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

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

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.[141] 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 analysis of 49 Australian families who had at least three melanoma cases and who were negative for CDKN2A and CDK4 pathogenic variants.[142] 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.[143] A GWAS of individuals from 34 high-risk melanoma families revealed three single nucleotide polymorphisms (SNPs) on 10q25.1 associated with melanoma risk.[144] 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.[145,146] 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.[147,148] 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,[149] initial studies did not demonstrate an association with melanoma.[150] Additionally, variants in a transcription factor for ASIP, NCOA6, which is also on chromosome 20, showed a maximum OR of 1.82.[148] 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.[151-156] 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.[155] 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.[157] (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.[156]

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.[158]

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 mutations in CDKN2A.[159] 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.[160] 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).[160]

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.[161-164] 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.[165] Additional phenotypic associations have been found. In different studies, MC1R variants were found to be associated with lentigo maligna melanoma (OR, 2.16; 95% CI, 1.07–4.37; P = .044) [166] 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).[167] 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.[167]

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).[168] 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.[169] 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).[170] 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.[169] An independent study found a similar survival benefit in individuals carrying two MC1R variants (HR, 0.60; 95% CI, 0.40–0.90).[171]

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.[164] 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.[172]

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.[173,174] 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.[175]

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.[176] 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.[177] In contrast, a large consortium study did not show as large a decrease in age at onset of melanoma.[176] 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 MC1R variants.[178]

In addition to studies evaluating the relationship between germline variants and MC1R variants, multiple groups have assessed whether MC1R variants are associated with somatic BRAF mutations. Studies indicate that there may be an association between MC1R variants and BRAF V600E somatic mutations.[179-182] However, it is difficult to determine the impact of pigmentary influences on BRAF somatic mutations versus genetic effects.

Other pigmentary genes

Pathogenic variants in albinism genes may also account for a small proportion of familial melanoma. For example, variants in TYRP1, TYR, and OCA2 were observed at an increased frequency in one study of individuals with familial cutaneous melanoma compared with population controls.[183] 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 OCA2, SLC45A2, TYR, 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.[184] 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 CDK4 pathogenic 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.[185] 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).[186] 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.[184] Spanish and Italian case-control studies found ORs of approximately 3.0 for melanoma in carriers of the E318K variant.[187,188] However, the Spanish study also included melanoma cases from families with and without CDKN2A pathogenic variants.[187] 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.[188] 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.[189]

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).[190] A second study reported a similar increase in risk, although the result fell short of statistical significance.[191] 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.[192] 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.[193] Overall, the evidence for increased risk of melanoma in the BRCA2 population is inconsistent at this time.[194]

(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.[195] 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.[196] 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.[197] 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.[198] 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 CDKN2A pathogenic variants in individuals or families for research purposes (Table 8). MelPREDICT [199] uses logistic regression and MelaPRO [200] 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 Exit Disclaimer [200]	MelPREDICT [199]
Features of Model	Incorporates three different penetrance models	Uses logistic regression
	Can input information for large families	Accounts for a number of primary melanomas in family and age of onset
	Includes information for unaffected individuals on risk of developing melanoma
Limitations	The model has not been validated on unaffected probands.	Cannot incorporate complex pedigree structure information into the model
Limitations		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 CDKN2A pathogenic 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.[201]

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.[202] 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.[203,204] A cost-utility analysis has demonstrated the benefits of screening in the high-risk population.[205]

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.[206]

Standard recommendations for screening and management of patients with BAP1 germline 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.[127]

Level of evidence: 5

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.

Level of evidence: 5

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 [207] 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.[208]

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 CDKN2A pathogenic 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.

Level of evidence: 5

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.[209]

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.[210] 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.[211] 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.[212-214] As survival is inversely correlated with Breslow depth for melanoma, early diagnosis leads to better prognosis.

Level of evidence: 5

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.[215] Tanning beds should be avoided, as studies suggest that they increase the risk of melanoma.[216,217] 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.[218]

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.[219,220] However, regular sunscreen use has been shown to reduce melanoma incidence in a prospective, randomized controlled trial.[221]

