Genetic predisposition to melanoma

Genetic predisposition to melanoma

Author’s Accepted Manuscript Genetic Predisposition to Melanoma Jason E. Hawkes, Amanda Truong, Laurence J. Meyer www.elsevier.com/locate/seminoncol ...

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Author’s Accepted Manuscript Genetic Predisposition to Melanoma Jason E. Hawkes, Amanda Truong, Laurence J. Meyer

www.elsevier.com/locate/seminoncol

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S0093-7754(16)30040-9 http://dx.doi.org/10.1053/j.seminoncol.2016.08.003 YSONC51952

To appear in: Seminars in Oncology Received date: 13 June 2016 Accepted date: 16 August 2016 Cite this article as: Jason E. Hawkes, Amanda Truong and Laurence J. Meyer, Genetic Predisposition to Melanoma, Seminars in Oncology, http://dx.doi.org/10.1053/j.seminoncol.2016.08.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Genetic Predisposition to Melanoma

Jason E. Hawkes, MD1,*, Amanda Truong, BS1,*, Laurence J. Meyer, MD, PhD1,2,# 1

Department of Dermatology, University of Utah, Salt Lake City, UT; 2

Veterans Administration Hospital, Salt Lake City, UT;

*These authors contributed equally and should be considered co-first authors

#

Corresponding author:

Laurence J. Meyer, MD PhD Veterans Administration Hospital 500 S. Foothill Blvd Salt Lake City, UT 84149 Phone: (801) 582-1565; Fax: (801) 581-6465 Email: [email protected]

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Abstract Malignant melanoma is a rare, often fatal form of skin cancer with a complex multigenic etiology. The incidence of melanoma is increasing at an alarming rate. A number of heritable factors contribute to a patient’s overall melanoma risk, including response to ultraviolet light, nevus number, and pigmentation characteristics, such as eye and hair color. Approximately 5-10% of melanoma cases are familial, yet the majority of familial cases lack identifiable germ-line mutations in known susceptibility genes. Additionally, most familial melanomas lack germ-line mutations in genes that are commonly mutated in sporadic melanoma. Candidate and systematic genome-wide association studies have led to an improved understanding of the risk factors for melanoma and the identification of susceptibility genes. In this review, we provide an overview of the major risk factors and known genes implicated in familial melanoma susceptibility.

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Introduction Malignant melanoma is a rare, heterogeneous form of skin cancer with a complex, multigenic etiology. Approximately 5-10% of melanoma cases are familial.1 A number of heritable factors contribute to a patient’s overall melanoma risk, including pigmentation characteristics, response to ultraviolet light, and nevus number. However, the majority of familial melanoma cases lack identifiable germ-line mutations in known susceptibility genes. The alarming increase in the incidence of melanoma has stimulated increased research efforts aimed at elucidating the genetic, environmental, behavioral, and phenotypic factors that contribute to the pathogenesis of this disease. This collective effort, including the candidate and systematic genomewide association studies (GWAS), has led to an improved understanding of the risk factors for melanoma and the identification of both common low-penetrant and rare high-penetrant genes. In this review, we provide an overview of the major risk factors and known genes implicated in familial melanoma susceptibility. We will not discuss the more common, somatic genetic mutations associated with sporadic melanoma cases, such as those found in B-Raf protooncogene (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS).

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Melanoma Risk Factors Sun Exposure Sun or ultraviolet radiation (UVR) exposure is the strongest known environmental factor associated with the development of melanoma and nonmelanoma skin cancers, such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Interestingly, the UVR exposure pattern impacts the degree of melanoma risk. Intermittent or sporadic sun exposure is most strongly associated with an increased melanoma risk, whereas chronic or continuous exposure is either protective or without increased risk.2 The risk of melanoma associated with UVR exposure is also greatly affected by geographic location and genetic factors (e.g. cyclin-dependent kinase inhibitor 2A or CDKN2A penetrance).3 The specific molecular mechanisms underlying these differences in UVR exposure patterns and melanoma risk are not fully understood. The lack of a standardized approach to measuring UVR exposure and the presence of confounding factors, such as pigmentary characteristics and sunscreen use, makes the study of this environmental risk factor challenging.

