lunes, 3 de junio de 2019

Genetics of Skin Cancer (PDQ®) 3/4 —Health Professional Version - National Cancer Institute

Genetics of Skin Cancer (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute

Genetics of Skin Cancer (PDQ®)–Health Professional Version

Melanoma

Introduction

Rare, high-penetrance and common, low-penetrance genetic factors for melanoma have been identified, and approximately 5% to 10% of all melanomas arise in multiple-case families. However, a significant fraction of these families do not have detectable pathogenic variants in specific susceptibility genes. The frequency with which multiple-case families are ascertained and specific genetic variants are identified differs substantially between populations and geographic regions. A major population-based study has concluded that the high-penetrance susceptibility gene CDKN2A does not make a large contribution to the incidence of melanoma.[1]

Risk Factors for Melanoma

This section focuses on risk factors in individuals at increased hereditary risk of developing melanoma. (Refer to the PDQ summary on Skin Cancer Prevention for information about risk factors for melanoma in the general population.)

Sun exposure

Sun exposure is well established as a major etiologic factor in all forms of skin cancer, although its effects differ by cancer type. The relationship between sun exposure, sunscreen use, and the development of skin cancer is complex. It is complicated by negative confounding (i.e., subjects who are extremely sun sensitive deliberately engage in fewer activities in direct sunlight, and they are more likely to wear sunscreen when they do). These subjects are genetically susceptible to the development of skin cancer by virtue of their cutaneous phenotype and thus may develop skin cancer regardless of the amount of sunlight exposure or the sun protection factor of the sunscreen.[2,3]

Pigmentary characteristics

Pigmentary characteristics are important determinants of melanoma susceptibility. There is an inverse correlation between melanoma risk and skin color that goes from lightest skin to darkest skin. Dark-skinned ethnic groups have a very low risk of melanoma on pigmented skin surfaces; however, individuals in these groups develop melanoma on less-pigmented acral surfaces (palms, soles, nail beds) at the same frequency as light-skinned individuals. Among relatively light-skinned individuals, skin color is modified by genetics and behavior. Melanocortin 1 receptor (MC1R) is one of the major genes controlling pigmentation (refer to the MC1R section of this summary); other pigmentation genes are under investigation.[4]
Clinically, several pigmentary characteristics are evaluated to assess the risk of melanoma and other types of skin cancer. These include the following:
  • Fitzpatrick skin type. The following six skin phenotypes were defined on the basis of response to sun exposure at the beginning of summer.[5]
    1. Type I: Extremely fair skin, always burns, never tans.
    2. Type II: Fair skin, always burns, sometimes tans.
    3. Type III: Medium skin, sometimes burns, always tans.
    4. Type IV: Olive skin, rarely burns, always tans.
    5. Type V: Moderately pigmented brown skin, never burns, always tans.
    6. Type VI: Markedly pigmented black skin, never burns, always tans.
  • Number of nevi or nevus density.
  • Abnormal or atypical nevi.
  • Freckling.

Nevi

Nevi (or moles) are sharply circumscribed benign pigmented lesions of the skin or mucosa composed of nest melanocytes. Patients with multiple nevi demonstrate increased risk of melanoma. While there is evidence that both the presence of multiple nevi and the presence of multiple clinically atypical nevi are associated with an increased risk of melanoma, most studies demonstrate a stronger risk of melanoma with the presence of atypical nevi.[6-9] In addition, patients with multiple atypical nevi, regardless of personal and/or family history of melanoma, are at significantly increased risk of developing melanoma than are patients without atypical nevi.[10] A population-based study in the United Kingdom that identified genetic risk factors for the development of nevi showed that some of the same variants are modestly associated with melanoma risk.[11]
The phenotype of multiple nevi has both familial and environmental affecters. The number of nevi can increase with childhood sun exposure.[12,13] The analysis of this association is complex because the use of sun protection strongly correlates with sun exposure. Inheritance of the specific phenotype of a high number of nevi, including clinically atypical nevi, was initially reported as an autosomal dominant trait under the names dysplastic nevus syndrome [14] and familial atypical multiple mole-melanoma syndrome.[15] A portion of this inherited phenotype is attributed to the major melanoma risk gene CDKN2Adiscussed below. Even within gene carriers in high-risk families, sun exposure seems to affect nevus number.[16]

Family history

Generally, a family history of melanoma appears to increase risk of melanoma by about twofold. A family cancer registry study assessed over 20,000 individuals with melanoma and found a standardized incidence ratio (SIR) of 2.62 for offspring of individuals with melanoma and 2.94 for siblings.[17] Slightly higher melanoma risks were found in a population-based study of 1,506,961 individuals in Western Australia; first-degree relatives(FDRs) of 5,660 individuals with melanoma showed an HR for melanoma of 3.58 (95% confidence interval [CI], 2.43–5.43).[18] Another population-based study of more than 238,000 FDRs of 23,000 melanoma patients found a lifetime cumulative risk of melanoma of 2.5% to 3%, which is about double the risk of the general population.[19] Risk based on family history is dependent not only on the number of individuals in the family who have a melanoma but also on the number of melanomas in each family member.[19] For example, the familial risk of melanoma was found to increase 2.2-fold (95% CI, 2.2–2.3) with a single FDR who has one melanoma and up to 16.3-fold (95% CI, 9.5–26.1) with a single FDR who has five or more melanomas.[19] When two or more family members were diagnosed with melanoma before age 30 years, the lifetime cumulative risk for the family members rose to 14%.[20]
A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that melanoma has a heritability of 58% (95% CI, 43%–73%), suggesting that more than half of the risk of melanoma is caused by inherited factors.[21] A study looking at the contribution of family history to melanoma risk showed a population-attributable fraction ranging from less than 1% in northern Europe to 6.4% in Australia,[22] suggesting that only a small percentage of melanoma cases are caused by familial factors. Rarely, however, in some families many generations and multiple individuals develop melanoma and are at much higher risk. For individuals from these families, the incidence of melanoma is higher for sun-protected rather than sun-exposed skin.[23]
The major hereditary melanoma susceptibility gene, CDKN2A, is found to be altered in approximately 35% to 40% of families with three or more melanoma cases. To date, more than half of the families with multiple cases of melanoma have no identified pathogenic variant.[24,25] The definition of a familial cluster of melanoma varies by geographical region, worldwide, because of the role played by UV radiation in melanoma pathogenesis. In heavily insolated regions (regions with high ambient sun exposure), three or more affected family members are required; in regions with lower levels of ambient sunlight, two or more affected family members are considered sufficient to define a familial cluster. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommend that an individual with any of the following characteristics be referred for a cancer genetics consultation:[26]
  • A personal history of three or more primary melanomas.
  • A personal history of melanoma and pancreatic cancer.
  • A personal history of melanoma and astrocytoma.
  • Three or more cases of melanoma and/or pancreatic cancer in FDRs.
  • Melanoma and astrocytoma in two FDRs.

