomics and inherited inherited and genomics CancerK. fit onogenic and polygenic determinants determinants and polygenic onogenic tive clinical genomics of advanced ofadvanced genomics clinical tive d risk of prostate cancer among men among men cancer of prostate risk d 2013;8(7):e69026. 2013;8(7):e69026. 2016;17(9):1261 1271. 2016;17(9):1261 1271. 2015;23(5):581 587. 2015;23(5):581 587. Eur J Eur Page 16of31 Page 17of31 5. Maier C, Herkommer K, Luedeke M, Rinckleb A, Sc A, LuedekeRinckleb M, K, Herkommer MaierC, 5.
0. Chang X, Wang K. wANNOVAR: annotating geneticv annotating wANNOVAR: K. ChangWang X, 0. 7. Meric Bernstam F, Brusco L, Daniels M, et al. I L, al. et M, Brusco Daniels F, Meric Bernstam 7. 6. Na R, Zheng SL, Han M, et al. Germline Mutation Germline al. et Han M, SL, Zheng NaR, 6. 1. Harrison SM, Riggs ER, Maglott DR, et al. Using al. et DR, Maglott ER, Riggs HarrisonSM, 1. 2. Rehm HL, Berg JS, Brooks LD,Brooks ClinGen th al. et JS, Berg HL, Rehm 2. 4. Hart SN, Ellingson MS, Schahl K, et al. Determi al. etK, Schahl MS, Ellingson HartSN, 4. 3. Richards S, Aziz N, Bale S, et al. Standards an Bale N, Standards al. et S, Aziz S, Richards 3. Eur Urol. Urol. Eur Med. Med. cancer. sequencing patients in exome from variants germline mutations. mutations. consid with cancer prostate and aggressive familial the web. the advanced cancers on a prospective somatic genomic p genomic somatic a prospective cancers on advanced Risk for Lethal and Indolent Prostate Cancer and ar Cancer Prostate Indolent Lethalfor and Risk Variant Interpretation. Interpretation. Variant 2016;27(5):795 800. 2016;27(5):795 800. Medical Genetics and Genomics and the Association f Association and the and Genomics Genetics Medical recommendation consensus a joint sequencevariants: 2015;17(5):405 424. 2015;17(5):405 424. Accepted Article 2015;372(23):2235 2242. BMJ Open. BMJ J Med Genet. Genet. J Med 2016. 2016. Prostate. Prostate. This article isprotected by copyright. All rights reserved. 2016;6(4):e010332. 2016;6(4):e010332. 2014;74(14):1444 1451. 2014;74(14):1444 1451. Curr Protoc Hum Genet. Hum Protoc Curr 2012;49(7):433 436. 2012;49(7):433 436. Cancer 17 17 d guidelines for the interpretation of for interpretation the guidelines d ncidental germline variants in 1000 1000 in variants germline ncidental 2016;89:8 16 11 18 16 23. 23. 16 11 18 16 2016;89:8 ning the frequency of pathogenic of pathogenic ningfrequency the ClinVar as a Resource to Support Support to as a Resource ClinVar e Clinical Genome Resource. Genome Resource. eClinical s in ATM and BRCA1/2 Distinguish Distinguish and BRCA1/2 ATM in s erable frequencies of BRCA2 BRCA2 of frequencies erable e Associated with Early Age at Death. AgeDeath. at Early with e Associated with castrate resistant prostate prostate castrate resistant with hrader M, Vogel W. Subgroups of of Subgroups W. Vogel hrader M, of the American College of College American of the rofiling protocol. rofiling protocol. or Molecular Pathology. Pathology. orMolecular ariants for personal genomes via via genomes personal for ariants Ann Oncol. Oncol. Ann Genet Genet N Engl J Engl N
2. Jemal A, Fedewa SA, Ma J, et al. Prostate Cance Prostate al. et J, Ma FedewaA, SA, Jemal 2. 9. Schrader KA, Cheng DT, Joseph V, et al. Germlin al. etV, Joseph DT, KA,Cheng Schrader 9.