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Pigmentary Characteristics An individual’s pigmentation is an important determinant of melanoma risk with the highest risk correlating with the lightest skin phenotypes. In contrast, dark-skinned ethnic groups tend to have a very low melanoma risk. The overall risk of melanoma related to skin pigmentation is further modified by environmental risk factors and genetics. The major genes that affect pigmentation and melanoma susceptibility will be discussed in greater detail below.

Nevi Nevus number is influenced by both environmental and genetic factors. The risk of melanoma is increased in patients with multiple nevi. This increased risk, however, appears to be most strongly related to the presence of multiple atypical nevi (Figure 1) rather than multiple benign appearing nevi.4 The genetic determinants of the number of inherited nevi, including atypical nevi, are due in part to the major melanoma risk gene CDKN2A and were originally described clinically under the names dysplastic nevus syndrome (DNS) and familial atypical mole-melanoma syndrome (FAMMM). The phenotype of multiple nevi is also influenced by UVR exposure. Though childhood UVR exposure is associated with increased nevus number,5 it

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is difficult to sort out whether an individual’s subsequent increased risk for melanoma is determined primarily by their nevi, UVR exposure history, or a combination of both. Additionally, the number of nevi in individuals with atypical nevus syndromes or high-risk familial melanoma kindreds is further modified by environmental factors, such as UVR exposure.6

Family History The definition of a positive family history of melanoma varies between studies, but commonly refers to kindreds where three or more first-degree relatives have been diagnosed with primary melanoma. A positive family history for melanoma is associated with an approximate two-fold increase in melanoma risk.1 The increased risk associated with a positive family history is further increased when affected first-degree relatives have multiple primary melanomas.7 Melanoma families are also at an increased risk of other cancers, including pancreatic cancer, suggesting a role for melanoma susceptibility genes in other cancer syndromes.8

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Personal History of Melanoma or Non-melanoma Skin Cancers A personal history of melanoma increases an individual’s risk of developing a second primary melanoma. Following the first diagnosis of melanoma, the risk of a second primary melanoma is approximately 5% and this risk is greater in patients who are male, older, and have primary melanomas involving the head or neck.9 Having a personal history of BCC or SCC also increases an individual’s risk for a second primary melanoma.10 The relationship between non-melanoma skin cancer and a second primary melanoma is more likely related to shared risk factors, such as UVR exposure and pigmentation characteristics, rather than specific underlying gene mutations which increase the risk for all three skin cancer types simultaneously.

Immunosuppression Organ transplant patients are at a significantly increased risk of all skin cancer types, including melanoma. The increased risk of melanoma in this group of patients has been estimated to be 1.6 to 2.5 times higher than in the general population.11 However, immunosuppressed patients are at a tremendously higher risk for non-melanoma skin cancers, with estimates of 65 to 250 times higher for squamous cell cancer and a 10-fold increase for basal cell cancer. 12,13

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Major Genes for Melanoma CDKN2A/p16 and ARF/p14 CDKN2A (also known as P16, INK4A, MTS1, or MLM), was the first highrisk melanoma susceptibility gene locus discovered in melanoma-prone families.14 Found to be located on chromosome 9p21 by linkage analysis of melanoma families,15 CDKN2A encodes two proteins, p16INK4a and p14ARF, both of which are potent suppressors of cellular senescence. Curiously, p14ARF shares the DNA encoding the structural protein with p16INK4a, but with an out-of-frame coding sequence and differing exon structure. Mutations in the area of overlapping coding most commonly affect the structure of both proteins. The main effect of p16INK4a is the inhibition of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) resulting in maintenance of the retinoblastoma (RB) pathway.16 In contrast, p14ARF is a positive regulator of p53.17 Mutations in CDKN2A, therefore, result in the loss of p16INK4a and p14ARF and disruption of the RB and p53 pathways, respectively. Approximately 30-40% of familial melanoma kindreds have been found to harbor mutations in CDKN2A, the most common gene mutation observed in

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melanoma families.3 Most mutations in CDKN2A occur within exons 1 and 2, though multiple founder mutations, which are unique to specific populations and their geographic origins, have also been reported. Melanoma penetrance related to CDKN2A mutations is highly variable depending on the study design and the specific population being studied. Its penetrance also differs by geographic location, which may be related to gene modifiers and differences in UVR exposure. In the United States, the penetrance or risk of melanoma by age 50 is 50% and 76% by age 80.18 Several clinical features were found to be associated with CDKN2A germline mutations in an Italian cohort, including multiple primary melanomas, Breslow thickness  0.4mm, younger age at diagnosis, and more than three family members with melanoma.19 In this same study, having multiple primary melanomas appears to be the strongest clinical predictor of CDKN2A mutation status. CDKN2A mutation carriers also display higher numbers of nevi and increased nevi density compared with non-carriers.20 CDKN2A mutations are also associated with an increase in other human cancers, suggesting its broader role in carcinogenesis. Data from the Genes, Environment, and Melanoma (GEM) study demonstrated an approximate 50% increased risk of non-melanoma cancers in first-degree relatives of CDKN2A mutation carriers compared with first-degree relatives from families with

