The Role of Gene Fusions in Melanocytic Neoplasms

Home , CRTC1, DYNC1I2, ERC1, KHDRBS1, MAP3K3, MAP3K8

Received: 26 April 2019 Revised: 28 May 2019 Accepted: 29 May 2019 DOI: 10.1111/cup.13521

REVIEW

The role of gene fusions in melanocytic neoplasms

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Abstract Chicago, Illinois Recent advances in next generation sequencing (NGS) have allowed for efficient whole

Correspondence transcriptome sequencing, leading to the identification of important kinase fusions as Pedram Gerami, MD, Department of the primary driver in some melanocytic neoplasms. These fusions typically occur mutu- Dermatology, Northwestern University, 676 North St. Clair Street, Suite 1765, ally exclusively of one another and other well-known initiating mutations such as BRAF, Chicago, IL 60611. NRAS, NF1, KIT,andGNAQ. Fusions are found in over 50% of Spitz neoplasms, including Email: [email protected] ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8,andRET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS,orNF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are cost- effective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies.

KEYWORDS fusions, genomics, melanocytic lesions, melanoma, spitzoid

1 | INTRODUCTION Spitz tumors as those harboring activating mutations in HRAS or kinase fusions.2 Familiarity with the morphologic features typical of specific Recent advances in next generation sequencing (NGS) have allowed for fusion-driven melanocytic neoplasms can help with (a) classification and efficient whole transcriptome sequencing of melanocytic tumors, yielding diagnosis and (b) identification of targeted therapeutic options in some the identification of many important kinase fusions as the primary driver malignant fusion-driven melanocytic neoplasms. In this review, we in some cases. Kinase fusions are a common initiating genomic event describe recent discoveries regarding the role of kinase fusions in various across many cancers and are critical targets for molecular therapy.1 Cer- subgroups of melanocytic neoplasms and their associated morphologies. tain classes of melanocytic neoplasms such as Spitz tumors and pigmented epithelioid melanocytomas (PEMs) are highly enriched with kinase fusions but other classes, including melanomas, have much less frequent involve- 2 | MECHANISM OF FUSIONS ment by fusions. The newest WHO Classification of Skin Tumors defines Kinase fusions result from genomic rearrangements: (a) translocations,

Victor L. Quan and Elnaz Panah should be considered joint authors. (b) inversions, (c) deletions, (d) duplications, or (e) complex

878 wileyonlinelibrary.com/journal/cup J Cutan Pathol. 2019;46:878–887. QUAN ET AL. 879 rearrangements3,4 (Figure 1). NTRK1 fusions typically arise by small dele- involvement (Table 1). As these fusions can be seen across the entire tions. The AGK-BRAF fusion arises through an inversion. However, spectrum of Spitz melanocytic neoplasms, their presence does not help in because most studies are RNA-based, many of the precise genomic discerning an AST from Spitz melanoma. However, awareness of their mechanisms are not yet characterized. The resulting fusion transcript presence or absence can help determine whether to classify a case in a encodes a chimeric protein with loss of a regulatory domain of the native Spitz category versus a non-Spitz category. For example, if the differential gene and, in some cases, addition of an oligomerization domain, leading diagnosis is AST vs nevoid melanoma, the presence of a characteristic to constitutive activation of the kinase domain. Most fusions have been fusion of Spitz tumors favors AST while a BRAF or NRAS mutation favors identified with a variety of N-terminal partners. Kinase genes identified in a nevoid melanoma. In addition, different fusions vary in their likelihood these fusions include ALK, MET, RET, ROS1, NTRK1, NTRK3, BRAF, of causing a melanocytic tumor to progress to full malignant transforma- MAP3K8, MAP3K3,andPRKCA and increase activation of downstream tion. For example, while the vast majority of Spitz neoplasms with ALK, Ras-Raf-MEK-ERK, PI3K-Akt, and PLC pathways to promote cellular pro- NTRK1, NTRK3, RET, and ROS1 fusions are diagnosed as either Spitz nevus or ASTs, with only a small percentage diagnosed as Spitz mela- liferation and migration. These fusions typically occur mutually exclu- noma, a significantly greater proportion of BRAF, MET, andinparticular, sively of one another and other well-known initiating driver mutations in MAP3K8 fusions are diagnosed as Spitz melanoma. Two recent indepen- melanocytic neoplasia such as BRAF, NRAS, NF1, KIT, GNAQ, GNA11, dent publications identified MAP3K8 fusions as the most common fusion and HRAS. in Spitz melanomas.6