8. Mork ME, You YN, Ying J, et al. High al. et Prevalence J, YN, Ying You ME, Mork 8.
1. Meeks HD, Song H, Michailidou K, et al. BRCA2 P BRCA2 al. etK, Michailidou H, MeeksHD, Song 1. 0. Zhang J, Walsh MF, Wu G, et al. Germline Mutati Germline al. etG, MF, Wu Walsh ZhangJ, 0. Adolescents and Young Adults With Cancer Colorectal With Adults and Young Adolescents 3549. 3549. Relation to USPSTF Screening Recommendations. ScreeningRecommendations. USPSTF to Relation Sequencing Using Matched Normal DNA. DNA. Normal Matched Using Sequencing Pediatric Cancer. Cancer. Pediatric Accepted Article Cancers. and Ovarian Prostate, of Breast, Risk the N Engl J Med. Engl N This article isprotected by copyright. All rights reserved. 2015;373(24):2336 2346. 2015;373(24):2336 2346. Cancer 18 18 JAMA Oncol. Oncol. JAMA r Incidence and PSA Testing Patterns in in Testing IncidencePatterns and PSA r e Variants in Targeted Tumor Tumor Targeted eVariants in ons in Predisposition Genes in Predisposition in ons J Natl Cancer Inst. Inst. Cancer J Natl of Hereditary Cancer Syndromes in in Syndromes Cancer of Hereditary JAMA. olymorphic Stop Codon K3326X and K3326X Codon olymorphicStop . . J Clin Oncol. Oncol. JClin 2016;2(1):104 111. 2016;2(1):104 111. 2015;314(19):2054 2061. 2015;314(19):2054 2061. 2016;108(2). 2016;108(2). 2015;33(31):3544 Page 18of31 Page 19of31 primary malignant neoplasm phenotype. H&N= head &n H&N=head phenotype. neoplasm malignant primary Figure2. a single in individual. malignancies more primary sarc cancer, pancreatic rarecancers including with men. Criteria included: 1) early age of onset of fi ageof onset early 1) included: Criteria men. Figure 1. FigureLegends Pedigree analysis of proband with BRCA2 q1429fs ge q1429fs BRCA2 of with proband analysis Pedigree Accepted Articlec qualifying the inclusion summarizing Venndiagram This article isprotected by copyright. All rights reserved. Cancer 19 19 rst malignancy (<55 years 2) diagnosed old), (<55 malignancy rst oma, male breast cancer and/or 3) three or 3) and/or three cancer breast male oma, eck cancer. cancer. eck riteria of the final cohort of 102 of cohort 102 final of the riteria rmline mutation and multiple and multiple mutation rmline
N(percentage) N(percentage) N(percentage) N(percentage) PSA>15ng/ml, sum=7Gleason PSA>10 pre-diagnosis and the following of Gleason criteria: sum>7,tumor sta Table 1. 1. Table € Aggressive Clinically Cancer Prostate Syndrome Cancer Criteria (includingprostate cancer) number Total of multiple primaries Score Gleason Median (range) at diagnosis PSA (percentage) Race Median (range) Age at diagnosis at Age years in more or additional primarycancers. syndrome),LF(Li-Fraumeni); genetic clinical testing for: HBOC brea (hereditary PSA=prostate specific PSA=prostate antigen;
Accepted Article Clinical& pedigree features forthe cohort of 102 €
This article isprotected by copyright. All rights reserved. ¶