Level of evidence: 1aii

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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Cust AE, Goumas C, Vuong K, et al.: MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: an Australian case-control-family study. BMC Cancer 13: 406, 2013. [PUBMED Abstract]
Demenais F, Mohamdi H, Chaudru V, et al.: Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst 102 (20): 1568-83, 2010. [PUBMED Abstract]
Fargnoli MC, Gandini S, Peris K, et al.: MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer 46 (8): 1413-20, 2010. [PUBMED Abstract]
Helsing P, Nymoen DA, Rootwelt H, et al.: MC1R, ASIP, TYR, and TYRP1 gene variants in a population-based series of multiple primary melanomas. Genes Chromosomes Cancer 51 (7): 654-61, 2012. [PUBMED Abstract]
Fargnoli MC, Fargnoli MC, Pike K, et al.: MC1R variants increase risk of melanomas harboring BRAF mutations. J Invest Dermatol 128 (10): 2485-90, 2008. [PUBMED Abstract]
Guida M, Strippoli S, Ferretta A, et al.: Detrimental effects of melanocortin-1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors. Pigment Cell Melanoma Res 29 (6): 679-687, 2016. [PUBMED Abstract]
Hacker E, Olsen CM, Kvaskoff M, et al.: Histologic and Phenotypic Factors and MC1R Status Associated with BRAF(V600E), BRAF(V600K), and NRAS Mutations in a Community-Based Sample of 414 Cutaneous Melanomas. J Invest Dermatol 136 (4): 829-837, 2016. [PUBMED Abstract]
Thomas NE, Edmiston SN, Kanetsky PA, et al.: Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma. J Invest Dermatol 137 (12): 2588-2598, 2017. [PUBMED Abstract]
Goldstein AM, Xiao Y, Sampson J, et al.: Rare germline variants in known melanoma susceptibility genes in familial melanoma. Hum Mol Genet 26 (24): 4886-4895, 2017. [PUBMED Abstract]
Yokoyama S, Woods SL, Boyle GM, et al.: A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480 (7375): 99-103, 2011. [PUBMED Abstract]
Sturm RA, Fox C, McClenahan P, et al.: Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. J Invest Dermatol 134 (1): 141-9, 2014. [PUBMED Abstract]
Berwick M, MacArthur J, Orlow I, et al.: MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors. Pigment Cell Melanoma Res 27 (3): 485-8, 2014. [PUBMED Abstract]
Potrony M, Puig-Butille JA, Aguilera P, et al.: Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. JAMA Dermatol 152 (4): 405-12, 2016. [PUBMED Abstract]
Ghiorzo P, Pastorino L, Queirolo P, et al.: Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res 26 (2): 259-62, 2013. [PUBMED Abstract]
Gromowski T, Masojć B, Scott RJ, et al.: Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study. Cancer Genet 207 (4): 128-32, 2014. [PUBMED Abstract]
Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999. [PUBMED Abstract]
Moran A, O'Hara C, Khan S, et al.: Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 11 (2): 235-42, 2012. [PUBMED Abstract]
van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42 (9): 711-9, 2005. [PUBMED Abstract]
Kadouri L, Temper M, Grenader T, et al.: Absence of founder BRCA1 and BRCA2 mutations in cutaneous malignant melanoma patients of Ashkenazi origin. Fam Cancer 8 (1): 29-32, 2009. [PUBMED Abstract]
Gumaste PV, Penn LA, Cymerman RM, et al.: Skin cancer risk in BRCA1/2 mutation carriers. Br J Dermatol 172 (6): 1498-506, 2015. [PUBMED Abstract]
Greene MH: The genetics of hereditary melanoma and nevi. 1998 update. Cancer 86 (11 Suppl): 2464-77, 1999. [PUBMED Abstract]
Olsen CM, Neale RE, Green AC, et al.: Independent validation of six melanoma risk prediction models. J Invest Dermatol 135 (5): 1377-84, 2015. [PUBMED Abstract]
Cho E, Rosner BA, Feskanich D, et al.: Risk factors and individual probabilities of melanoma for whites. J Clin Oncol 23 (12): 2669-75, 2005. [PUBMED Abstract]
Fears TR, Guerry D, Pfeiffer RM, et al.: Identifying individuals at high risk of melanoma: a practical predictor of absolute risk. J Clin Oncol 24 (22): 3590-6, 2006. [PUBMED Abstract]
Niendorf KB, Goggins W, Yang G, et al.: MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. J Med Genet 43 (6): 501-6, 2006. [PUBMED Abstract]