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sporadic melanomas.21 Multiple cancers have been reported to be increased in this specific high-risk population such as pancreatic, gastrointestinal, lung, breast, and tobacco-related cancers (Table 1).21-24 The association between pancreatic cancer and CDKN2A-positive melanoma families has been replicated in a number of independent studies.22,25,26 The lifetime risk of developing pancreatic cancer in these melanoma-prone families is estimated to be between 11% and 17%.27 This increased risk of pancreatic cancer in melanoma families varies across studies and geographic location, suggesting that specific CDKN2A variants or additional environmental factors can alter a specific individual’s overall risk.26

Additional evidence for 9p21 loci While the identification of germ-line CDKN2A mutations in familial melanoma has had a tremendous impact on the way that these high-risk families are evaluated and managed, it is clear that these mutations do not account for all melanoma cases where 9p21 loss of heterozygosity is observed.28 These findings emphasize the importance of the 9p21 locus in melanoma pathogenesis and suggest the involvement of yet unidentified genes or loci that also contribute to the pathogenesis of this disease.

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CDK4 and CDK6 Germ-line mutations in CDK4 and CDK6 allow cells to progress through the cell cycle more rapidly similar to that seen with mutations in CDKN2A. Mutations in CDK4 are very rare, but have been described in a small number of CDKN2A-negative melanoma families.29,30 These CDK4 mutations result in an altered protein structure rendering it insensitive to the inhibitory effects of p16, and patients carrying such mutations are phenotypically indistinguishable from those with CDKN2A germ-line mutations.30 Despite the analogous functions of CDK4 and CDK6, germ-line mutations in CDK6 have not yet been reported in melanoma-prone families. The importance of the CDKN2A/CDK/RB pathway in melanoma and carcinogenesis is further underscored by the observation that carriers of germ-line RB1 mutations have a significantly increased risk of melanoma.31

Minor Genes for Melanoma MC1R Located on chromosome 16, the melanocortin 1 receptor (MC1R) gene is a seven transmembrane G-protein-coupled receptor that binds alpha melanocyte stimulating hormone (-MSH) and subsequently activates cAMP via adenylate cyclase. This increase in cAMP promotes preferential production of

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brown/black eumelanins over red/yellow pheomelanin pigments. Functional polymorphisms of the MC1R gene are common in the general population. Specific variants of MC1R disrupt cascade signaling and cell surface expression of the -MSH receptor that results in a greater proportion of pheomelanin production. MC1R gene variants are present in >80% of individuals with fair skin and/or the red hair color (RHC) phenotype.32 Valverde et al. was the first to describe the association between MC1R nonsynonymous mutations and an increased risk for melanoma.32 They reported a significantly increased number of MC1R variants in melanoma cases versus controls and a nearly four-fold increased melanoma risk in carriers. The increased prevalence of MC1R variants in melanoma cases compared to healthy controls has been confirmed in numerous subsequent studies.33-36 MC1R variants appear to confer an approximate two- to four-fold increase in melanoma risk, and this risk appears to be additive in individuals carrying more than one variant.35,36 Interestingly, the association between MC1R variants and melanoma susceptibility appears to be stronger in individuals lacking fair skin or the RHC phenotype, suggesting that MC1R variants may promote melanoma tumor growth via a mechanism that is at least in part independent of cutaneous pigmentation.37

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MC1R variants also interact with the risk of other genes, such as CDKN2A, to increase the risk for melanoma. A GenoMEL study that looked at 815 CDKN2A mutations carriers from 186 families and found that the presence of one of the four most common MC1R variants (V60L, V92M, R151C, and R160W) increased an individual’s melanoma risk two-fold; the presence of two or more variants increased the melanoma risk nearly six-fold.38 After stratification for hair color, the increased risk of melanoma in this population was limited to brown or black hair phenotypes, thus providing further evidence of the role for MC1R in melanoma pathogenesis independent of its impact on pigmentation.