Personal history of melanoma

A previous melanoma places one at high risk of developing additional primary melanomas, particularly for people with the most common risk factors for melanoma, such as cutaneous phenotype, family history, a pathogenic variant in CDKN2A, a great deal of early-life sun exposure, and numerous or atypical nevi. In the sporadic setting, approximately 5% of melanoma patients develop more than one primary cancer, while in the familial setting the corresponding estimate is 30%. This greater-than-expected rate of multiple primary cancers of the same organ is a common feature of hereditary cancer susceptibility syndromes; it represents a clinical finding that should raise the level of suspicion that a given patient’s melanoma may be related to an underlying genetic predisposition. Risk of a second primary melanoma after diagnosis of a first primary melanoma is approximately 5% and is greater for males and older patients.[27-30] A study in Sweden of more than 65,000 individuals with melanoma found a SIR of 2.8 (95% CI, 2.3–3.4) for a second melanoma in individuals with a family history of melanoma and a SIR of 2.5 (95% CI, 2.3–2.7) in individuals with no family history.[31] The risk of a second melanoma increased when the first melanoma was diagnosed before age 40 years (SIR, 4.7; 95% CI, 3.9–5.6%). The SIRs increased with increasing numbers of melanomas.

Personal history of nonmelanoma skin cancer

Having a personal history of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) is also associated with an increase in risk of a subsequent melanoma.[32-34] Depending on the study, this risk ranges from a nonsignificant increase for melanoma with a previous SCC of 1.04 (95% CI, 0.13–8.18) to a highly significant risk of 7.94 (95% CI, 4.11–15.35).[35,36] It is likely that this relationship is the result of shared risk factors (of which sun exposure is presumably one), rather than a specific genetic factor that increases risk of both. Pigmentary characteristics are critically important for the development of melanoma, and cutaneous phenotype (described above), in combination with excessive sun exposure, is associated with an increased risk of all three types of skin cancers.