Wang W, Niendorf KB, Patel D, et al.: Estimating CDKN2A carrier probability and personalizing cancer risk assessments in hereditary melanoma using MelaPRO. Cancer Res 70 (2): 552-9, 2010. [PUBMED Abstract]
Hansson J: Familial melanoma. Surg Clin North Am 88 (4): 897-916, viii, 2008. [PUBMED Abstract]
Kefford RF, Newton Bishop JA, Bergman W, et al.: Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 17 (10): 3245-51, 1999. [PUBMED Abstract]
Hansson J, Bergenmar M, Hofer PA, et al.: Monitoring of kindreds with hereditary predisposition for cutaneous melanoma and dysplastic nevus syndrome: results of a Swedish preventive program. J Clin Oncol 25 (19): 2819-24, 2007. [PUBMED Abstract]
Salerni G, Carrera C, Lovatto L, et al.: Benefits of total body photography and digital dermatoscopy ("two-step method of digital follow-up") in the early diagnosis of melanoma in patients at high risk for melanoma. J Am Acad Dermatol 67 (1): e17-27, 2012. [PUBMED Abstract]
Freedberg KA, Geller AC, Miller DR, et al.: Screening for malignant melanoma: A cost-effectiveness analysis. J Am Acad Dermatol 41 (5 Pt 1): 738-45, 1999. [PUBMED Abstract]
Tucker MA, Fraser MC, Goldstein AM, et al.: A natural history of melanomas and dysplastic nevi: an atlas of lesions in melanoma-prone families. Cancer 94 (12): 3192-209, 2002. [PUBMED Abstract]
Parker JF, Florell SR, Alexander A, et al.: Pancreatic carcinoma surveillance in patients with familial melanoma. Arch Dermatol 139 (8): 1019-25, 2003. [PUBMED Abstract]
Rulyak SJ, Kimmey MB, Veenstra DL, et al.: Cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds. Gastrointest Endosc 57 (1): 23-9, 2003. [PUBMED Abstract]
Crowson AN, Magro CM, Mihm MC: Prognosticators of melanoma, the melanoma report, and the sentinel lymph node. Mod Pathol 19 (Suppl 2): S71-87, 2006. [PUBMED Abstract]
Berwick M, Begg CB, Fine JA, et al.: Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 88 (1): 17-23, 1996. [PUBMED Abstract]
Olson SH, Kelsey JL, Pearson TA, et al.: Evaluation of random digit dialing as a method of control selection in case-control studies. Am J Epidemiol 135 (2): 210-22, 1992. [PUBMED Abstract]
Masri GD, Clark WH, Guerry D, et al.: Screening and surveillance of patients at high risk for malignant melanoma result in detection of earlier disease. J Am Acad Dermatol 22 (6 Pt 1): 1042-8, 1990. [PUBMED Abstract]
Carli P, De Giorgi V, Palli D, et al.: Dermatologist detection and skin self-examination are associated with thinner melanomas: results from a survey of the Italian Multidisciplinary Group on Melanoma. Arch Dermatol 139 (5): 607-12, 2003. [PUBMED Abstract]
van der Rhee JI, de Snoo FA, Vasen HF, et al.: Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J Am Acad Dermatol 65 (2): 289-96, 2011. [PUBMED Abstract]
Armstrong BK, Kricker A: The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63 (1-3): 8-18, 2001. [PUBMED Abstract]
International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer: The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. Int J Cancer 120 (5): 1116-22, 2007. [PUBMED Abstract]
Fears TR, Sagebiel RW, Halpern A, et al.: Sunbeds and sunlamps: who used them and their risk for melanoma. Pigment Cell Melanoma Res 24 (3): 574-81, 2011. [PUBMED Abstract]
National Conference of State Legislatures: Indoor Tanning Restrictions for Minors: A State-By-State Comparison. Denver, Co: National Conference of State Legislatures, 2016. Available online Exit Disclaimer. Last accessed October 10, 2019.
Goldsmith L, Koh HK, Bewerse B, et al.: Proceedings from the national conference to develop a national skin cancer agenda. American Academy of Dermatology and Centers for Disease Control and Prevention, April 8-10, 1995. J Am Acad Dermatol 34 (5 Pt 1): 822-3, 1996. [PUBMED Abstract]
Harmful effects of ultraviolet radiation. Council on Scientific Affairs. JAMA 262 (3): 380-4, 1989. [PUBMED Abstract]
Green AC, Williams GM, Logan V, et al.: Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol 29 (3): 257-63, 2011. [PUBMED Abstract]