3 | SPITZ NEOPLASMS 3.1 | ALK

Spitz neoplasms including Spitz nevi, atypical Spitz nevi, atypical Spitz ALK fusions are found in over 10% to 20% of Spitz nevi and ASTs and tumors (ASTs), and Spitz melanomas are predominantly fusion-driven. approximately 1% of Spitz melanomas.4,5,7-11 ALK fusions have also been Wiesner et al5 described mutually exclusive fusions in over 50% of found in plexiform areas of melanocytic myxoid spindle cell tumors, as 140 Spitz neoplasms. The kinase component of the fusions found in Spitz well as some cases of acral melanoma.12,13 Spitz tumors with ALK fusions neoplasms to date include ALK, MET, RET, ROS, NTRK1, NTRK3, BRAF, tend to be large, solitary dome-shaped papules or nodules found on the MAP3K3,andMAP3K8. Some fusions appear to have highly characteristic extremity of young patients. Clinically, the differential includes irritated morphologic features allowing familiar pathologists to anticipate their nevus, molluscum, or pyogenic granuloma.4,8,10 The most characteristic

FIGURE 1 Mechanisms for kinase gene fusion events in melanocytic neoplasms. Each colored segment (red, purple, green, orange) represents a distinct gene on the chromosome, and the blue segment denotes a kinase gene. Fusions (F) may result from translocation, inversion, deletion, and duplication events or other complex rearrangements. In other cases, chromothripsis may also produce a fusion. Because most studies are RNA-based, many of the precise genomic mechanisms are unknown. Most fusions have a variety of N-terminal partners. A segment of a kinase (K) gene is transcribed in-frame with another gene, resulting in the production of a new fusion transcript. After the fusion transcript is translated into a chimeric protein, the loss of the regulatory (R) or autoinhibitory domain of the native kinase gene leads to overexpression of the kinase. An example of a chimeric protein structure is shown, consisting of exons 1-7 of TPM3 (in orange) containing a transmembrane (TM) domain towards the N-terminus joined to exons 20-29 of ALK (in blue) containing a kinase domain at the C-terminal end TABLE 1 Fusion genes in melanocytic neoplasia with associated subtypes and key clinical and morphologic characteristics 880

Fusion gene Subtypes 5’ partners 3’ partners Associated characteristics ALK Spitz nevus, AST TPM3, DCTN1, GTF3C2, NPM1, CLIP1, - Large diameter lesions TRR, FBXO27, Spitz melanoma (infrequently) PPFIBP1, MLPH, NPAS2 - Fascicles of wavy to fusiform melanocytes with wedge-shaped and plexiform growth. Occasionally with a dumbbell-shaped base Acral melanoma SDHA -- BRAF Spitz nevus, AST CEP89, LSM14A, SOX6 - Sheet-like growth of epithelioid melanocytes, disorganized nesting Spitz melanoma MAD1L1, AGK, TRIM24, DYNC1I2, - May be more likely to progress to Spitz AKAP9, ZKSCAN1, AGK, MZT1, CUX1, melanoma SLC12A7 Melanoma, various types KCTD7, ZSCAN5, AGK, KIAA1549, - May be driver in 8% to 22% of pan- including superficial spreading, ZSCAN5, PLIN3, PAPSS1, TRIM24, negative melanomas acral, mucosal, metastatic, CDC27, TAX1BP1, AGT7, GTF21, unknown primary ARMC10, ERC1, CNTNAP2 Unclassified sclerosing melanomas AKAP9 - Deeply infiltrating melanocytes with sclerotic stroma Large CMN FCHSD1 -- MAP3K3 Spitz nevus, AST ATP2A2 -- MAP3K8 AST - DIP2C, UBL3, SVIL, PCDH7, High grade epithelioid melanocytes with Spitz melanoma STX7, SPECC1, PRKACB, focal or extensive pigment CUBN Higher proportion of Spitz melanomas (~20%) Acral melanoma (rarely) - DEK - MET AST ZKSCAN1, PPFIBP1, LRRFIP1, TRIM4, - Large junctional nests Spitz melanoma DCTN1, EPS15 NTRK1 Spitz nevus, AST LMNA, TP53, TPM3, KHDRBS1 - Small spindled melanocytes in rosettes or Spitz melanoma (infrequently) lobulated nests with Kamino bodies RET Spitz nevus, AST GOLGA5, KIF5B -- Spitz melanoma (infrequently) PSCN of Reed (infrequently) MYO5A -- ROS1 Spitz nevus, AST CLIP1, 2PPFIBP1, TPM3, ZCCHC8, -- Spitz melanoma (infrequently) MYO5A, 2PWWP2A, HLA-A, ERC1, KIAA1598 PSCN of Reed (infrequently) MYO5A -- QUAN NTRK3 Spitz nevus, AST ETV6, MYO5A, MYH9 - Predominantly spindled melanocytes