MITF Microphthalmia-associated transcription factor (MITF) has important functions in regulating the development and differentiation of melanocytes. It is also activated downstream of the MC1R/cAMP signaling pathway to produce eumelanin. The identification of the MITF E318K variant, a gain-of-function mutation, was found in both familial and sporadic melanomas.39 This mutation decreases the binding affinity to the small-ubiquitin-like modifier (SUMO) protein, a transcriptional regulator that leads to dysregulated cellular proliferation. The E318K variant confers an approximate two-fold increase of melanoma and is associated with specific phenotypes, including non-blue eye

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color, increased nevi, and multiple primary melanomas.40 It has also been found to be associated with an increased risk of other malignancies, such as renal and pancreatic cancers (Table 1).39,41,42

POLE The DNA polymerase epsilon (POLE) gene encodes the catalytic subunit for DNA polymerase  and is involved in DNA repair. Germ-line mutations affecting the proofreading domains of POLE have been reported to predispose affected individuals to colorectal adenomas and carcinomas.43 Recently, one group found a novel germ-line mutation in POLE in a 7-case cutaneous melanoma family in Australia; novel and rare POLE variants were subsequently identified in 10 additional probands.44 Interestingly, affected individuals appeared to be at increased risk for multiple other cancers including uveal melanoma, renal, prostate, and colon, tumors. Additional studies are necessary to confirm these findings and determine the degree of risk for melanoma associated with inherited POLE mutations.

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Telomere Maintenance Genes TERT The telomerase reverse transcriptase (TERT) gene is located on chromosome 5 and encodes the catalytic subunit of telomerase. The telomerase enzyme maintains telomere length, preventing the cell from damage and apoptosis. Telomerase is usually detected in rapidly dividing cells, such as epithelial cells of the intestine and lungs. Mutations in the TERT promoter region have been identified in a number of primary cancers (Table 1).45-47 TERT promoter mutations in familial melanoma have been identified, but are exceedingly rare.46,48 In a 2013 study by Horn et al. looking at a 14-case German family, 33% of primary melanomas and 85% of metastatic tissue that they analyzed contained TERT promoter mutations.46 Most of these mutations were found in two specific locations within the TERT promoter region, which are thought to enhance TERT expression. In a large UK patient cohort, mutations in TERT accounted for <1% of familial melanoma cases.48 The frequency of TERT mutations in larger, more diverse melanoma families is not entirely clear.

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POT1 Protection of telomeres 1 (POT1) is a highly penetrant melanoma susceptibility gene located on chromosome 7. It comprises a subunit of shelterin, a protein complex involved in telomere protection and maintenance. Germ-line carriers of POT1 loss-of-function mutations have been found to have longer telomeres, a finding previously found to be a risk factor for melanoma in melanoma-prone families.49 Two recent studies have identified nine germ-line missense variants of this gene in 13 melanoma-prone families, though POT1 mutations were observed more commonly in sporadic melanomas.50,51 Several non-cutaneous cancers have been reported in association with germ-line POT1 mutations (Table 1).50,52

ACD and TERF2IP Adrenocortical dysplasia homolog (ACD) and telomeric repeat binding factor 2, interacting protein (TERF2IP) are two recently identified genes that have been implicated in melanoma risk. ACD and TERF2IP, like POT1, are also major subunits in the shelterin complex. In a study of 510 melanoma-prone families, 6 were found to have ACD mutations, mainly clustered within the POT1 binding domain.53 In addition, 4 families were found to have TERF2IP mutations. Individuals with ACD and TERF2IP mutations have an increased risk for multiple

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primary melanomas at an early age of onset (e.g., ages 15, 26, and 35 in one family), as well as a susceptibility for other cancers (Table 1).53

DNA Repair Genes XP Xeroderma pigmentosum (XP) is a rare disease caused by mutations in DNA repair genes. Individuals with XP are unable to effectively repair UV-induced DNA damage and are, therefore, at an extremely increased risk of developing skin cancers. The melanoma risk associated with these patients has been estimated as nearly 1,000 times higher than the general population.54 There is also evidence suggesting that specific XP disease variants may confer a higher melanoma risk than other less common variants.55 This specific genetic disease also underscores the importance of UVR exposure for the development of melanoma and non-melanoma skin cancers.