Rare Skin Cancer Syndromes

Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis

Brooke-Spiegler Syndrome (BSS), familial cylindromatosis, and multiple familial trichoepithelioma (MFT) are all autosomal dominant syndromes with overlapping clinical characteristics with allelic variance.[1] Features of BSS include multiple skin appendage tumors such as cylindromas (tumors arising in the hair follicle stem cells), trichoepitheliomas (tumors arising in the hair follicle), and spiradenomas (benign tumors arising in the sweat gland). MFT is characterized by nonmalignant skin tumors, primarily trichoepitheliomas, and familial cylindromatosis manifests predominantly as cutaneous cylindromas. Onset of tumors for these syndromes is typically in late childhood or early adolescence, suggesting a hormonal influence.[2] There is some evidence of greater severity in females than in males. UV radiation appears to be a major initiating factor for cylindromas. Typical tumor sites for cylindromas in familial cylindromatosis are the scalp (81% of carriers), the trunk (69% of carriers), and the pubic area (42% of carriers).[3] Other tumors that can be associated with these syndromes include parotid gland tumors, basal cell adenomas, and basal cell carcinomas. Refer to Table 3, Basal Cell Carcinoma (BCC) Syndromes, for more information about BSS.

Because pathogenic variants in CYLD on16q12-q13 have been identified in individuals with each of these disorders, these syndromes are thought to represent different phenotypic manifestations of the same disease.[4] Penetrance of pathogenic variants in CYLD is reported to be 60% to 100%.[3,5] In one study, 85% of the BSS families, 100% of familial cylindromatosis families, and only 44% of MFT families were found to have pathogenic variants in CYLD.[6] A second locus for MFT maps to 9p21, but the gene for this locus remains unknown.[7]

Given the potential for progressive enlargement, the preferred approach for cylindromas is ablation while the tumors are small and easily managed. Electrosurgery or Mohs micrographic surgery may be utilized for therapy, although excision of large lesions may require skin grafting for closure.[8] Trichoepitheliomas and spiradenomas typically remain smaller in size; thus, after the diagnosis is confirmed by skin biopsy, unless there is impingement on critical structures, further intervention is not required. If therapy is deemed necessary and appropriate, either electrosurgery or ablative laser therapy is a valid option.[8] Radiotherapy is not recommended for treatment of any of these tumors because a potential for increased tumor induction.

Level of evidence: 4

Sebaceous Carcinoma

Cutaneous sebaceous neoplasms may be associated with Muir-Torre syndrome (MTS). Multiple types of sebaceous tumors including sebaceous adenomas, epitheliomas, carcinomas, and keratoacanthomas or BCCs with sebaceous differentiation have been described. A variant of Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome, the MTS phenotype involves the synchronous or metachronous development of at least one cutaneous sebaceous neoplasm and at least one visceral malignancy. The visceral malignancies may be of gastrointestinal (colorectal, stomach, small bowel, liver, and bile duct) and/or genitourinary (endometrial and bladder) origin and typically demonstrate a less aggressive phenotype than non-MTS equivalent tumors.[9,10] MTS, inherited in an autosomal dominant fashion with high penetrance and variable expressivity, is associated with pathogenic variants in the mismatch repair genes MLH1, MSH2, and less commonly, MSH6.[11-16] In a study of 36 sebaceous lesions that included sebaceous carcinomas, sebaceous adenomas, and sebaceomas, 38.9% of lesions were missing one or more mismatch repair proteins by immunohistochemistry (IHC).[17] Of the ten individuals with absent staining of one or more proteins, five had gene testing that confirmed a diagnosis of Lynch syndrome. This result suggests that routine screening of sebaceous lesions by IHC may be useful in identification of individuals with Lynch syndrome. One study of the incidence of skin cancer in Lynch syndrome suggests there is an increase in sebaceous carcinoma and squamous cell carcinoma in these patients.[18]

While the commonly noted sebaceous hyperplasia has not been associated with MTS, any sebaceous lesion with atypical or difficult to classify histologic features should prompt further exploration of the patient’s family and personal medical history. Consideration should be given to referring patients with sebaceous neoplasms to medical geneticists or gastroenterologists to evaluate further for Lynch syndrome. While the diagnosis of visceral malignancy precedes that of cutaneous sebaceous neoplasms in the majority of patients, 22% of patients develop cutaneous sebaceous neoplasms first, offering an opportunity for visceral malignancy screening.[19] Current diagnosis of MTS is based upon clinical criteria but may be supported by immunohistochemical staining for MSH2, MLH1, and MSH6 as a screening mechanism before molecular genetic analysis.[12,14-16,20] Genetic counseling and testing for the patient and family members, with appropriate visceral malignancy screening regimens, should be pursued.

Level of evidence: 3

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

Although cutaneous smooth muscle tumors (leiomyomas) are not themselves a form of skin cancer, multiple cutaneous leiomyomas are associated with renal cell cancer (RCC) in an inherited syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). Cutaneous leiomyomas present as firm, pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 y) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement.[21] The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. (Refer to the HLRCC section in the PDQ summary on Genetics of Kidney Cancer (RCC) for more information.)