(Continues) AL ET . QUAN ET AL. 881

morphology includes fascicles of amelanotic wavy to fusiform and spindled melanocytes with a wedge-shaped and plexiform growth pattern (Figure 2).4,7,8 In a series of 49 Spitz tumors, over 20% of ALK fusion cases had a diameter > 10.5 mm compared with none of the cases with NTRK1, RET, BRAF,ornofusion.7 Cases with ALK fusions commonly have mild to moderate nuclear atypia and no Kamino bodies. Immunohisto- chemistry (IHC) is a relatively reliable diagnostic screening tool for ALK fusions.7,8,11 fluorescence in situ hybridization (FISH) studies using a break apart probe for the ALK gene or NGS can be used for further confirmation. confluent nests and fascicles with atypical spindled and epithelioid melanocytes; may be cutaneous subtype of clear cell sarcoma pigmented epithelioid melanocytes with adnexal involvement Sheet-like growth of monomorphic 3.2 | BRAF

BRAF encodes a cytoplasmic serine/threonine kinase upstream of ERK/MEK in the MAPK pathway. Although BRAF mutations are frequent in common nevi and cutaneous melanomas, BRAF fusions are less frequent.14 They are found in 5% of Spitz neoplasms.5,7,15,16 Spitz tumors with BRAF fusions often have a sheet-like growth pattern of intermediate to large epithelioid melanocytes with high grade nuclear atypia. Nesting is less organized and cells may disperse into single cells within a 7 7

partners Associated characteristics sclerotic stroma. Amin et al found 3/14 (24%) cases with a diagnosis of ’ - Intradermal, amelanotic nodules in --- Sporadic cases -- - Heavily pigmented spindled melanocytes melanoma. Hence, BRAF-fusions likely have a greater tendency to progress to Spitz melanoma relative to ROS, RET, ALK, NTRK1, or NTRK3 fusions.16 BRAF-rearranged cases are also more likely than ALK or NTRK fusions to have copy number gains of the kinase domain.7 IHC staining for wildtype BRAF is not specific to BRAF fusions, as wildtype BRAF can be overexpressed in other melanocytic tumors. A significant proportion of BRAF fusions are the result of inversions or deletions. Hence, when using a FISH break apart probe, the space between the 50 and 30 ends of the gene may not be sufficient to definitively determine the presence of a fusion, and NGS would be more reliable in such cases.