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Cancer stand ovarian cancer),LS (Lynch ge or T3b pre-diagnosisT4, Three primary Three malignancies: Two primary Two malignancies: Four primary Four malignancies: ng/ml,at diagnosis. M1 N1or men prostatecancer with and one Prostate Cancer: Prostate African American: African First Cancer: First Caucasian: Caucasian: HBOC: HBOC: None: None: Any: Any: 5.6 (1.0-75.5) 5.6 >7: <7: LF: LS: 53 53 (31-84) eting one 50 (56.8) 50 38 (43.2) 38 76 76 (74.5) 51(5-76) 31 (30.4) 31 40 (39.2) 40 22 22 (21.6) 96 96 (94.1) 38 (37.3) 38 62 62 (60.8) 6 (5.9) 6 (2.0) 2 6(5.9) 4 4 (3.9) r r
Page 20of31 Page 21of31
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Venn diagram summarizingdiagram Venn qualifying the inclusion c pancreatic cancer, sarcoma, and/ cancer, cancer malebreast pancreatic Accepted(<55 firstyear of 1) onset malignancy early of age Article This article isprotected by copyright. All rights reserved. 78x75mm (600 x 600 DPI) (600 60078x75mm DPI) x individual. individual. Cancer riteria of the final cohort of 102 men. Criteria 102men. of finalin the cohort of riteria
or 3)threesingl malignancies orin more a primary s old), s 2) diagnosed with rare cancers including
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Accepted Articleq1429fs ger Pedigreeprobandwith BRCA2 of analysis This article isprotected by copyright. All rights reserved. neoplasm phenotype. H&N= head & neck cancer. neck H&N=phenotype. neoplasm & head 75x33mm (600 x 600 DPI) (600 60075x33mm DPI) x Cancer
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CTNNA1 CSF1R CRLF2 CREBBP CIC CHEK2 CEBPA CDKN2A CDK4 CDK12 CDH1 CDC73 CD79B CD79A CBLB CBL CASP8 CARD11 BUB1B BTK BRIP1 BRCA2 BRCA1 BRAF BCOR BCL6 BAP1 ATRX ATM ASXL1 ARID2 ARID1A AR APC AMER1 ALK AKT3 AKT2 AKT1 ABL1 ABCC1 DNAseq CCPversions1and2. Genes includedintheQiagenGeneRead Supporting InformationTable1. Gene Included in Version 1 yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Acceptedyes yes Article Included in Version 2 This article isprotected by copyright. All rights reserved. yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Cancer Page 24of31 Page 25of31 H3F3A GRIN2A GPC3 GNAS GNAQ GNA11 GATA3 GATA2 GATA1 FUBP1 FOXL2 FLT4 FLT3 FLT1 FLCN FKBP9 FIGF FH FGFR3 FGFR2 FGFR1 FBXW7 FBXO11 FAS FANCE FANCD2 FANCA FAM46C FAM123B EZH2 ESR1 ERCC5 ERBB4 ERBB3 ERBB2 EPCAM EP300 EGFR ECT2L DNMT3A DICER1 DDR2 DDB2 DAXX CYLD CTSL1 CTNNB1 yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Acceptedyes yes yes Article This article isprotected by copyright. All rights reserved. yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Cancer
NRAS NPM1 NOTCH2 NOTCH1 NOS1 NFKBIA NFE2L2 NF2 NF1 MYD88 MYC MUTYH MTOR MSH6 MSH2 MPL MLH1 MET MEN1 MED12 MDM2 MAP4K3 MAP3K1 MAP2K4 MAP2K2 MAP2K1 KRAS KMT2D KLF6 KIT KDR KDM6A JAK3 JAK2 JAK1 IL7R IL6ST IKZF1 IGF2R IDH2 IDH1 HSPH1 HSP90B1 HRAS HNF1A HIST1H3B HDAC4 yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Acceptedyes yes Article This article isprotected by copyright. All rights reserved. yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Cancer Page 26of31 Page 27of31 TNFAIP3 TGFBR2 TET2 TERT SUFU STK11 SRC SPOP SOCS1 SMO SMARCB1 SMARCA4 SMAD4 SMAD2 SLC7A8 SF3B1 SETD2 SDHB RUNX1 ROS1 RET RB1 RAC1 PTPRC PTPN11 PTGS2 PTEN PTCH1 PRKCE PRKAR1A PRDM1 PPP2R1A POLR3A PMS2 PIK3R5 PIK3R1 PIK3CA PIK3C2A PHF6 PDGFRB PDGFRA PBRM1 PAX5 PARP4 PARP1 PALB2 NTN3 yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Acceptedyes yes yes yes Article This article isprotected by copyright. All rights reserved. yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes Cancer