Major Genes for Melanoma

CDKN2A/p16 and p14/ARF

The major gene associated with melanoma is CDKN2A/p16, cyclin-dependent kinase inhibitor 2A, which is located on chromosome 9p21. This gene has multiple names (MTS1INK4, and MLM) and is commonly called by the name of its protein, p16. It is an upstream regulator of the retinoblastoma gene pathway, acting through the cyclin D1/cyclin-dependent kinase 4 complex. This tumor suppressor gene has been intensively studied in multiple-case families and in population-based series of melanoma cases. CDKN2A controls the passage of cells through the cell cycle and provides a mechanism for holding damaged cells at the G1/S checkpoint to permit repair of DNA damage before cellular replication. Loss of function of tumor suppressor genes—a good example of which is CDKN2A—is a critical step in carcinogenesis for many tumor systems.
CDKN2A encodes two proteins, p16INK4a and p14ARF, both inhibitors of cellular senescence. The protein produced when the alternate reading frame (ARF) for exon 1 is transcribed instead of the standard reading frame exerts its biological effects through the p53 pathway. It mediates cell cycle arrest at the G1 and G2/M checkpoints, complementing p16’s block of G1/S progression—thereby facilitating cellular repair of DNA damage.
Pathogenic variants in CDKN2A account for 35% to 40% of familial melanomas [24] and fewer than 1% of unselected melanoma cases.[37] A study of more than 1,000 individuals in Spain showed that 6.6% of individuals with melanoma have a family history of two or more FDRs with melanoma, and up to 15% have a family history suggestive of familial melanoma that includes melanoma or pancreatic cancer diagnoses in FDRs or second-degree relatives(SDRs).[38] A large case series from Britain found that CDKN2A pathogenic variants were present in 100% of families with seven to ten individuals affected with melanoma, 60% to 71% of families with four to six cases, and 14% of families with two cases.[25] A similar study of Greek individuals with melanoma found CDKN2A pathogenic variants in 3.3% of single melanoma cases, 22% of familial melanoma cases, and 57% of individuals with multiple primary melanomas (MPM).[39] A study of 92 sequential cases of Italian individuals with familial atypical multiple mole-melanoma syndrome (defined as three or more individuals with primary cutaneous melanoma or one individual with MPM) found CDKN2A pathogenic variants in 20% of individuals, including three unrelated individuals with a p.D84V variant.[40Cascade testing identified 14 of 40 unaffected family members undergoing testing who carried their family’s CDKN2A pathogenic variant. However, a second study of 106 familial melanoma cases (defined as at least two melanoma cases) only found CDKN2A pathogenic variants in 8.3% of cases.[41] The frequency of CDKN2Apathogenic variants is as high as 22% in families with two cases of melanoma who have other features of hereditary melanoma, such as an age at diagnosis younger than 50 years or one or more individuals diagnosed with MPM.[42] A study of 587 individuals with a single primary melanoma or MPM found CDKN2A pathogenic variants in 19% of individuals with MPM relative to 4.4% of individuals with a single primary melanoma.[43CDKN2Apathogenic variants were found in 29.6% of individuals with three or more primary melanomas. Individuals with more than three primary melanomas and a family history of melanoma (undefined) had a frequency of CDKN2A pathogenic variants of 58.8%. Many pathogenic variants reported among families consist of founder variants, which are unique to specific populations and the geographic areas from which they originate.[44-51]
Depending on the study design and target population, melanoma penetrance related to CDKN2A pathogenic variants differs widely. One study of 80 multiple-case families demonstrated that the penetrance varied by country, an observation that was attributed to major differences in sun exposure.[52] For example, in Australia, the penetrance was 30% by age 50 years and 91% by age 80 years; in the United States, the penetrance was 50% by age 50 years and 76% by age 80 years; in Europe, the penetrance was 13% by age 50 years and 58% by age 80 years. In contrast, a comparison of families with the CDKN2A pathogenic variant in the United Kingdom and Australia demonstrated the same cumulative risk of melanoma; for CDKN2A carriers, the risk of developing melanoma seemed independent of ambient UV radiation.[53] Another study of individuals with melanoma identified in eight population-based cancer registries and one hospital-based sample obtained a self-reported family history and sequenced CDKN2A in all individuals. The penetrance was estimated as 14% by age 50 years and 28% by age 80 years.[30] The explanation for these differences lies in the method of identifying the individuals tested, with penetrance estimates increasing with the number of affected family members. The method of family ascertainment in the latter study made it much less likely that “heavily loaded” melanoma families would be identified. Coinheritance of MC1R variants also increases CDKN2Apenetrance; this genetic variant, described in further detail below, is therefore both a low-penetrance susceptibility gene and a modifier gene.[54] (Refer to the MC1R section of this summary for more information.) Other modifier loci have also been assessed in CDKN2Acarriers; interleukin-9 (IL9) and GSTT1 were the only loci with effects that reached statistical significance, suggesting that other minor risk factors may interact with major risk loci.[55,56]
One study reported a melanoma incidence rate of 9.9 per 1,000 person years among 354 FDRs and 2.1 per 1,000 person years among 391 SDRs of probands with a p16-Leiden (c.225-243del19) CDKN2A pathogenic variant (95% CIs of 7.4–13.3 and 1.2–3.8, respectively). These data indicate a melanoma rate that is much higher than that of the general population (12.9-fold increased incidence) for SDRs in untested relatives of carriers of CDKN2A pathogenic variants.[57]
A comparison of clinical features from 182 patients with CDKN2A pathogenic variants and 7,513 individuals without variants found that individuals with CDKN2A pathogenic variants were statistically significantly younger at diagnosis (mean age at diagnosis, 39.0 y vs. 54.3 y; P < .001). There was also a 5-year cumulative incidence of a second melanoma of 23.4% in carriers of pathogenic variants and a rate of 2.3% in controls who were negative for a pathogenic variant.[58] A study of pediatric patients with melanoma (aged 9–19 y) in melanoma-prone families reported a significant increase in melanoma prevalence (6-fold to 28-fold) relative to the general population. In this series, 7 of 21 patients (33%) with CDKN2A pathogenic variants were diagnosed with MPMs before age 20 years.[59] An Italian study performed genotype-phenotype correlations in 100 families with familial melanoma to determine clinical features predictive of the identification of a CDKN2A pathogenic variant. Probands with MPM, at least one melanoma with Breslow thickness greater than 0.4 mm, and more than three affected family members had a greater than 90% likelihood of having a pathogenic variant; probands with none of these features had less than a 1% likelihood of having a CDKN2A pathogenic variant. The most predictive feature was MPM.[60]
Melanomas in carriers of CDKN2A pathogenic variants largely resemble those found sporadically. A large study that compared melanoma pathology between CDKN2A carriers and individuals with sporadic melanoma found few significant differences, with a minor trend of increased pigmentation among pathogenic variant carriers.[61] Another study of more than 670 carriers of CDKN2A pathogenic variants and 1,258 carriers of wild-type or benign CDKN2A variants found that participants with pathogenic variants were more likely to be diagnosed at an earlier age (median age, 38 vs. 46 y) and have MPM (average number of melanomas, 2.3 vs. 1.4).[62] Two pathogenic variants in CDKN2A (p.Arg112dup, p.Pro48Leu) may be prognostic factors in patients with melanoma. After adjusting for age, sex, and tumor classification, carriers of these CDKN2A pathogenic variants had poorer melanoma-specific survival than did non-CDKN2A carriers (hazard ratio [HR], 2.5; 95% CI, 1.49–2.21).[63]
CDKN2A exon 1ß pathogenic variants (p14ARF) have been identified in a small percentage of families negative for p16INK4a pathogenic variants. In a study of 94 Italian families with two or more cases of melanoma, 3.2% of families had variants in p14ARF.[64] A patient with a balanced translocation between chromosomes 9 and 22 that disrupted p14ARF had melanoma, DNA repair deficiency, and features of DiGeorge syndrome, including deafness and malformed inner ears.[65]
CDKN2A, cutaneous phenotypes, and cancers other than melanoma
In a Melanoma Genetics Consortium (GenoMEL) study of 1,641 family members of melanoma probands, family members with a CDKN2A pathogenic variant were more likely to have atypical nevi than were family members of CDKN2A noncarriers (odds ratio [OR], 1.65; 95% CI, 1.18–2.28).[66] Another study of individuals in Sweden with MPM and two or more cases of melanoma in their first-, second-, or third-degree relatives found CDKN2Apathogenic variants in 43 of 100 cases. Familial MPM cases with CDKN2A variants, familial MPM cases wild-type for CDKN2A, and nonfamilial MPM cases all showed increased risks of future cutaneous SCCs compared with controls (relative risk [RR], 4.8; 95% CI, 1.5–15.1).[67]
Results from the Genes, Environment, and Melanoma study showed that FDRs of carriers of CDKN2A pathogenic variants with melanoma had an approximately 50% increased risk of cancers other than melanoma, compared with FDRs of other melanoma patients.[68] Cancers with increased risk in this population included gastrointestinal cancers (RR, 2.4; 95% CI, 1.4–3.7), pancreatic cancers (RR, 7.4; 95% CI, 2.3–18.7), and Wilms tumor (RR, 40.4; 95% CI, 3.4–352.7). A Spanish study of the FDRs of 66 melanoma patients with known CDKN2A pathogenic variants also showed an increase in prevalence of other cancers, including pancreatic (prevalence ratio [PR], 2.97; 95% CI, 1.72–5.15), lung (PR, 3.04; 95% CI, 1.93–4.80), and breast cancers (PR, 2.19; 95% CI, 1.36–3.55).[69] A large registry study from Sweden that included 27 families carrying the Arg112dup pathogenic variant in CDKN2Aobserved excess nonmelanoma cancers in both carriers (n = 120) and FDRs (n = 275). For carriers of CDKN2A pathogenic variants, increased risks relative to a control population were seen for pancreatic (RR, 43.8; 95% CI, 13.8–139), upper digestive (RR, 17.1; 95% CI, 6.3–46.5), respiratory (RR, 15.6; 95% CI, 5.4–46.0), and breast cancers (RR 3.0; 95% CI, 0.9–9.9), among others (all cancers: RR, 5.0; 95% CI, 3.7–7.3). The RRs in FDRs were 20.6 (95% CI, 11.6–36.7) for pancreatic cancers, 6.0 (95% CI, 2.8–13.1) for respiratory cancers, 3.3 (95% CI, 1.5–7.6) for upper digestive cancers, and 1.9 (95% CI, 0.9–4.0) for breast cancers, with a RR of all cancers of 2.1 (95% CI, 1.6–2.7). A lesser-increased cancer risk was seen among SDRs. They also observed a significant association between smoking and risk of pancreatic, respiratory, and upper digestive cancers, with an OR of 9.3 (95% CI, 1.9–44.7) for ever-smoking carriers compared with never-smoking carriers.[70]
A few studies have identified individuals with sarcoma who have germline pathogenic variants in CDKN2A, but the number of cases is too small to determine the risk of sarcoma associated with this gene.[71,72] One patient with features of Li-Fraumeni syndrome did not carry a TP53 pathogenic variant, but a deletion of CDKN2A and CDKN2B.[72] A whole-exome sequencing study of a Li-Fraumeni–like family with three individuals with soft tissue sarcoma identified a shared pathogenic CDKN2A variant.[71] An evaluation of 474 melanoma families with cases of sarcoma and 190 TP53 variant–negative Li-Fraumeni–like families found eight additional individuals with sarcoma and pathogenic CDKN2A variants.
Pancreatic cancer
A subset of families carrying a CDKN2A pathogenic variant also displays an increased risk of pancreatic cancer.[73,74] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%.[75] The RR has been reported as high as 47.8.[76] Although at least 18 different variants in p16 have been identified in such families, specific pathogenic variants appear to have a particularly elevated risk of pancreatic cancer.[24,77] Pathogenic variants affecting splice sites or Ankyrin repeats were found more commonly in families with both pancreatic cancer and melanoma than in those with melanoma alone. The p16Leiden variant is a 19-base pair deletion in CDKN2A exon 2 and is a founder pathogenic variant originating in the Netherlands. In one major Dutch study, 19 families with 86 members who had melanoma also had 19 members with pancreatic cancer in their families, a cumulative risk of 17% by age 75 years. In this study, the median age of pancreatic cancer onset was 58 years, similar to the median age at onset for sporadic pancreatic cancer.[78] However, other reports indicate that the average age at diagnosis is 5.8 years earlier for these carriers of pathogenic variants than for those with sporadic pancreatic cancer.[79] Geographic variation may play a role in determining pancreatic risk in these families carrying known pathogenic variants. In a multicontinent study of the features of germline CDKN2A pathogenic variants, Australian families carrying these variants did not have an increased risk of pancreatic cancer.[80] It was also reported that similar CDKN2A variants were involved in families with and without pancreatic cancer;[81] therefore, there are additional factors involved in the development of melanoma and pancreatic cancer. Some families with CDKN2A pathogenic variants may have a pattern of site-specific pancreatic cancer only.[82-84] Conversely, melanoma-prone families that do not have a CDKN2A pathogenic variant have not been shown to have an increased risk of pancreatic cancer.[78]
In a review of 110 families with multiple cases of pancreatic cancer, 18 showed an association between pancreatic cancer and melanoma.[85] Only 5 of the 18 families with cases of both pancreatic cancer and melanoma had individuals with multiple dysplastic nevi. These 18 families were assessed for pathogenic variants in CDKN2A; variants were identified in only 2 of the 18 families, neither of which had a dysplastic nevi phenotype.
Melanoma-astrocytoma syndrome
The melanoma-astrocytoma syndrome is another phenotype caused by pathogenic variants in CDKN2A. The possible existence of this disorder was first described in 1993.[86] A study of 904 individuals with melanoma and their families found 15 families with 17 members who had both melanoma and multiple types of tumors of the nervous system.[87] Another study found a family with multiple melanoma and neural cell tumors that appeared to be caused by loss of p14ARF function or to disruption of expression of p16.[88] Plexiform neurofibromas have also been reported in individuals with deleterious CDKN2Avariants.[89-92]