3.3 | NTRK1 partners 3 MAP3K3 ’ CTCN1 ATP2B4, RNF13, SCARB1, CD63, ATP2B4 MYO5A ETV6, MYO5A NTRK1, NTRK2,andNTRK3 encode the family of transmembrane tyrosine kinase receptors comprising TrkA, TrkB, and TrkC. When expressed in melanocytes, Trk proteins regulate proliferation and migration.17 NTRK1 fusions have been found in 20% of Spitz neoplasms. Most cases have been diagnosed as ASTs, Spitz nevi and more rarely Spitz melanoma.5,7,11,18 NTRK1-rearranged cases have predominantly small spindled cells forming rosettes or lobulated nests with filigree-like rete ridges and marked maturation of dermal melanocytes.18 It has been suggested that this growth pattern may reflect a greater dependence on epidermal growth factors than other Spitz tumors. This variant of Spitz tumor is most likely to have Kamino bodies (Figure 3). In fact, Kamino bodies and epidermal hyperplasia are present in the majority of cases. The silhouette may Unclassified cutaneous melanocytomas Acral melanoma (rarely) Pigmented epithelioid melanocytoma Acral melanoma (rarely) PSCN of Reed be exophytic, plaque-like, or nodular with wedge-shaped growth or non- specific nesting. Notably, diffuse intense IHC staining is fairly specific for NTRK1 fusions, allowing for cost-efficient assessment of these (Continued) lesions.7,11,18 For cases that may be aggressive and malignant, NTRK1 and NTRK3 may be a crucial target for therapy with Food and Drug Administration-approved Trk inhibitors such as entrectinib and TRIM11 PRKCA Fusion gene Subtypes 5 19 TABLE 1 Abbreviations: AST, atypical Spitz tumor; CMN, congenital melanocytic nevus; PSCN, pigmented spindle cell nevus. larotrectinib. 882 QUAN ET AL.

FIGURE 2 Hematoxylin & eosin section of a large diameter TPM3-ALK fusion Spitz nevus from the right cheek of a 1-year-old male. A, Low power (2×) shows a symmetric wedge-shaped Spitz nevus with an overlying serohemorrhagic crust. B and C, Higher magnification (10×,20×) shows fascicles of nonpigmented wavy to spindle shaped spitzoid melanocytes with a plexiform growth pattern. D, Highest power (40×) shows elongated spindle shaped spitzoid melanocytes with vesicular nuclei and prominent nucleolus. A dermal mitotic figure is noted

3.4 | ROS1 fusions, can occur in ASTs and Spitz melanomas. Among six cases with MAP3K8 fusions in Quan et al, three were Spitz melanomas. Although Fewer than 20% of Spitz neoplasms carry ROS1 fusions, with the the number of cases was small, the percentage diagnosed as mela- majority classified as Spitz nevi and ASTs, but 9% as Spitz melano- noma is higher than any other fusion type, including NTRK1, NTRK3, mas.5 They can occasionally also be seen in pigmented spindle cell ROS, RET, ALK, and even BRAF, suggesting this particular fusion has a nevus (PSCN) of Reed.20 No clear histologic correlates have yet been relatively high likelihood to progress to Spitz melanoma. described. The ROS1 fusion is a well-known oncogenic mechanism in MAP3K8, also known as COT and Tpl2, is a serine-threonine kinase non-small-cell lung cancer, lymphoma, and sarcoma, and thus a com- that directly phosphorylates MEK and activates ERK1/2. Importantly, it mon targetable alteration. ROS1 IHC is available for screening. acts as a mechanism for resistance to BRAF inhibitors in BRAF V600E melanomas.22 MAP3K8 truncating mutations and fusions eliminate the 3.5 | MAPK final exon 9 , which codes for the autoinhibitory C-terminal domain, from

Two recent independent studies identified structural alterations in the translated protein leading to increased catalytic activity of the kinase. MAPK genes in 9% to 33% of Spitz neoplasms, using transcriptome One ATP2A2-MAP3K3 fusion has been found in an AST. MAP3K3 sequencing to detect MAP2K1 in-frame deletions, MAP3K3 fusions, codes for MEKK3 which phosphorylates SEK, MEK1, MEK2, and and MAP3K8 kinase fusions and truncations as initiating oncogenic MEK5 to cause cellular growth and proliferation. events. In both, structural alterations in non-BRAF MAPK genes were Among reported cases, MAPK-activated cases tend to occur in youn- identified as the single most frequent driver in their Spitz melanomas ger patients (median age 18) and on extremity sites. Similar to BRAF (22%).6,21 Non-BRAF MAPK fusions, consisting mostly of MAP3K8 fusion cases, they tend to be epithelioid with high grade nuclear atypia QUAN ET AL. 883