BRCA2 The breast cancer 2 (BRCA2) gene is a tumor suppressor gene located on chromosome 13 and is important in DNA repair by regulating chromosomal stability via its interaction with RAD51.56 Mutations in BRCA2 are clearly associated with an increased risk of breast, ovarian, and other cancers (Table

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1).57 These mutations may also influence melanoma susceptibility. The Breast Cancer Linkage Consortium surveyed 3278 individuals with confirmed or suspected BRCA2 mutations and found that carriers had an increased risk of developing melanoma.58 Subsequent studies have failed to confirm this association or reported conflicting information. Additionally, no studies have identified an increased risk for melanoma associated with BRCA1.

PTEN hamartoma tumor syndromes/Cowden Syndrome Cowden Syndrome is a hamartomatous disease with an autosomal dominant inheritance pattern. It is mainly caused by mutations in the phosphatase and tensin homolog (PTEN) gene. PTEN is a tumor suppressor gene located on chromosome 10 and has a significant role in triggering apoptosis. Other genes that have been associated with Cowden syndrome are Killin, P53regulated DNA replication inhibitor (KLLN), succinate dehydrogenase complex, subunit B, iron sulfur (SDHB), and succinate dehydrogenase complex subunit D, integral membrane protein (SDHD). Individuals with Cowden syndrome are at an increased risk of developing multiple cancers, particularly tumors of the breast, kidney, colorectal, endometrium, and thyroid (Table 1).59-61 A study of 154 PTEN

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hamartoma tumor syndrome patients also found a higher than predicted rate of melanoma with a prevalence rate of 6% for patients with Cowden syndrome.61

MGMT O-6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that plays a protective role in DNA repair by removing aberrant alkyl groups. The MGMT gene is located on chromosome 10 and mutations in this gene are rare. A recent study found only one family with a MGMT mutation out of 64 melanomaprone families.62 The activity level of this gene has also been studied as a marker of sensitivity to alkylating chemotherapy drugs, with higher levels correlating with drug resistance.63 Therefore, determining the level of this gene in melanoma patients undergoing chemotherapy may have some prognostic value.

Other Melanoma Predisposition Genes Which Influence Pigmentary Characteristics OCA-related Genes Oculocutaneous albinism (OCA) is one of the most common inherited pigmentation disorders of the skin resulting in absent or decreased melanin synthesis in melanocytes. There are four major types (OCA type 1-4), all of which are inherited in an autosomal recessive manner. As with other forms of albinism,

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the disruption of melanin synthesis in OCA places these patients at significant risk for UV-related skin cancer, including melanoma. Despite the expected association between increased skin cancer risk and albinism phenotypes, several studies have reported an increased melanoma susceptibility in OCA patients that appears to be independent of its effect on pigmentation.64,65 The role of OCArelated genes in the pathogenesis of melanoma via a pigmentation-independent manner is also suggested by the observation that the increase in melanoma risk is not evenly distributed across all OCA types despite the fact that all disease types reduce melanin synthesis. Located on chromosome 5p, solute carrier family 45, member 2 (SLC45A2) encodes for the membrane associated transporter (MATP) protein, which is thought to be involved in the trafficking of melanosome proteins. Pathogenic mutations in SLC45A2 results in OCA type 4 and have been found to be associated with an increased risk of melanoma.64 However, in contrast to most other genes that affect pigmentation characteristics, one SLC45A2 variant (rs16891982) is associated with olive or darker pigmentation phenotypes and appears to confer a protective effect against melanoma in Southern European populations.66 This protective effect persisted even after stratification for lighter phenotypes. Other studies have confirmed the association with a protection from melanoma for this specific variant.67

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ASIP The agouti signaling protein (ASIP) gene is located on chromosome 20q11 and encodes the agouti signaling protein, which antagonizes the interaction of MC1R and -MSH thereby affecting pigmentation. Similar to MC1R, ASIP is also associated with freckling and the RHC phenotype. Despite early reports, the positive association between ASIP and melanoma susceptibility has been variable.68,69 The role for the 20q11 loci in melanoma susceptibility and other skin cancers remains unclear. Uveal Melanoma BAP1 BRCA1-associated protein-1 (BAP1) is a tumor suppressor gene located on chromosome 3. Germ-line inactivating mutations for this gene have been found to predispose to familial uveal melanoma, as well as some familial and sporadic cutaneous melanomas.70,71 BAP1 has also been associated with other cancers, including mesothelioma, renal cell carcinoma, meningiomas, paragangliomas, and cholangiocarcinomas (Table 1).72-74 One recent report also suggests that mutations in BAP1 may also be associated with atypical nevi.75 A distinct clinical phenotype of light papules called melanocytic BAP1-mutated atypical intradermal tumors (MBAITS) or “BAPomas” have also been found to be