CDK4 and CDK6

Cyclin-dependent kinases have important roles in progression of cells from G1 to S phase. CDK4 and CDK6 partner with the cyclin–D associated kinases to accelerate the function of the cell cycle. Phosphorylation of the retinoblastoma (Rb) protein in G1 by cyclin-dependent kinases releases transcription factors, inducing gene expression and metabolic changes that precede DNA replication, thus allowing the cell to progress through the cell cycle. These genes are of conceptual significance because they are in the same signaling pathway as CDKN2A.
Germline CDK4 pathogenic variants are very rare, being found in only a handful of melanoma kindreds.[93-95] All described families demonstrated a substitution of amino acid 24, suggesting this position as a variant hotspot within the CDK4 gene. Three Latvian families with melanoma have a R24H substitution arising on the same haplotype, which suggests that it could be a founder pathogenic variant in this population.[96] A CDK4pathogenic variant affects binding of p16 with its subsequent inhibition of CDK4functionality. With constitutive activation of germline CDK4CDK4 acts as a dominant oncogene. A small study showed that the melanoma cancer risk in 17 families with CDK4pathogenic variants was similar to the risk seen in families with CDKN2A variants.[97] (Refer to the CDKN2A/p16 and p14/ARF section of this summary for more information.)
Despite its functional similarity to CDK4germline variants in CDK6 have not been identified in any melanoma kindreds.[98]

Telomere maintenance genes

Telomerase reverse transcriptase (TERT)
Linkage of melanoma to a region of chromosome 5p was observed in a single, large kindred with multiple melanomas and other cancers.[99] Sequencing demonstrated a pathogenic variant in the promoter region of a subunit of TERT, which demonstrated increased promoter activity in construct assays. This variant cosegregated with melanoma and other cancers (ovarian, renal, bladder, and lung), with multiple cancers observed in single individuals. At least one affected family member was observed to have numerous nevi. Somatic pathogenic variants in the same region were observed in 125 of 168 sporadic melanomas in the same report.[99] A separate study reported pathogenic variants that also increased promoter activity in the same TERT promoter region in 50 of 70 sporadic melanomas.[100] Similar pathogenic variants were seen in 16% of a diverse set of established cancer cell lines, suggesting this might be a common activation variant in multiple cancer types. The frequency of this variant in melanoma families has not been fully investigated, but one study of 273 families with three or more cases of melanoma identified only one family (with 7 melanoma cases) that carried a c.-57 T>G promoter variant.[101] A study of 106 familial melanoma cases (defined as at least two melanoma cases or MPM in the proband) found that 47% of MPM cases and 58% of familial melanoma cases carried a risk-associated TERT promoter variant, rs2853669.[41] The prevalence of this variant in the general population is estimated to be between 25% and 29%.[102]
POT1
Exome and genome-sequencing in individuals from hereditary melanoma families led to the identification of missense pathogenic variants in POT1 that segregate with disease in numerous studies.[103,104] A POT1 Ser270Asn missense pathogenic variant was found in 5 of 56 unrelated melanoma families from Italy.[103] This variant was not observed in over 2,000 Italian controls. Ser270Asn is thought to be a founder pathogenic variant, as all families with the variant shared a haplotype. Additional POT1 missense pathogenic variants, including Tyr89Cys, Arg137His, and Gln623His, were identified in other melanoma families and were not seen in unaffected controls.[103,104] Together, POT1 pathogenic variants were found in approximately 4% of melanoma families who lacked CDKN2A or CDK4 variants, suggesting it may be another gene in hereditary melanoma. POT1 binds to single-stranded telomeric repeat regions and is thought to aid in maintenance of telomerelength. Most of the variants segregating in families occur in the two oligonucleotide/oligosaccharide-binding domains of the protein, which are the portion of the protein critical for binding DNA. Individuals carrying POT1 pathogenic variants showed longer telomere lengths than melanoma cases without the POT1 variants, suggesting a link between disruption in normal telomere length and melanoma.[103,104] The clinical utility of testing this gene has not yet been established.
ACD and TERF2IP
In one study, 510 melanoma families were screened by next-generation sequencing for pathogenic variants in genes in the shelterin complex, which protects chromosomal ends. Six families were found to have variants in ACD, and four families had variants in TERF2IP.[105] The ACD variants clustered in the POT1 binding domain. Because some of these variants did not lead to a truncated protein, the functional significance is not confirmed.