FIGURE 3 Hematoxylin & eosin section of a LMNA-NTRK1 fusion atypical Spitz tumor (AST) from the left arm of a 3-year-old boy. A, Low power (2×) shows a predominantly dermal AST with many nests and no pigment. B and C, The predominantly epithelioid melanocytes are arranged in organized, rosette-like nests in a collagenous stroma (10×,20×). D, High power (40×) highlights the rosette-like and lobulated nesting. There is moderate cytologic atypia and have a higher likelihood of notable melanin pigment compared to 3.7 | RET other fusions (Figure 4).21 One patient with a MAP3K8-GNG2 fusion RET fusions are reported in <5% of Spitz neoplasms.5 Given the rarity Spitz melanoma and metastatic disease showed a transient response to of cases, specific morphologic correlations have not yet been described. trametinib for 1 month, but developed cardiotoxicity and eventually died RET inhibitors vandetanib and cabozantinib reduces overactivation of of metastatic disease.6 key signaling pathways in RET-rearranged melanocyte lines.

3.6 | MET 4 | NEVUS OF REED

The MET gene codes for the hepatocyte growth factor receptor, also 4.1 | NTRK3 known as c-MET, a tyrosine kinase receptor.23,24 Yeh et al25 identified MET fusions in two Spitz melanomas and four ASTs. There were large NTRK3 rearrangements are the single most common and characteristic junctional nests of spindled and epithelioid melanocytes with moder- fusion in PSCN of Reed, found in 57% of cases.20 A small number of ate to large amounts of amphophilic cytoplasm with epidermal hyper- predominantly spindle cell Spitz nevi and ASTs may also have NTRK3 plasia. Cases showed strong diffuse staining with IHC in spitzoid fusions.20,26,27 melanocytes compared with common nevomelanocyte controls.25 Overall, 78% of sequenced PSCN of Reed have an in-frame fusion The MET kinase may be a good therapeutic target with the MET transcript of any kind as the primary driver, involving RET, ROS1, BRAF, inhibitor cabozantinib. MERTK,andPITX3. Characteristic of PSCN of Reed, NTRK3-fused cases 884 QUAN ET AL.

FIGURE 4 Hematoxylin & eosin section of a MAP3K8-UBL3 fusion Spitz melanoma, Breslow 2.9 mm, without ulceration from the left knee of a 20-year-old man. A, A compound proliferation of spitzoid melanocytes (4×). B, There is disorganized growth (10×) of large, severely atypical spitzoid melanocytes with poor maturation. Mitotic figures are seen throughout the superficial and dermal portions of the lesion. C and D, High power (20×,40×) highlights the severe cytologic atypia and epithelioid morphology characteristic of MAP3K8 fusions. A bizarre mitotic figure and syncytial cells are seen develop in younger patients (median age 17) predominantly on the they are predominantly dermal proliferations of heavily pigmented epi- extremities and show expansile nests of heavily pigmented spindle- thelioid and dendritic melanocytes with many melanophages and charac- shaped melanocytes with a plaque-like silhouette. Compared to NTRK3- teristic large, multinucleated cells with vesicular nuclei and macronucleoli negative PSCN cases, they tend to have greater adnexal involvement. with some cytoplasmic pigmentation. The two most common genomic patterns identified in PEM include (a) fusions in PRKCA and (b) inactivating alterations in 5 | PIGMENTED EPITHELIOID PRKAR1A with a preceding mutation of BRAF or less frequently NRAS. MELANOCYTOMA These two alterations give rise to distinct morphologic patterns of PEM. The PRKCA fusion subtype of PEM forms solid sheets of mono- 5.1 | PRKCA morphic pigmented epithelioid melanocytes and occurs frequently in PEM is an intermediate grade lesion with frequent involvement of younger patients (Figure 5).29-31 Alternatively, the PRKAR1A-mutated regional lymph nodes but rare distant metastasis. It was first recognized cases have more cytologic heterogeneity and may have a conven- by Zembowicz et al28 as a subgroup of melanocytic tumors characterized tional nevus component with smaller nests separated by fibrous bands by heavily pigmented epithelioid and dendritic melanocytes with many of collagen. The PRKAR1A-mutated subtype occurs in CC patients melanophages, resembling epithelioid blue nevus of Carney complex while both subtypes can occur sporadically. (CC). Clinically, PEMs appear as slow-growing, blue-black nodules on the PRKCA is located closely to the PRKAR1A gene on chromosome face, trunk, extremities, and genitals of young patients. Histologically, 17 and codes for PKCα which phosphorylates BCL-2 to prevent QUAN ET AL. 885