References

Bowen S, Gill M, Lee DA, et al.: Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol 124 (5): 919-20, 2005. [PUBMED Abstract]
Burrows NP, Jones RR, Smith NP: The clinicopathological features of familial cylindromas and trichoepitheliomas (Brooke-Spiegler syndrome): a report of two families. Clin Exp Dermatol 17 (5): 332-6, 1992. [PUBMED Abstract]
Rajan N, Langtry JA, Ashworth A, et al.: Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction. Arch Dermatol 145 (11): 1277-84, 2009. [PUBMED Abstract]
Young AL, Kellermayer R, Szigeti R, et al.: CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet 70 (3): 246-9, 2006. [PUBMED Abstract]
Welch JP, Wells RS, Kerr CB: Ancell-Spiegler cylindromas (turban tumours) and Brooke-Fordyce Trichoepitheliomas: evidence for a single genetic entity. J Med Genet 5 (1): 29-35, 1968. [PUBMED Abstract]
Saggar S, Chernoff KA, Lodha S, et al.: CYLD mutations in familial skin appendage tumours. J Med Genet 45 (5): 298-302, 2008. [PUBMED Abstract]
Harada H, Hashimoto K, Ko MS: The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J Invest Dermatol 107 (1): 41-3, 1996. [PUBMED Abstract]
Rajan N, Trainer AH, Burn J, et al.: Familial cylindromatosis and brooke-spiegler syndrome: a review of current therapeutic approaches and the surgical challenges posed by two affected families. Dermatol Surg 35 (5): 845-52, 2009. [PUBMED Abstract]
Schwartz RA, Torre DP: The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol 33 (1): 90-104, 1995. [PUBMED Abstract]
Cohen PR, Kohn SR, Kurzrock R: Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 90 (5): 606-13, 1991. [PUBMED Abstract]
Cerosaletti KM, Lange E, Stringham HM, et al.: Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype. Am J Hum Genet 63 (1): 125-34, 1998. [PUBMED Abstract]
Mangold E, Pagenstecher C, Leister M, et al.: A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. J Med Genet 41 (7): 567-72, 2004. [PUBMED Abstract]
Mathiak M, Rütten A, Mangold E, et al.: Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol 26 (3): 338-43, 2002. [PUBMED Abstract]
Mangold E, Rahner N, Friedrichs N, et al.: MSH6 mutation in Muir-Torre syndrome: could this be a rare finding? Br J Dermatol 156 (1): 158-62, 2007. [PUBMED Abstract]
Arnold A, Payne S, Fisher S, et al.: An individual with Muir-Torre syndrome found to have a pathogenic MSH6 gene mutation. Fam Cancer 6 (3): 317-21, 2007. [PUBMED Abstract]
Murphy HR, Armstrong R, Cairns D, et al.: Muir-Torre Syndrome: expanding the genotype and phenotype--a further family with a MSH6 mutation. Fam Cancer 7 (3): 255-7, 2008. [PUBMED Abstract]
Plocharczyk EF, Frankel WL, Hampel H, et al.: Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the importance of screening for Lynch syndrome. Am J Dermatopathol 35 (2): 191-5, 2013. [PUBMED Abstract]
Adan F, Crijns MB, Zandstra WSE, et al.: Cumulative risk of skin tumours in patients with Lynch syndrome. Br J Dermatol 179 (2): 522-523, 2018. [PUBMED Abstract]
Akhtar S, Oza KK, Khan SA, et al.: Muir-Torre syndrome: case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature. J Am Acad Dermatol 41 (5 Pt 1): 681-6, 1999. [PUBMED Abstract]
Entius MM, Keller JJ, Drillenburg P, et al.: Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Clin Cancer Res 6 (5): 1784-9, 2000. [PUBMED Abstract]
Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PUBMED Abstract]

Psychosocial Issues in Familial Melanoma

Introduction

This section reviews the literature examining risk reduction and early-detection behaviors in individuals with heightened risk of melanoma resulting from their family history of the disease and in individuals from hereditary families who have been tested for melanoma high-risk pathogenic variant status. The review also addresses risk perception and communication in individuals at heightened risk of melanoma.

Interest in and Uptake of Genetic Testing for Risk of Melanoma

Currently, clinical testing for CDKN2A is not recommended outside the research context because most individuals from multiple-case families will not be identified as having a pathogenic variant in this gene, and because recommendations for those testing positive do not differ for multiple-case family members who test negative, or do not pursue testing.[1,2] Despite these cautions, CDKN2A testing is commercially available, and thus demand for the test will likely increase.[3] Arguments for the availability of genetic testing include that the results of testing could provide psychological security and contribute to enhanced screening and prevention efforts for those testing positive for CDKN2A.[4] (Refer to the Melanoma Risk Assessment section of this summary for more information about clinical genetic testing for melanoma susceptibility.)

Few studies have examined motivation and interest in genetic testing for melanoma risk. In summary, the findings include the following:

High, but not universal interest in genetic testing.[5-7]
Articulated benefits of testing among those at heightened risk.[5,6,8]
A relative lack of examination of potential limitations of testing or reasons to forgo testing.[5-7]

In Australia, a qualitative study (N = 40) found that almost all participants with a strong family history of melanoma were interested in genetic testing.[6,9] Genetic testing was favored by the participants as a means to gain information about their children's susceptibility to melanoma, to increase their understanding of their own risk, to advance melanoma research, and to provide increased motivation for sun-protective behavior.

A Dutch study examined interest in CDKN2A testing (p16-Leiden pathogenic variant). Of 510 letters sent to members of 18 p16-Leiden-positive families recruited from the Pigmented Lesions Clinic at the Leiden University Medical Center in the Netherlands, 488 individuals responded by attending clinic for physical examination; an additional 15 family members also accompanied these individuals. Of these, 403 individuals were eligible for genetic counseling. A total of 184 family members followed through with counseling, and 141 of them opted for genetic testing. After the counseling session, 94 individuals returned a completed questionnaire. Older age predicted higher interest in genetic testing; reasons for having genetic testing included learning personal risk (57%) and learning the risk of one's child carrying the pathogenic variant (69%). Most participants (88%) felt that genetic testing would make a contribution to diagnostics within their family. However, some individuals (40%) reported that they had not expected to receive risk information concerning pancreatic cancer, and half of the participants (49%) reported increased worry about the possibility of developing pancreatic cancer.[7] Finally, in an Arizona qualitative study of 22 individuals with a strong family history of melanoma, none elected genetic testing even though it was provided as an option for them.[8]

In an Australian study of 121 individuals with a strong family history of melanoma, participants completed questionnaires before genetic counseling and testing.[9] Distress (melanoma-specific distress and general distress) levels were very low in this population. The most important predictors of distress included a personal history of melanoma, having concerns about the impact of melanoma on family, having a high information-seeking disposition (monitoring style), a perceived importance of sun exposure in causing melanoma, and not having children.