DNA repair genes

Xeroderma pigmentosum (XP) patients with defective DNA repair have a more than 1,000-fold increase in melanoma risk. These patients are diagnosed with melanoma at a significantly younger age than individuals in the general population; on average, melanoma diagnosis occurs at age 22 years in XP patients.[106] The anatomic site distribution of melanomas in XP patients is similar to that of the general population.[107,108]
Genetic polymorphisms associated with DNA repair genes have been associated with mildly increased melanoma risk in the general population.[109] A meta-analysis of eight case-control studies comprising more than 5,000 cases and 7,000 controls found that individuals carrying the Asp1104His polymorphism in XPG had an increased risk of melanoma (OR, 2.42; 95% CI, 2.26–2.60).[110]
(Refer to the Xeroderma pigmentosum section in the Squamous Cell Carcinoma section of this summary for more information.)

BRCA1-associated protein 1 (BAP1)

BAP1 has recently emerged as a gene implicated both in sporadic and hereditary melanomas.[111] Originally described in a cohort of uveal melanoma patients, BAP1 is a tumor suppressor gene that was found to be inactivated in 84% of uveal melanoma patients with metastases.[112] Although the majority of these variants were somatic, one patient was found to have a germline frameshift variant. A phenotype associated with BAP1pathogenic variants was subsequently described.[113] Two families with multiple, elevated melanocytic tumors that were clinically and histopathologically distinct from other melanocytic neoplasms were found to have inactivating germline pathogenic variants of BAP1. These tumors, which have been termed melanocytic BAP1-mutated atypical intradermal tumors, or MBAITs, are found throughout the body, generally measure approximately 5 mm, and begin to appear in the second decade of life. MBAITs are 2 mm to 10 mm in diameter, and affected individuals (about 67% of BAP1 pathogenic variant carriers) can have 5 to more than 50 skin lesions.[113,114] Cases of cutaneous melanoma were present in these families, but the rate of malignant progression is thought to be low due to the relative lack of melanomas in comparison with the number of more papular tumors. This syndrome has been called BAP1 tumor syndrome or the COMMON (cutaneous and ocular melanoma and atypical melanocytic proliferation with other internal neoplasms) syndrome, and it is inherited in an autosomal dominant pattern.[115] Further investigation has supported the association between familial cutaneous melanoma and uveal melanoma in BAP1 carriers.[116-120] However, potentially pathogenic BAP1 germline variants occur in a low percentage of melanoma cases. One targeted sequencing study of 1,109 unselected cutaneous melanoma cases found only seven germline missense pathogenic variants (<1%).[37] A second series of 1,977 melanoma cases and 754 controls identified 22 rare variants in BAP1 among cases and 5 rare variants among controls; three of the variants found only among cases were confirmed to disrupt BAP1 function and were associated with family histories of other BAP1-associated cancers.[121] In support of a link between melanoma risk and BAP1, in one series, about 18% of individuals with a BAP1pathogenic variant developed melanoma.[117] In addition, although data are currently limited, patients with germline pathogenic variants in BAP1 may be at increased risk of lung adenocarcinoma, mesothelioma, BCC, and clear cell carcinoma of the kidney.[114,116,118,119,122,123]
Other studies have reported pathogenic variants in BAP1. A missense pathogenic variant (p.Leu570Val) in a family with multiple cases of melanoma was described to affect splicingand result in a frameshift. This family also had cases of uveal melanoma and paraganglioma.[122] Another family with a Y646X BAP1 pathogenic variant had multiple cancers, including multiple cutaneous melanomas and BCCs, uveal melanoma, and mesotheliomas.[124] The authors hypothesized that a gene-environment interaction between BAP1 pathogenic variants and UV radiation and asbestos exposure contributed to the high incidence of multiple cancers in this family.

PTEN hamartoma tumor syndromes (including Cowden syndrome)

Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[125] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[126] The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN pathogenic variant, irrespective of clinical presentation.
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. Pathogenic variants of PTEN are diverse, including nonsense, missense, frameshift, and splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif, and several recurrent pathogenic variants have been observed.[127] Individuals with variants in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[128]
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[129,130] These included major, minor, and pathognomonic criteria consisting of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [131] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[132] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTENpathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[26] Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[26,132] Additionally, a predictive model that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[133]
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTENtesting in the United States, Europe, and Asia.[134] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN pathogenic variants. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.[135]
The risk of melanoma in PTEN carriers is controversial. In the study of 100 patients referenced above, four women and four men were diagnosed with melanoma and less than one case was expected, for a SIR of 28.3 for women (95% CI, 7.6–35.4) and 39.4 for men (95% CI, 10.6–100.9) (P < .001).[135] In the ICC study described above, an elevated SIR of 8.5 (95% CI, 4.1–15.6) was reported in 368 carriers of PTEN pathogenic variants.[134] In this cohort, the estimated lifetime risk of melanoma in carriers of PTEN pathogenic variants was 6% (range, 1.6%–9.4%). However, it is important to recognize that a subsequent prospective study did not observe an elevated melanoma risk.[136] In this study, only 1 of 180 carriers was diagnosed with melanoma. (Refer to the PDQ summaries on the Genetics of Colorectal Cancer and the Genetics of Breast and Gynecologic Cancers for more information about risks of other cancers in PTEN hamartoma tumor syndromes.)

O-6-methylguanine DNA methyltransferase (MGMT)

In one study of 64 families with familial melanoma that looked for germline genomic rearrangements of 34 tumor suppressor genes, a deletion of the promoter and exon 1 of the MGMT gene was found.[137] The wild-type allele was lost in individuals with melanoma in this family. MGMT is an enzyme involved in DNA repair. Additional melanoma families with variants in this gene need to be identified before a definitive connection between MGMT and familial melanoma can be made.