FIGURE 5 Hematoxylin & eosin section of a CD63-PRKCA fusion pigmented epithelioid melanocytoma from the right parietal scalp of a 21-year-old male. A and B, Low power (4×) shows a wedge-shaped and heavily pigmented dermal proliferation of epithelioid melanocytes. There is prominent epidermal hyperplasia. B, There is sheet-like growth of monomorphic, pigmented epithelioid melanocytes surrounded by many heavily pigmented dermal melanophages (10×). C and D, The melanocytes are of intermediate size with vesicular nuclei with central prominent nucleoli and heavily pigmented cytoplasm (20×,40×) apoptosis. The PKC pathway activates tyrosinase in melanosomes to fusions or truncations in 1.5% (7/472) melanomas and two acral mela- promote melanin synthesis, which may explain the heavy pigmenta- nomas (MAP3K8-DEK fusion, probable MAP3K8 truncation).6 tion characteristic of PEM. AKAP9-BRAF fusions were identified in two deeply infiltrating melanomas with a sclerosing background.35 One case had features of 6 | MELANOMAS desmoplastic melanoma with fascicles of atypical nonpigmented spindled melanocytes in the deep dermis in a sclerosing fibrotic stroma. The other case was a compound melanocytic tumor with large vertical Fusions may be the initiating genomic event in up to 8% to 20% of melanomas without other key initiating mutations, sometimes nests of pigmented spindled melanocytes surmounted by epidermal referred to as “pan-negative melanomas”.14,32 These include acral mel- hyperplasia in the junctional component and a dermal component of anomas, mucosal melanomas, Spitz melanomas, and other melanomas wide nests and strands of nevoid melanocytes down to the hypoder- without BRAF, NRAS,orNF1 mutations. With NGS, BRAF fusions were mis with limited maturation. Both lesions were slow growing for found by Hutchinson et al33 in 8% of 44 pan-negative melanomas and years. by Kim et al. in two mucosal, one acral, and one unspecified mela- Of note, cases of BRAF-fused melanomas treated with BRAF or noma. Among 30 acral melanomas, Niu et al13 identified 4 (13%) with MEK inhibitors have showed reductions in tumor size and prolifera- ALK fusions using FISH break apart probes. Yeh et al34 detected tion.15,36 If cost allows, NGS may be useful in screening for targetable fusions in BRAF, ALK, PRKCA, and NTRK3 with NGS in 8 (6.6%) of fusions in advanced melanomas without characteristic driver 122 cases. Analysis of TCGA data by Newman et al. revealed MAP3K8 mutations. 886 QUAN ET AL.

7 | NON-SPITZ MELANOCYTIC NEVI AND REFERENCES

OTHER UNCLASSIFIED MELANOCYTIC 1. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of TUMORS kinase fusions in cancer. Nat Commun. 2014;5:4846. 2. Elder DE, Massi D, Scolyer RA, Willemze R. WHO Classification of Skin 7.1 | TRIM11 Tumours. Vol 11. Lyon, France: IARC; 2018. 3. Busam KJ, Vilain RE, Lum T, et al. Primary and metastatic cutaneous A recent series identified five cutaneous melanocytomas with melanomas express ALK through alternative transcriptional initiation. Am J Surg Pathol. 2016;40(6):786-795. CRTC1-TRIM11 fusions with a specific low-grade phenotype of 4. Yeh I, de la Fouchardiere A, Pissaloux D, et al. Clinical, histopatho- amelanotic, dermal proliferation of melanocytes resembling clear cell sar- logic, and genomic features of Spitz tumors with ALK fusions. 37 coma. TRIM proteins mainly function as E3 ubiquitin ligases. Because Am J Surg Pathol. 2015;39(5):581-591. there is no kinase in this fusion, its contribution to oncogenesis is unclear. 5. 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Activating structural alterations Elnaz Panah https://orcid.org/0000-0003-2378-9254 in MAPK genes are distinct genetic drivers in a unique subgroup of Spitzoid neoplasms. Am J Surg Pathol. 2019;43(4):538-548. Pedram Gerami https://orcid.org/0000-0002-6194-1037 QUAN ET AL. 887

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