Genetics of Skin Cancer (PDQ®) 2/3 –Health Professional Version - National Cancer Institute

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

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

Interventions

Prevention and treatment of skin cancers

A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[231] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 30% reduction in the incidence of new SCCs (95% CI, 0%–51%; P = .05). A statistically significant reduction was also seen in actinic keratoses, the precursor skin lesions to SCCs. The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 4–38, P = .02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to SCC.

Level of evidence (nicotinamide): 1aii

Because many of the syndromes described above are rare, few clinical trials have been conducted in these specific populations. However, valuable information has been developed from the clinical management experience related to skin cancer risk and treatment in the XP population. Strict sun avoidance beginning in infancy, use of protective clothing, and close clinical monitoring of the skin are key components to management of XP. Full-body photography of the skin, conjunctivae, and eyelids is recommended to aid in follow-up.[232] Although few studies on treatment of SCC in the XP population have been done, in most cases treatment is similar to what would be recommended for the general population. Actinic keratoses are treated with topical therapies such as 5-fluorouracil (5-FU), cryotherapy with liquid nitrogen, or dermabrasion, whereas cutaneous cancers are generally managed surgically.[233]

Level of evidence: 5

Oral isotretinoin has been used as chemoprevention in XP patients with promising results. A small study of daily use of isotretinoin (13-cis retinoic acid; given as 2 mg/kg/day) reduced NMSC incidence by 63% in a small number of people with XP. Toxicities associated with this treatment included mucocutaneous symptoms, abnormalities in liver function tests and triglyceride levels, and musculoskeletal symptoms such as arthralgias, calcifications of tendons and ligaments, and osteoporosis.[234,235] Dose reduction to 0.5 mg/kg/day reduced toxicity and decreased skin cancer frequency in three of seven subjects (43%); increasing the dose to 1 mg/kg/day resulted in decreased skin cancer frequency in three of the four subjects who did not respond at the lower dose.[236] Oral isotretinoin use may be useful as a chemopreventive agent in other hereditary skin cancer syndromes, including basal cell nevus syndrome (BCNS), Rombo syndrome, EB, and epidermodysplasia verruciformis.[237,238]

Level of evidence (oral isotretinoin for XP): 3aii

Level of evidence (oral isotretinoin for BCNS, Rombo syndrome, epidermodysplasia verruciformis): 5

Topical T4N5 liposome lotion, containing the bacterial enzyme T4 endonuclease V, was also investigated as a chemopreventive agent in a randomized, placebo-controlled trial of 30 XP patients.[239] Although no effect was seen on incidence of SCC, 17.7 fewer actinic keratoses per year were seen in the treatment group. Additionally, 1.6 fewer BCCs per year were observed in patients being treated with this therapy. Both of these results were statistically significant. The risk of BCC was reduced by 47%, which was of borderline statistical significance. No significant adverse effects of this agent were reported. To date, this agent has not been approved for use by the U.S. Food and Drug Administration.

Level of evidence: 1aii

For patients with XP and unresectable SCC, therapy with 5-FU has been investigated. Several treatment methods were used in this prospective study, including topical therapy to the lesions, short systemic infusion with folic acid, and continuous systemic infusion in combination with cisplatin. Topical 5-FU demonstrated some efficacy, but in some cases viable tumor remained in the deeper dermis. The systemic chemotherapy resulted in one complete response and three partial responses in a total of five patients, suggesting that this therapy may be an option for treatment of extensive lesions.[240] A dose reduction of 30% to 50% has been recommended for systemic chemotherapeutic agents in this population because of the increased sensitivity of XP cells.[241]

Level of evidence: 3diii

For patients with EB, wide local excision of SCC with 2 cm margins remains the treatment of choice. Amputation may be considered as an option to reduce disease recurrence, although it is not clear that this has an impact on survival. The role of sentinel lymph node biopsy remains unclear in this population.[238]