ZRSR2 ZNF2 XPO1 XPC WT1 VHL U2AF1 TSHR TSC2 TSC1 TRRAP TP53 TOP1 TNKS TNFRSF14 yes yes Accepted Articleyes yes yes yes yes yes This article isprotected by copyright. All rights reserved. yes yes yes yes yes yes yes yes yes yes yes Cancer Page 28of31 Page 29of31 cancer. InformationSupporting 2. Table Additional Primary Cancers Number of Subjects Number Additional PrimaryCancers Renal cancer & Thyroid 1 1 1 1 1 Thyroid Testicular 1 & Renal cancer Thyroid & SarcomaRenal cancer (2 primaries) Parathyroid 1 Pancreas 1 1 AcceptedMelanomacancer & Renal Melanoma & Mantle cell Thyroid Lymphomacancer & Renal 5 Lymphoma 1 Lung && Melanoma Pancreas 1 Lung&& Melanoma Sarcoma 1 Lung Liposarcoma 1 1 Kidney& Melanoma 1 Kidney Hodgkins 1 Neckand Head & Sarcoma Neckand Head primaries)& (2 Thyroid Neckand Head & Lung Neckand Head 1 2 & Esophagus Pancreas 1 1 2 Esophagus Colon/rectum& Lung 3 & Colon cord Vocal ArticleColon 1 1 bowelCarcinoid,small Brain-Glioblastoma& Melanoma Brain Bone & Bladder Melanoma 1 & Bladder Lymphoma & Bladder Lung & Bladder Liver & Bladder Kidney & Bladder Esophageal & Bladder Colon Bladder Atypical fibroushistiocytoma This article isprotected by copyright. All rights reserved. Additional primary in of the 102cohort cancers men Cancer 28 28 3 3 4 1 4 1 4 1 5 1 3 5 2 1 6 with prostate with
Accepted Article This article isprotected by copyright. All rights reserved. Cancer Page 30of31 Page 31of
non-carriers. versus diagnosis PSA; ****N=88 PSA; diagnosis samples with total availabl t-test;*Two **Fisher’s sided exact ***N=83test; t (N/%) Criteria Clinical Testing for of Cancers Number Aggressive Clinically PC Ancestry Score Gleason Pre-DxPSA*** (median/range) Dx at Age Cancer of Prostate InformationSupporting No 62 (60.8) 7 (63.6) 56 (61.5) 56 (63.6) 7 (60.8) 62 (70.3) 64 (63.6) 7 (69.6) 71 No No Yes 40 (39.2) 4 (36.4) 35 (38.5) 1** 1** (38.5) 35 (36.4) 4 0.4649** (75.8) 69 (39.2) 40 (24.2) 22 (63.6) 7 0.7316** (36.4) 4 (29.7) 27 (74.5) 76 (5.5) 5 (25.5) 26 (36.4) 4 (7.8) 6 (30.4) 31 (9.1) 1 0.5050** (94.5) 86 (51.9) 40 0.5158**(9.1) 1 Yes 31(40.2) (5.9) 6 (90.9) 10 (36.4) 4 (8.0) 7 (54.5) 6 (94.1) 96 more or 3 (48.9) 43 2 (43.2) 38 Yes African European >7 7 <7
(N/%)
Accepted Article (N/%)****
(median/range) (N/%) Table Table This article isprotected by copyright. All rights reserved. (N/%)
3
. Clinicopathologic characteristicsof mutation carr
All Samples All 3(18) 4(67) 3(18) 0.8750* (31-84) 53 (46-71) 54 (31-84) 53 (N=102) 5.55 (1- 5.55 75.56)
Cancer
otalwith availablesamples pre- 1 1 5.5 (3.47- 5.5 escore. Gleason Carriers Carriers (N=11) 21.4) Carriers Carriers (N=91) 5.6 (1- 5.6 75.56) Non
0.6498* PValue iers iers