Additional candidate regions for familial melanoma susceptibility

Several additional loci for familial melanoma have been identified through genome-wide studies. A melanoma susceptibility locus on 1p22 was identified through a linkage analysisof 49 Australian families who had at least three melanoma cases and who were negative for CDKN2A and CDK4 pathogenic variants.[138] Deletion mapping in tumors shows a minimal region of loss of a 9-Mb interval within the peak linkage region, but none of the linkage families have pathogenic variants in the genes tested thus far.[139] A GWAS of individuals from 34 high-risk melanoma families revealed three single nucleotide polymorphisms (SNPs) on 10q25.1 associated with melanoma risk.[140] The ORs for risk for the SNPs ranged from 6.8 to 8.4. Subsequent parametric linkage analysis in one family showed logarithm of the odd scores of 1.5, whereas the other two families assessed did not show linkage. No obvious candidate gene was identified in the genomic region of interest. Two genome-wide linkage studies of 35 and 42 Swedish families identified evidence of linkage on chromosomal regions 3p29, 17p11-12, and 18q22.[141,142] No causative genes have been confirmed, but candidates map to all of the loci. None of these loci have been confirmed in independent studies.
Several GWAS have suggested a risk locus for melanoma on chromosome 20q11, with an OR of 1.27.[143,144] This is the location of the ASIP locus that encodes the agouti signaling protein, which controls hair color during the hair growth cycle in some mammals. It acts as an antagonist to MC1R. Although ASIP variation has been associated with variation in human pigmentation,[145] initial studies did not demonstrate an association with melanoma.[146] Additionally, variants in a transcription factor for ASIPNCOA6, which is also on chromosome 20, showed a maximum OR of 1.82.[144] However, no interaction was seen between these variants and MC1R variants and melanoma risk. The mechanism by which variants at 20q11 cause an increased risk of melanoma remains unclear.
Other risk loci have been reported on chromosomes 2, 5, 6, 7, 9, 10, 11, 15, 16, and 22.[147-152] A GWAS of melanoma published in 2014 examined eight of the loci with a previous significant association with melanoma, but without a confirmed causal gene.[151] Researchers were able to confirm seven of eight loci and found some evidence supporting the eighth. These included the chromosome 20 locus discussed above and a 9p21 locus distinct from CDKN2A. Candidate genes at these loci seem to be clustered in functional groups associated with skin pigmentation and nevus development, both traits with a known melanoma association.[153] (Refer to the Risk Factors for Melanoma section of this summary for more information about these traits.) A multicenter meta-analysis of 11 GWAS and two data sets included 15,990 cutaneous melanoma cases and 26,409 controls. They reported five melanoma susceptibility loci that involved putative melanocyte regulatory elements, telomere biology, and DNA repair.[152]
A publically available database, MelGene, maintains lists of variants that have been associated with melanoma risk through GWAS. MelGene also includes network and potential functional relationships between these genes and variants.[154]

9q21 and GOLM1

When the first data linking CDKN2A pathogenic variants to melanoma risk became available, it was clear that these variants did not account for all the melanoma tumors in which 9p21 loss of heterozygosity could be demonstrated. In fact, 51% of informative cases had deletions that did not involve somatic pathogenic variants in CDKN2A.[155] There are data that the golgi membrane protein 1 (GOLM1) gene, mapping to 9q21, may be involved in melanoma risk. Exome sequencing of DNA from 12 sets of cousins with cutaneous melanoma who were negative for known high-risk melanoma genes led to the identification of a rare GOLM1 variant (rs149739829) in three affected individuals in one pedigree.[156] Two additional pairs of related melanoma cases with the putative risk allele were identified. Family-based case-control studies showed association with melanoma risk (OR, 9.81; P < .001). In a population-based case-control study of 1,534 melanoma cases, unselected for family history, and 1,146 controls, there was an increased risk of melanoma in individuals that carried the GOLM1 rs149739829 risk allele (OR, 2.45; P = .02).[156]

Minor Genes (Genetic Modifiers) for Melanoma

MC1R

The MC1R gene, otherwise known as the alpha melanocyte-stimulating hormone receptor, is located on chromosome 8. Partial loss-of-function pathogenic variants, of which there are at least ten, are associated not only with red hair, fair skin, and poor tanning, but also with increased skin cancer risk independent of cutaneous pigmentation.[157-160] A comprehensive meta-analysis of more than 8,000 cases and 50,000 controls showed the highest risk of melanoma in individuals with MC1R variants associated with red hair; however, alleles not associated with red hair have also been linked to increased melanoma risk.[161] Additional phenotypic associations have been found. In different studies, MC1Rvariants were found to be associated with lentigo maligna melanoma (OR, 2.16; 95% CI, 1.07–4.37; P = .044) [162] and increased risk of melanoma for individuals with no red hair, no freckles, and Fitzpatrick type III or IV skin (summary OR, 3.14; 95% CI, 2.06–4.80).[163] Pooled studies of 5,160 cases and 12,119 controls from 17 sites calculated that melanoma risk attributable to MC1R variants is 28%, suggesting that these variants may be an important contributor to melanoma risk in the general population.[163]
A scoring system for MC1R polymorphisms has been proposed to identify associations between the degree of functional impairment of the melanogenesis pathway and the clinical characteristics of the patients and their melanoma presentation. The initial classification system designated MC1R variants that were strongly associated with red hair and fair skin as strong (R) red hair variants with an OR of 63.3 (95% CI, 31.9–139.6), whereas those with weaker association were designated weak (r) variants and had an OR of 5.1 (95% CI, 2.5–11.3).[164] This work was expanded to evaluate additional MC1R variants and to add a summary score between zero and four, with a consensus sequence allele valued at zero, an r allele valued at one, and an R allele valued at two.[165] In a study of 1,044 melanoma patients, those with a score of three or more were more likely to develop melanoma before age 50 years (OR, 1.47; 95% CI, 1.01–2.14).[166] The MC1R score has been subsequently found to have implications for a survival benefit in melanoma patients. There was a lower risk of death in melanoma patients with no consensus MC1R alleles (HR, 0.78; 95% CI, 0.65–0.94) when compared with those with at least one consensus allele.[165] An independent study found a similar survival benefit in individuals carrying two MC1Rvariants (HR, 0.60; 95% CI, 0.40–0.90).[167]
A meta-analysis showed that the more MC1R variants an individual carried, the higher the risk of SCC and BCC. Individuals with two or more MC1R variants had a summary OR of 2.48 (95% CI, 1.96–3.15) for BCC and a summary OR of 2.80 (95% CI, 1.71–4.57) for SCC; these risks appeared to be stronger in individuals with red hair.[160] Data from a study of individuals diagnosed with BCC before age 40 years also found a stronger association between BCC and MC1R variants in those with phenotypic characteristics not traditionally considered high risk.[168]
Although variants in this gene are associated with increased risk of all three types of skin cancer, adding MC1R information to predictions based on age, sex, and cutaneous melanin density offers only a small improvement to risk prediction.[169,170] However, one study that examined predictors of early-onset melanoma in both population- and family-based studies showed that the addition of MC1R genotypes improved the area under the receiver operator curve (AUC) by 6% over demographic information alone (P < .001). When genotypes were combined with nevi and history of NMSC, the AUC was 0.78 (95% CI, 0.75–0.82) for self-reported nevi and 0.83 (95% CI, 0.80–0.86) for physician-described nevi.[171]
MC1R variants can also modify melanoma risk in individuals with CDKN2A pathogenic variants. A study consisting of 815 carriers of CDKN2A pathogenic variants looked at four common non-synonymous MC1R variants and found that having one variant increased the melanoma risk twofold, but having two or more variants increased melanoma risk nearly sixfold.[172] After stratification for hair color, the increased risk of melanoma appeared to be limited to subjects with brown or black hair. These data suggest that MC1R variants increase melanoma risk in a manner independent of their effect on pigmentation. A meta-analysis of individuals with CDKN2A pathogenic variants showed that those with greater than one variant in MC1R had approximately fourfold increased risk of melanoma. Individuals with one or more variants in MC1R showed an average 10-year decrease in age of onset from 47 to 37 years.[173] In contrast, a large consortium study did not show as large a decrease in age at onset of melanoma.[172] Another study of Norwegian melanoma cases and controls showed that carriers of CDKN2A pathogenic variants had an increased risk of melanoma when they carried either the Arg160Trp or Asp84Glu MC1Rvariants.[174]

Other pigmentary genes

Pathogenic variants in albinism genes may also account for a small proportion of familial melanoma. For example, variants in TYRP1TYR, and OCA2 were observed at an increased frequency in one study of individuals with familial cutaneous melanoma compared with population controls.[175] Further studies are needed to confirm these findings. (Refer to the Oculocutaneous albinism section in the Squamous Cell Carcinoma section of this summary for a discussion of the pigmentary genes OCA2SLC45A2TYR, and TYRP1, which have also been associated with melanoma.)