Testing in children

Among 61 people tested for CDKN2A pathogenic variants (52.5% tested positive) from two large melanoma kindreds, most (75.4%) had children or grandchildren younger than 18 years and expressed interest in testing of minors (73.8%).[10] Among carriers of CDKN2A pathogenic variants, most (86.7%) wanted their children or grandchildren to be tested, and among noncarriers, half (50%) wanted testing for their own children or grandchildren. The most cited reason for testing children was to aid in risk awareness and to improve protection and screening behavior.

Risk Awareness and Risk Reduction in Individuals at Increased Familial Risk of Melanoma

A number of studies have been conducted examining risk reduction via adoption of sun protection (including the use of sunscreen and protective clothing and shade seeking behavior) in individuals with a family history of melanoma. Overall, these studies indicate inconsistent adoption and maintenance of these behaviors. Most of these studies have been conducted with clinic-based populations that might be more prone to risk reduction and screening behaviors than those with a similar risk profile in the general population.[11]

In terms of sun protection, in a Swedish population, 87 young adults with dysplastic nevi were surveyed, and 70% estimated their melanoma risk to be equal or lower than that of the Swedish population in general, and one third reported frequent sunbathing behavior.[12] Another study examined 229 first-degree relatives (FDRs) referred by melanoma patients attending clinic appointments; those who were older, female, and had greater confidence in their ability to practice sun-protection were most likely to do so, but the utilization of sun-protective behavior was inconsistent.[13] Another study in the United States examined sun-protective behavior in 100 FDRs of melanoma clinic patients and found that less than one-third of patients use sunscreen routinely when in the sun and that more regular usage was related to higher education levels, higher self-efficacy for sun protection, and higher perceived melanoma risk. Perceived severity of melanoma and response-efficacy were not related to adoption of sun-protective behaviors.[14]

A study that focused on 68 minor children (aged 17 years or younger) of melanoma survivors demonstrated that while overall rates of sun-protective behavior were high (near 80%), the rates of sunburn were also high (49%).[15] The authors concluded that multiple methods of sun-protective behavior are warranted in these individuals. However, in the teenage years, there were significant reductions in sun protection indicating an even greater need for intervention in this group.

Another study based in the United Kingdom examined sunburn rates in 170 individuals with a family history of melanoma compared with 140 controls matched to age, sex, and geographical location. Of those with a melanoma family history, 31% reported sunburn in the previous summer (compared with 41% of controls); melanoma families reported better sun-protection behaviors than controls overall. Across controls and those with a family history of melanoma, younger males were more likely to report recent sunburns; also, across controls and those with a family history of melanoma, those relatives with atypical mole syndrome and a belief in their ability to prevent melanoma showed better sun protection.[16]

One qualitative study of 20 FDRs of melanoma patients recruited from a high-risk clinic at the University of Arizona identified perceived unmet needs for physician communication of risk status, including greater consistency in communication, education for patients concerning the importance of family history to risk status, and needs and desire for more complex advice (e.g., reapplication of sunscreen and wearing clothing with ultraviolet protection factor).[17]

A prospective study examined interest in and 3-month behavioral and psychosocial outcomes associated with disclosure of melanoma high-risk pathogenic variant research results in 19 individuals (three CDKN2A carriers).[18] All of the variant carriers, but only four of the noncarriers, had a family history of melanoma. Carrier status did not affect risk perception, distress, or sun-protection behaviors.

Intervention studies

A few intervention studies have targeted knowledge about melanoma, sun protection, and screening in family members of melanoma patients. In one study among siblings, participants drawn from a clinic population were randomly assigned to an intervention that included telephone messages and tailored print materials about risk reduction and screening recommendations. The usual care group received a standard physician-practice recommendation that patients notify family members about their diagnosis. The intervention group showed improvements in knowledge about melanoma, confidence in seeing a dermatologist and having a screening examination, and greater improvements in skin self-examination practices compared with control participants after 12 months; both groups showed twofold increases in physician examinations after 12 months; there was no change in sunscreen behaviors in either group.[19]

In another study, 443 family members of melanoma patients were randomly assigned to either a generic or tailored intervention that consisted of three (untailored or tailored) print mailings and one (untailored or tailored) telephone counseling session. Overall, the tailored intervention group showed an almost twofold increase in frequency of total cutaneous skin examinations by a health care provider compared with the generic intervention. However, no differences were observed for skin self-examinations between intervention arms. In contrast to the previous study, which did not show improvements in sun protection habits,[19] participants in this study who received the tailored intervention were significantly more likely to report improvements in sun protection habits than were those who received the generic intervention.[20]