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associated with BAP1 mutations in some affected individuals. It is not clear whether these atypical lesions eventually progress to melanoma, but their presence in a patient may implicate a BAP1 mutation syndrome and indicates the need for genetic testing.

GNAQ and GNA11 The guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), found on chromosome 9q21, and guanine nucleotide-binding protein G(q) subunit alpha-11 (GNA11), found on chromosome 19p13.3, encode subunits of the heterotrimeric GTP-binding proteins. This pathway is required for melanocyte development (Shin PMID 10591209). Somatic GNAQ and GNA11 mutations result in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and somatic mutations have been linked with uveal melanoma and blue nevi.76 However, several studies have reported the lack of GNAQ and GNA11 germ-line mutations in melanoma families suggesting that these genes play no significant role in the inherited susceptibility for melanoma.77,78

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Other Familial Cancer Syndromes and Melanoma Risk Li-Fraumeni (TP53) Li-Fraumeni is a hereditary autosomal dominant cancer syndrome, mainly caused by a germ-line mutation in the p53 tumor suppressor gene. Although it is associated with numerous cancer types, its association with melanoma is both controversial and rarely seen. Nevertheless, germ-line mutations in TP53 have been reported in patients with multiple primary melanomas.79,80

Werner Syndrome Werner syndrome or progeroid is a premature aging syndrome caused by a mutation in the WRN gene in chromosome 8. The WRN protein plays an important role in regulating helicase activity and DNA repair, specifically responding to double stranded breaks and maintaining telomere length. 81 It also functions as an exonuclease. A 2013 study found that melanoma accounted for 13.3% of cancer cases in Werner syndrome patients, representing a 53-fold increased risk for melanoma in this patient population.82 Werner syndrome patients are also at increased risk for other cancers including leukemia, thyroid, and primary bone neoplasms.82

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Future Directions and Discussion There has been a major increase in our understanding of the basic molecular mechanisms contributing to melanoma familial risk, somatic progression, and immune surveillance over the past two decades. However, the pathogenesis of melanoma has proven to be convoluted with multiple causative genes and likely unappreciated gene-gene and epigenetic interactions. Many of the major susceptibility genes for melanoma have been identified, although there are still familial melanoma families with no identifiable specific risk alleles. Additionally, many GWAS-identified familial melanoma susceptibility regions, such as the 9p21 locus, have not yet been mapped to a specific causative gene.18 Our increasing ability to better handle “big data” in combination with recent technical advances in genetic technologies, like next-generation sequencing, will certainly facilitate the unraveling of the unidentified genetic aspects of melanoma pathogenesis. To date, only a few examples exist which show a clear demonstration of gene-gene and gene-environment interactions in melanoma pathogenesis. Genes clearly affecting pigment phenotype, such as MC1R, interact with other melanoma risk genes, and sun exposure is also additive (if not synergistic) with alleles associated with increased melanoma risk. Such clear gene-gene and gene-

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environment interactions are uncommonly demonstrated and should motivate future in vivo and in vitro studies. The inherited genes contributing to cutaneous melanoma risk in susceptible families predominantly fall into several molecular pathways, none of which are surprising: cell cycle regulation, pigmentation, DNA repair, and telomere maintenance. What is somewhat surprising is that none of the major germline mutations driving familial melanoma risk are somatically mutated in a significant number of sporadic melanoma cases. It is also surprising that none of the known inherited genetic mutations and the signaling pathways they perturb are yet major targets of melanoma therapy or chemoprevention. The differences between familial and sporadic melanomas highlight the genetic heterogeneity of this disease and the need for continued research on the genetics of melanoma. A specific somatic activating mutation (V600E or V600X) in the BRAF gene was discovered to be associated with roughly half of the cases of sporadic melanoma in 2002.83 Although the scope of this review does not focus on somatic events, this mutation deserves mention for several reasons. First, it is surprising that polymorphisms in this gene are not seen in families associated with increased melanoma risk,84 echoing the findings regarding GNAQ and GNA11 in uveal melanoma discussed previously. Activating somatic mutations in BRAF are seen in familial cases of melanoma with roughly equal frequency to