MITF

Whole-genome sequencing led to the identification of an E318K variant in the microphthalmia–associated transcription factor (MITF) gene in a family with seven cases of melanoma.[176] MITF is a transcription factor that has been shown to regulate multiple genes important in melanocyte function and the E318K variant impairs the normal SUMOylation of MITF. The E318K variant was found in three of seven melanoma cases tested in this family and was present at a higher frequency in melanoma cases than controls. Six additional families among 182 families negative for CDKN2A and CDK4pathogenic variants were found to carry the variant. Another study found six individuals with the E318K variant in a cohort of 168 individuals with melanoma (frequency, 0.018); no unaffected controls carried the variant. Individuals with the E318K variant were more likely to be fair skinned, with high nevus counts and high freckling scores, and all had MPM.[177] There was also a high frequency of amelanotic melanomas. Another study showed that the E318K variant was associated with melanoma (OR, 1.7; 95% CI, 1.1–2.7) but that it had a stronger effect in individuals with dark hair (OR, 3.8; 95% CI, 1.5–9.6).[178] Population-based studies in Australia and the United Kingdom consisting of 3,920 cases and 4,036 controls show a twofold increased risk of melanoma in carriers.[176] Spanish and Italian case-control studies found ORs of approximately 3.0 for melanoma in carriers of the E318K variant.[179,180] However, the Spanish study also included melanoma cases from families with and without CDKN2A pathogenic variants.[179] The prevalence of the MITF E318K variant was similar in families with and without CDKN2A pathogenic variants (2.9% and 1.9%, respectively). The MITF E318K variant may be associated with nodular melanoma, as 5 of 12 carriers (42%) in the Italian study had nodular melanoma compared with only 90 of 655 (14%) melanoma patients not carrying the variant.[180] These data suggest that the E318K variant may be a moderate-risk allele for melanoma. However, these data remain controversial. Another study in a Polish population of 4,266 cancer patients and 2,114 controls found no association with melanoma.[181]

BRCA2

The Breast Cancer Linkage Consortium found that pathogenic variants in BRCA2 were associated with a RR of melanoma of 2.58 (95% CI, 1.3–5.2).[182] A second study reported a similar increase in risk, although the result fell short of statistical significance.[183] In contrast, another large cohort study of carriers of BRCA2 pathogenic variants in the Netherlands showed a decreased risk of melanoma; however, the expected incidence of melanoma was rare in this population, and this result reflects a difference of only two melanoma cases.[184] Ashkenazi Jewish melanoma patients have not been shown to have an increased prevalence of the three founder pathogenic variants in BRCA1 and BRCA2 that are commonly found in this population.[185] Overall, the evidence for increased risk of melanoma in the BRCA2 population is inconsistent at this time.[186]
(Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Melanoma Risk Assessment

Patients with a personal history of melanoma or dysplastic nevi should be asked to provide information regarding a family history of melanoma and other cancers to detect the presence of familial melanoma. Age at diagnosis in family members and pathologic confirmation, if available, should also be sought. The presence of MPM in the same individual may also provide a clue to an underlying genetic susceptibility. Approximately 30% of affected individuals in hereditary melanoma kindreds have more than one primary melanoma, versus 4% of sporadic melanoma patients.[187] Family histories should be updated regularly; an annual review is often recommended.
For individuals without a personal history of melanoma, several models have been suggested for prediction of melanoma risk.[188] The models differ in performance with respect to sensitivity and specificity, including differences by sex in some models. Data from the Nurses' Health Study were used to create a model that included gender, age, family history of melanoma, number of severe sunburns, number of moles larger than 3 mm on the limbs, and hair color.[189] The concordance statistic for this model was 0.62 (95% CI, 0.58–0.65). Another measure of baseline melanoma risk was derived from a case-control study of individuals with and without melanoma in the Philadelphia and San Francisco areas.[190] This model focused on gender, history of blistering sunburn, color of the complexion, number and size of moles, presence of freckling, presence of solar damage to the skin, absence of a tan, age, and geographic area of the United States. Attributable risk with this model was 86% for men and 89% for women. This predictive tool, the Melanoma Risk Assessment Tool, is available online. However, this tool was developed using a cohort of primarily white individuals without a personal or family history of melanoma or NMSC. It is designed for use by health professionals, and patients are encouraged to discuss results with their physicians. Additional external validation is appropriate before this tool can be adopted for widespread clinical use. Professional organizations have published genetic counseling referral guidelines for individuals with a history of melanoma.[26] (Refer to the Family history section of this summary for more information.)
Two models have been developed to predict the probability of identifying germline CDKN2Apathogenic variants in individuals or families for research purposes (Table 8). MelPREDICT [191] uses logistic regression and MelaPRO [192] uses a Mendelian modeling algorithm to estimate the chance of an individual carrying a pathogenic variant in CDKN2A.
Table 8. Characteristics of Common Models for Estimating the Likelihood of a CDKN2A Pathogenic Variant
 MelaPRO [192]MelPREDICT [191]
Features of ModelIncorporates three different penetrance modelsUses logistic regression
Can input information for large familiesAccounts for a number of primary melanomas in family and age of onset
Includes information for unaffected individuals on risk of developing melanoma 
LimitationsThe model has not been validated on unaffected probands.Cannot incorporate complex pedigree structure information into the model
 Does not take into account domain-specific penetrances or geographical differences in penetrance

Genetic testing

Clinical testing is available to identify germline pathogenic variants in CDKN2A. Multiple centers in the United States and overseas offer sequence analysis of the entire coding region, and a number of centers perform deletion and duplication analysis. For information on genetic testing laboratories, refer to GeneTests: Laboratory Directory.
Expert opinion regarding testing for germline pathogenic variants of CDKN2A follows two divergent schools of thought. Arguments for genetic testing include the value of identifying a cause of disease for the individual tested, the possibility of improved compliance with prevention protocols in individuals with an identified pathogenic variant, and the reassurance of a negative testing result in individuals in a family carrying a pathogenic variant. However, a negative test result in a family that does not have a known pathogenic variant is uninformative; the genetic cause of disease in these patients must still be identified. It should also be noted that members of families carrying a CDKN2Apathogenic variant who do not carry the variant themselves may remain at increased risk of melanoma. At this time, identification of a CDKN2A pathogenic variant does not affect the clinical management of the affected patient or family members. Close dermatologic follow-up of these people is indicated, regardless of genetic testing result, and pancreatic cancer screening has unclear utility, as discussed below.[193]
If genetic testing is undertaken in this population, experts suggest that it be performed after complete genetic counseling by a qualified genetics professional who is knowledgeable about the condition.
Refer to the Psychosocial Issues in Familial Melanoma section of this summary for information about psychosocial issues related to genetic testing for melanoma risk.