Screening Behaviors in Individuals at Increased Familial Risk of Melanoma

A number of studies have examined early-detection behaviors in individuals at increased risk of melanoma. In a U.S. sample of 404 siblings drawn from a clinic population of melanoma patients, only 42% of individuals had ever seen a dermatologist; 62% had engaged in skin self-examination; 27% had received a physician skin examination; and only 54% routinely used sunscreen. Female gender was related to greater sunscreen use; those older than age 50 years were more likely to have received a physician skin examination. Having a dermatologist was strongly related to all three outcomes (skin self-examination, physician examination, and sunscreen use).[21] In a U.S. study of 229 FDRs referred by patients attending clinic, about half (55%) reported ever having a total cutaneous examination, and slightly more (71%) reported ever performing skin self-examination. Common predictors of skin examination (physician and self-examinations) included physician recommendation and low perceived barriers of screening.[13] Interestingly, 14% of the sample had not told their primary care doctor about their sibling’s melanoma diagnosis. One U.S. study showed that half (53%) of FDRs had never received a total cutaneous screening by a physician; only 27% had received a physician recommendation to have a screening. Early detection adherence was related to the following: higher education level, more melanoma risk factors, health care provider recommendation for screening, perceived risk of melanoma, and perceived severity of melanoma. Parents of melanoma patients were less likely to have pursued screening than siblings and children.[22] A U.S. study examined intentions to receive a physician skin examination and to perform skin self-examination among FDRs of individuals diagnosed with melanoma who had not recently engaged in skin surveillance. Predictors of intentions included both benefits and barriers to screening and family support for screening, but not knowledge of recommended screening frequency.[23]

A cross-sectional Australian study of 120 individuals from families with a known CDKN2A pathogenic variant found that in the past 12 months, 50% reported engaging in skin self-examinations at least four times, and 43% had undergone at least one clinical skin examination. In contrast, 15% had not performed a skin self-examination in the past 12 months, and 27% had never had a clinical skin examination. Correlates of skin cancer screening behaviors included having a history of melanoma, a physician’s recommendation, and stronger behavioral intentions. Additional correlates for skin self-examination included self-efficacy, perceived efficacy of melanoma treatment, and melanoma-specific distress. Perceived risk of developing melanoma was not significantly associated with skin cancer screening behaviors.[24]

Intervention studies

Psychosocial Outcomes of Genetic Counseling and Genetic Testing

A few small studies have examined distress and behavioral factors associated with CDKN2A testing for melanoma. In a Swedish clinic for individuals at high risk of melanoma resulting from dysplastic nevus syndrome, 11 unaffected, untested individuals drawn from families in which a CDKN2A pathogenic variant has been identified were examined. Most (9 of 11) reported no worry about increased melanoma risk. In assessments after disclosure of results, there were no increasing trends towards depression, anxiety, or increased melanoma-risk perception by test results, and no systematic change in sun-related habits by test results.[25]

A prospective study examined interest in and 3-month behavioral and psychosocial outcomes associated with disclosure of melanoma high-risk pathogenic variant research results in 19 individuals (three CDKN2A carriers).[18] All of the pathogenic variant carriers, but only four of the noncarriers, had a family history of melanoma. Carrier status did not affect risk perception, distress, or sun-protection behaviors.

In a randomized controlled trial, 73 adults with a family history of melanoma were randomly assigned to receive either genetic counseling with genotyping results (CDKN2A and MC1R) or usual care. Overall, participants in the intervention group reported a significant increase in frequency of skin self-examinations, compared with a slight decrease among those in the control group. In addition, intervention participants reported a smaller decrease in frequency of wearing a shirt for sun protection compared with control participants. No other differences in sun protection habits were noted. These results should be interpreted with caution, as only five individuals (three in the intervention arm) had a pathogenic variant for one or both of the genes. Nonetheless, study results support the notion that genetic testing for melanoma does not lead to false reassurance and reduced sun protection behaviors among those who test negative.[26]

Another study examined behavioral factors associated with CDKN2A carrier status among 64 individuals from two large Utah families in which a CDKN2A pathogenic variant had been identified. The individuals received extensive recommendations for sun protection and screening. Questionnaires conducted one month after receipt of genetic test results and recommendations showed increased intention for skin examinations (self-examinations and health care professional examinations), regardless of whether individuals were found to be CDKN2A carriers or noncarriers. Rates of over screening (>1 skin self-examination per month) also increased in CDKN2A carriers.[27] In a follow-up study one month later with the same sample, CDKN2A carriers showed marginally increased intentions for sun-protective behaviors; CDKN2A noncarriers showed no increase in overall photoprotection but a shift to using sun-protective clothing rather than sun avoidance.[28] Thirty-seven individuals from the same cohort were assessed for psychosocial and behavioral outcomes 2 years posttesting. Levels of anxiety, depression, melanoma worry, and pancreatic cancer worry were all low and decreased over time, with more perceived benefits of testing noted than drawbacks of testing.[29] Adherence to annual total-body skin examinations significantly increased among unaffected carriers (from 40% at baseline to 70% at 2 years) but decreased among unaffected noncarriers (from 56% at baseline to 13% at 2 years). Affected carriers were adherent at both assessments (91% and 82%, respectively).[30]