Current guidelines recommend that individuals with EB and unresectable SCC be treated with radiation therapy, but the dose may need to be given in smaller fractions in order to decrease the risk of skin desquamation. Systemic therapy with epidermal growth factor receptor antagonists or tyrosine kinase inhibitors may also be considered for individuals with advanced SCC.[238]

Level of evidence: 5

For people who have genetic disorders other than XP, data are lacking, but general sun-safety measures remain important. Careful protection of the skin and eyes is the mainstay of prevention in all patients with increased susceptibility to skin cancer. Key points include avoidance of sun exposure at peak hours, protective clothing and lenses, and vigilant use of sunscreen. Avoidance of x-ray therapy has also been advocated for some groups with hereditary skin cancer syndromes, such as those with epidermodysplasia verruciformis.[144] However, XP patients with unresectable skin cancers or internal cancers, such as spinal cord astrocytoma or glioblastomas of the brain, have been treated successfully with standard therapeutic doses of x-ray radiation.[48] Some experts recommend dermatologic evaluation every 6 months and ophthalmologic evaluation at least annually in these high-risk populations. Guidelines for the management of patients with EB recommend skin examinations every 3 to 6 months starting at age 10 years for individuals with the RDEB-sev gen subtype of the disease.[238] For individuals with other subtypes of EB, skin examination every 6 to 12 months starting at age 20 years is recommended in the absence of an established SCC diagnosis. Dental examination every 6 months is also recommended in this population.[238]

Level of evidence: 5

For individuals with DEB, wound care is paramount. Use of silver sulfadiazine cream, medical grade honey, and soft silicone dressings can be helpful in these settings. Attention to nutritional status, which may be compromised because of esophageal strictures, iron-deficiency anemia, infection, and inflammation, is another critical consideration for wound healing for these patients. Multivitamin supplementation, often at higher doses than those routinely recommended for the general population, may be warranted.[242]

Level of evidence: 5

Bone marrow transplantation has been explored in patients with DEB; however, there is no evidence that this intervention results in a reduction of skin cancer.[243] A double-blind, randomized, placebo-controlled trial of infusion of nonhematopoietic bone marrow stem cells with or without cyclosporine was conducted in 14 patients with recessive DEB. The rationale for this study was that mesenchymal stem cells (MSCs) have the potential to differentiate into dermal fibroblasts, the main expressor of type VII collagen. Seven subjects were randomly assigned to receive MSCs with 5 mg/kg/day of cyclosporine and an additional seven subjects received only MSCs. The number of new blisters and the rate of blister healing were significantly improved in both groups (P = .003 for the number of new blisters in the combination therapy group and P = .004 in the group receiving MSCs only; P < .001 for the rate of blister healing in both groups). However, no difference was seen between the groups.[244]

Level of evidence (MSCs for blister prevention): 1b

Level of evidence (MSCs for blister treatment): 1

Future therapies for epidermolysis bullosa

Researchers are taking advantage of recent technological advances to study new strategies for the treatment of dominant and recessive EB.[245-248] Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) is a technology that can be used to edit DNA. One research group used CRISPR/Cas9 to correct an inherited pathogenic variant in COL7A1 in keratinocytes isolated from a patient with RDEB.[245] Keratinocytes that contained the corrected version of COL7A1 were successfully transplanted onto mice and staining of skin grafts after transplant showed normal skin. Another study used a different approach, retrovirus infection, to introduce normal COL7A1 into keratinocytes from four RDEB patients.[247] The corrected keratinocytes were then assembled into epidermal graft sheets and transplanted onto six wound areas of each of the four patients. The grafts were well tolerated and showed greater healing capabilities than did noncorrected skin after further study. All of these therapies are still in early research stages and have not yet been evaluated in clinical trials.