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that seen in sporadic melanoma.85 Secondly, this identical mutation is seen in well over half of all benign nevi.86 Activating BRAF mutations provide a target for small molecule inhibitors and has allowed the rapid development of drugs targeting this mutation, as well as other points in the MAPK pathway, leading to the rapid FDA approval of BRAF inhibitors. Finally, this specific mutation is also seen in other cancers, and clinical trials of these same inhibitors are ongoing. Another important area of ongoing melanoma research involves the study of the immune system and its regulation of melanocytic proliferations, melanoma, and the spread of metastatic disease. Such studies have led to tremendous advances in melanoma patient survival and melanoma immunotherapeutic agents like CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab) inhibitors.87,88 The variable clinical response of melanoma patients to novel immunotherapies based on differences in the genetic landscapes and overall burden of their tumors has already proven informative.89 Studies aimed at elucidating the complex interactions between the immune system, tumor microenvironment, and melanoma susceptibility genes may provide further insights into the biological basis and significance of specific nonsynonymous gene mutations. Finally, there is a clear clinical lesson from the aggregate of decades of melanoma research. Genes that affect pigment and cell cycle control affect

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nevus phenotype and interact with sun exposure to further increase melanoma risk. A significant proportion of melanoma risk, both familial and sporadic, can be easily assessed by the clinical appearance of multiple nevi, especially clinically atypical nevi and findings of actinic damage in fair skinned patients. Given this clear association and ease of clinically identifying melanoma risk, it is disheartening that melanoma incidence has increased so dramatically due to behavioral sun exposure.

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34

Figure Legend

Figure 1. Multiple clinically atypical-appearing nevi on the back of an individual from a melanoma-prone family. (Photo courtesy of Dr. Doug Grossman, Huntsman Cancer Institute and University of Utah Department of Dermatology)

35

Table Legend Table 1. Characteristics of the genes commonly implicated in familial melanoma and their cancer associations. Effe Effect Chromoso ct Associated Selected Biological on Penetra Gene mal on Non-Skin Referen Function Pigme nce Location Nev Cancers ces nt i Encodes Pancreatic, two breast, cervical, tumor lymphoma, GI, CDKN suppresso 21-24 9p21 No Yes High lung, Wilm’s 2A r proteins tumor, (p16INK4a tobaccoand related cancers p14ARF) 12q14

Cell cycle regulation

TERT

5p15.33

Telomere maintena nce

No

Yes

High

POT1

7q31.33

Telomere maintena nce

No

No

High

16q22.1

Telomere maintena nce

No

No

High

16q23.1

Telomere maintena nce

No

No

High

CDK4

ACD

TERF2 IP

No

Yes

36

High

Similar to CDKN2A Renal, bladder, myeloproliferat ive neoplasms, AML Glioma, brain, breast, lung, CLL, endometrial Breast, brain, lung, ovarian, cervical, colorectal, prostate, myeloproliferat ive neoplasms Similar to ACD

30

45-48

50,52

53

53

Uveal melanoma, mesothelioma, renal, meningioma, paraganglioma, cholangiocarcin oma Breast, thyroid, endometrium, colorectal, kidney

BAP1

3p21.1

Tumor suppresso r

No

Yes

High

PTEN

10q23.3

Tumor suppresso r

Yes

Yes

High

MC1R

16q24.3

Yes

No

Medium

None reported

BRCA2

13q12.3

No

No

Medium

Breast, ovarian, prostate, pancreatic

MITF

3p14.2– p14.1

Yes

Yes

Medium

Pancreatic, renal

Yes

No

Medium

None reported

64,66,67

Melanin productio n Tumor suppresso r and DNA repair Regulates melanocy te developm ent

72-74

59-61

32

57

39,41,42

SLC45 A2

5p13.2

Melanin productio n

MGM T

10q26

DNA repair

No

No

Low

None reported

62

15q12– 13.1

Melanin productio n via melanoso me trafficking

Yes

No

Low

None reported

64,65

OCA2

37

Melanin 68,69 ASIP productio Yes No Low None reported n Abbreviations: GI, gastrointestinal; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia 20q11.2– q12

38