Interventions

High-risk population

Management of members of melanoma-prone families
High-risk individuals, including first- and second-degree family members in melanoma-prone families, should be educated about sun safety and warning signs of melanoma.[57] Regular examination of the skin by a health care provider experienced in the evaluation of pigmented lesions is also recommended. One guideline suggests initiation of examination at age 10 years and conducting exams on a semiannual basis until nevi are considered stable, followed by annual examinations.[194] These individuals should also be taught skin self-examination techniques, to be performed on a monthly basis. Observation of lesions may be aided by techniques such as full-body photography and dermoscopy.[195,196] A cost-utility analysis has demonstrated the benefits of screening in the high-risk population.[197]
Biopsies of skin lesions in the high-risk population should be performed using the same criteria as those used for lesions in the general population. Prophylactic removal of nevi without clinically worrisome characteristics is not recommended. The reasons for this are practical: many individuals in these families have a large number of nevi, and complete removal of them all is not feasible, since new atypical nevi continue to develop. In addition, individuals with increased susceptibility to melanoma may have cancer arise de novo, without a precursor lesion such as a nevus.[198]
Standard recommendations for screening and management of patients with BAP1germline pathogenic variants are not currently available, but one group of experts has recommended annual ocular examinations starting at age 16 years, full-body skin examinations starting at age 20 years, and consideration of annual renal ultrasound and/or abdominal magnetic resonance imaging every 2 years.[123]
At present, chemoprevention of melanoma in high-risk individuals remains an area of active investigation; however, no medications are recommended for melanoma risk reduction at this time.
Pancreatic cancer screening in CDKN2A pathogenic variant carriers
Screening for pancreatic cancer remains an area of investigation and controversy for carriers of CDKN2A pathogenic variants. At present, no effective means of pancreatic cancer screening is available for the general population; however, serum and radiographic screening measures are under study in high-risk populations. One proposed protocol [199] suggested starting pancreatic screening in high-risk families at age 50 years or 10 years before the youngest age at diagnosis of pancreatic cancer in the family, whichever came first. In this algorithm, asymptomatic patients would be screened annually with serum cancer antigen 19-9 and endoscopic ultrasound, whereas symptomatic patients or those with abnormal test results would undergo endoscopic retrograde cholangiopancreatography (ERCP) and/or spiral computed tomography (CT) scanning. A study evaluating use of endoscopic ultrasound and ERCP in high-risk families concluded that these procedures were cost-effective in this setting.[200]
The disadvantages of screening include the limitations of available noninvasive testing methods and the risks associated with invasive screening procedures. ERCP is the gold standard for identifying early cancers and precancerous lesions in the pancreas. However, serious complications such as bleeding, pancreatitis, and intestinal perforation can occur with this procedure. Implementation of pancreatic screening in carriers of CDKN2Apathogenic variants is further complicated by the apparent lack of increased incidence of pancreatic cancer in many of these families.
Most experts suggest that pancreatic cancer screening should be considered for carriers of CDKN2A pathogenic variants only if there is a family history of pancreatic cancer and, even then, only in the context of a clinical trial.

General population

Screening
Screening for melanoma is not recommended by the U.S. Preventive Services Task Force (USPSTF), although the American Cancer Society, the Skin Cancer Foundation, and the American Academy of Dermatology recommend monthly skin self-examination and regular examination by a physician for people older than 50 years or those with multiple melanomas or dysplastic nevus syndrome. USPSTF does not recommend screening because they judge that the evidence for efficacy is not strong. On the other hand, the groups who recommend screening base their support on the logic that screening will find melanomas early in their development and that those melanomas will not progress further. This position is supported by the unusually detailed prognostic information that can be obtained through histopathology examination of primary melanoma tumors, in which a variety of features (lack of invasion through the basement membrane, thin cancers [≤ 0.76 mm], absence of vertical growth phase disease, ulceration, and histologic regression) have been solidly linked to favorable prognosis.[201]
The question of whether the lesions found through screening are programmed to progress or whether they will grow very slowly and never progress to metastatic disease has not been answered.[202] One study showed that skin self-examination might prevent the formation of melanomas and that skin self-examination was associated with reduced 5-year mortality. The primary preventive effect could be biased by the fact that healthy individuals who participate in studies are somewhat more likely to participate in screening activities.[203] The 63% reduction in mortality observed in that study was not statistically significant. Therefore, until a randomized trial of screening and mortality is undertaken, the utility of general population screening remains uncertain.
Nonetheless, it is well documented that, when a patient is under the care of a dermatologist, his or her second melanoma is diagnosed at a thinner Breslow depth than the index melanoma.[204-206] As survival is inversely correlated with Breslow depth for melanoma, early diagnosis leads to better prognosis.
Primary prevention
Primary prevention for melanoma consists of avoiding intense intermittent exposure to UV radiation, both solar and nonsolar. It should be stressed that the dose-response levels for such exposure are not defined, but that large, sporadic doses of UV radiation on skin are those epidemiologically most associated with later development of melanoma. Sunburn is a marker of that exposure, so that the amount of time spent in the sun should be calculated to avoid sunburn if at all possible.[207] Tanning beds should be avoided, as studies suggest that they increase the risk of melanoma.[208,209] In an attempt to prevent skin cancer, more than 40 states have laws prohibiting tanning bed use by teenagers or requiring signed parental consent for teenagers who request tanning bed use.[210]
Primary prevention should stress the need for caution in the sun and protection in the form of clothing, shade, and sunscreens when long periods of time are spent outdoors or at times of day when sunburn is likely. High-risk patients should understand that the application of sunscreens should not be used to prolong the time they spend in the sun because UV radiation makes its way through the sunscreen over time.[211,212] However, regular sunscreen use has been shown to reduce melanoma incidence in a prospective, randomized controlled trial.[213]
Treatment
As described in the PDQ summary on Melanoma Treatment, therapeutic options range widely from local excision in early melanoma to chemotherapy, radiation, and aggressive management in metastatic melanoma. The best defense against melanoma as a whole is to encourage sun-protective behaviors, regular skin examinations, and patient skin self-awareness in an effort to decrease high-risk behaviors and optimize early detection of potentially malignant lesions.
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