Level of evidence: None assigned

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232. Tamura D, DiGiovanna JJ, Khan SG, et al.: Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients. Photodermatol Photoimmunol Photomed 30 (2-3): 146-52, 2014 Apr-Jun. [PUBMED Abstract]
233. Tamura D, DiGiovanna JJ, Kraemer KH: Xeroderma pigmentosum. In: Lebwohl MG, Birth-Jones J, Heymann WR, et al., eds.: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 3rd ed. London, England: Saunders Elsevier, 2010, pp 789-92.
234. Kraemer KH, DiGiovanna JJ, Moshell AN, et al.: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318 (25): 1633-7, 1988. [PUBMED Abstract]
235. DiGiovanna JJ: Retinoid chemoprevention in the high-risk patient. J Am Acad Dermatol 39 (2 Pt 3): S82-5, 1998. [PUBMED Abstract]
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237. Otley CC, Stasko T, Tope WD, et al.: Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg 32 (4): 562-8, 2006. [PUBMED Abstract]
238. Mellerio JE, Robertson SJ, Bernardis C, et al.: Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines. Br J Dermatol 174 (1): 56-67, 2016. [PUBMED Abstract]
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240. Boussen H, Zwik J, Mili-Boussen I, et al.: [Therapeutic results of 5-fluorouracil in multiple and unresectable facial carcinoma secondary to xeroderma pigmentosum] Therapie 56 (6): 751-4, 2001 Nov-Dec. [PUBMED Abstract]
241. Sarasin A: Progress and prospects of xeroderma pigmentosum therapy. Adv Exp Med Biol 637: 144-51, 2008. [PUBMED Abstract]
242. Mellerio JE, Weiner M, Denyer JE, et al.: Medical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol 46 (8): 795-800, 2007. [PUBMED Abstract]
243. Wagner JE, Ishida-Yamamoto A, McGrath JA, et al.: Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 363 (7): 629-39, 2010. [PUBMED Abstract]
244. El-Darouti M, Fawzy M, Amin I, et al.: Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells: a randomized controlled trial. Dermatol Ther 29 (2): 96-100, 2016 Mar-Apr. [PUBMED Abstract]
245. Hainzl S, Peking P, Kocher T, et al.: COL7A1 Editing via CRISPR/Cas9 in Recessive Dystrophic Epidermolysis Bullosa. Mol Ther 25 (11): 2573-2584, 2017. [PUBMED Abstract]
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247. Siprashvili Z, Nguyen NT, Gorell ES, et al.: Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. JAMA 316 (17): 1808-1817, 2016. [PUBMED Abstract]
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Melanoma

In This Section

• Introduction
• Risk Factors for Melanoma
  • Sun exposure
  • Pigmentary characteristics
  • Nevi
  • Family history
  • Personal history of melanoma
  • Personal history of nonmelanoma skin cancer
• Major Genes for Melanoma
  • CDKN2A/p16 and p14/ARF
  • CDK4 and CDK6
  • Telomere maintenance genes
  • DNA repair genes
  • BRCA1-associated protein 1 (BAP1)
  • PTEN hamartoma tumor syndromes (including Cowden syndrome)
  • O-6-methylguanine DNA methyltransferase (MGMT)
  • Additional candidate regions for familial melanoma susceptibility
  • 9q21 and GOLM1
• Minor Genes (Genetic Modifiers) for Melanoma
  • MC1R
  • Other pigmentary genes
  • MITF
  • BRCA2
• Melanoma Risk Assessment
  • Genetic testing
• Interventions
  • High-risk population
  • General population

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 CDKN2A discussed 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 (MTS1, INK4, 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.[40] Cascade 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 CDKN2A pathogenic 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.[43] CDKN2A pathogenic 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 CDKN2A penetrance; 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 CDKN2A carriers; 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] An early study suggested that somatic NRAS mutations occurred at a higher rate in melanomas diagnosed in Swedish families who carry CDKN2A pathogenic variants as compared with those with sporadic melanomas.[64] However, subsequent studies have found that the rates of the common somatic mutations (BRAF, NRAS) in melanomas from CDKN2A carriers resemble or are lower than those described in the sporadic melanoma population.[65,66] Of note, melanomas from several patients with CDKN2A variants had coexisting BRAF and NRAS mutations, which is an uncommon occurrence in sporadic melanomas.[66]

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.[67] 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.[68]

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).[69] Another study of individuals in Sweden with MPM and two or more cases of melanoma in their first-, second-, or third-degree relatives found CDKN2A pathogenic 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).[70]

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.[71] 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).[72] A large registry study from Sweden that included 27 families carrying the Arg112dup pathogenic variant in CDKN2A observed 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.[73]

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.[74,75] One patient with features of Li-Fraumeni syndrome did not carry a TP53 pathogenic variant, but a deletion of CDKN2A and CDKN2B.[75] A whole-exome sequencing study of a Li-Fraumeni–like family with three individuals with soft tissue sarcoma identified a shared pathogenic CDKN2A variant.[74] 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.[76,77] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%.[78] The RR has been reported as high as 47.8.[79] 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.[24,80] 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 p16 Leiden 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.[81] 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.[82] 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.[83] It was also reported that similar CDKN2A variants were involved in families with and without pancreatic cancer;[84] 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.[85-87] Conversely, melanoma-prone families that do not have a CDKN2A pathogenic variant have not been shown to have an increased risk of pancreatic cancer.[81]

In a review of 110 families with multiple cases of pancreatic cancer, 18 showed an association between pancreatic cancer and melanoma.[88] 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.[89] 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.[90] 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.[91] Plexiform neurofibromas have also been reported in individuals with deleterious CDKN2A variants.[92-95]

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.[96-98] 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.[99] A CDK4 pathogenic variant affects binding of p16 with its subsequent inhibition of CDK4 functionality. With constitutive activation of germline CDK4, CDK4 acts as a dominant oncogene. A small study showed that the melanoma cancer risk in 17 families with CDK4 pathogenic variants was similar to the risk seen in families with CDKN2A variants.[100] (Refer to the CDKN2A/p16 and p14/ARF section of this summary for more information.) In addition, the melanomas found in CDK4 families appear to have similar rates of somatic BRAF mutations to those found in sporadic populations, although because of the rare nature of CDK4 germline variants, the data are necessarily limited.[101]

Despite its functional similarity to CDK4, germline variants in CDK6 have not been identified in any melanoma kindreds.[102]

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.[103] 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 mutations in the same region were observed in 125 of 168 sporadic melanomas in the same report.[103] A separate study reported pathogenic variants that also increased promoter activity in the same TERT promoter region in 50 of 70 sporadic melanomas.[104] 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.[105] 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%.[106]

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.[107,108] A POT1 Ser270Asn missense pathogenic variant was found in 5 of 56 unrelated melanoma families from Italy.[107] 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.[107,108] 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 telomere length. 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.[107,108] 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.[109] 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.[110] The anatomic site distribution of melanomas in XP patients is similar to that of the general population.[111,112]

Genetic polymorphisms associated with DNA repair genes have been associated with mildly increased melanoma risk in the general population.[113] 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).[114]

(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.[115] 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.[116] Although the majority of these variants were somatic, one patient was found to have a germline frameshift variant. A phenotype associated with BAP1 pathogenic variants was subsequently described.[117] 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.[117,118] 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.[119] Further investigation has supported the association between familial cutaneous melanoma and uveal melanoma in BAP1 carriers.[120-124] 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.[125] In support of a link between melanoma risk and BAP1, in one series, about 18% of individuals with a BAP1 pathogenic variant developed melanoma.[121] 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.[118,120,122,123,126,127]

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 splicing and result in a frameshift. This family also had cases of uveal melanoma and paraganglioma.[126] Another family with a Y646X BAP1 pathogenic variant had multiple cancers, including multiple cutaneous melanomas and BCCs, uveal melanoma, and mesotheliomas.[128] 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.[129] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[130] 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.[131] Individuals with variants in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[132]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[133,134] 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 [135] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[136] 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 PTEN pathogenic 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 criteriaExit Disclaimer for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[26,136] Additionally, a predictive modelExit Disclaimer 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%.[137]

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 PTEN testing in the United States, Europe, and Asia.[138] 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.[139]

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).[139] 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.[138] 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.[140] 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.)