References

de Snoo FA, Bergman W, Gruis NA: Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2 (2): 109-16, 2003. [PUBMED Abstract]
Kefford RF, Mann GJ: Is there a role for genetic testing in patients with melanoma? Curr Opin Oncol 15 (2): 157-61, 2003. [PUBMED Abstract]
Hansen CB, Wadge LM, Lowstuter K, et al.: Clinical germline genetic testing for melanoma. Lancet Oncol 5 (5): 314-9, 2004. [PUBMED Abstract]
Bergman W, Gruis NA: Phenotypic variation in familial melanoma: consequences for predictive DNA testing. Arch Dermatol 143 (4): 525-6, 2007. [PUBMED Abstract]
Bränström R, Kasparian NA, Affleck P, et al.: Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma. Eur J Cancer 48 (16): 3052-62, 2012. [PUBMED Abstract]
Kasparian NA, Meiser B, Butow PN, et al.: Anticipated uptake of genetic testing for familial melanoma in an Australian sample: An exploratory study. Psychooncology 16 (1): 69-78, 2007. [PUBMED Abstract]
de Snoo FA, Riedijk SR, van Mil AM, et al.: Genetic testing in familial melanoma: uptake and implications. Psychooncology 17 (8): 790-6, 2008. [PUBMED Abstract]
Loescher LJ, Crist JD, Siaki LA: Perceived intrafamily melanoma risk communication. Cancer Nurs 32 (3): 203-10, 2009 May-Jun. [PUBMED Abstract]
Kasparian NA, Butow PN, Meiser B, et al.: High- and average-risk individuals' beliefs about, and perceptions of, malignant melanoma: an Australian perspective. Psychooncology 17 (3): 270-9, 2008. [PUBMED Abstract]
Taber JM, Aspinwall LG, Kohlmann W, et al.: Parental preferences for CDKN2A/p16 testing of minors. Genet Med 12 (12): 823-38, 2010. [PUBMED Abstract]
Shuk E, Burkhalter JE, Baguer CF, et al.: Factors associated with inconsistent sun protection in first-degree relatives of melanoma survivors. Qual Health Res 22 (7): 934-45, 2012. [PUBMED Abstract]
Bergenmar M, Brandberg Y: Sunbathing and sun-protection behaviors and attitudes of young Swedish adults with hereditary risk for malignant melanoma. Cancer Nurs 24 (5): 341-50, 2001. [PUBMED Abstract]
Manne S, Fasanella N, Connors J, et al.: Sun protection and skin surveillance practices among relatives of patients with malignant melanoma: prevalence and predictors. Prev Med 39 (1): 36-47, 2004. [PUBMED Abstract]
Azzarello LM, Dessureault S, Jacobsen PB: Sun-protective behavior among individuals with a family history of melanoma. Cancer Epidemiol Biomarkers Prev 15 (1): 142-5, 2006. [PUBMED Abstract]
Glenn BA, Bastani R, Chang LC, et al.: Sun protection practices among children with a family history of melanoma: a pilot study. J Cancer Educ 27 (4): 731-7, 2012. [PUBMED Abstract]
Newton Bishop JA, Gruis NA: Genetics: what advice for patients who present with a family history of melanoma? Semin Oncol 34 (6): 452-9, 2007. [PUBMED Abstract]
Loescher LJ, Crist JD, Cranmer L, et al.: Melanoma high-risk families' perceived health care provider risk communication. J Cancer Educ 24 (4): 301-7, 2009. [PUBMED Abstract]
Christensen KD, Roberts JS, Shalowitz DI, et al.: Disclosing individual CDKN2A research results to melanoma survivors: interest, impact, and demands on researchers. Cancer Epidemiol Biomarkers Prev 20 (3): 522-9, 2011. [PUBMED Abstract]
Geller AC, Emmons KM, Brooks DR, et al.: A randomized trial to improve early detection and prevention practices among siblings of melanoma patients. Cancer 107 (4): 806-14, 2006. [PUBMED Abstract]
Manne S, Jacobsen PB, Ming ME, et al.: Tailored versus generic interventions for skin cancer risk reduction for family members of melanoma patients. Health Psychol 29 (6): 583-93, 2010. [PUBMED Abstract]
Geller AC, Emmons K, Brooks DR, et al.: Skin cancer prevention and detection practices among siblings of patients with melanoma. J Am Acad Dermatol 49 (4): 631-8, 2003. [PUBMED Abstract]
Azzarello LM, Jacobsen PB: Factors influencing participation in cutaneous screening among individuals with a family history of melanoma. J Am Acad Dermatol 56 (3): 398-406, 2007. [PUBMED Abstract]
Coups EJ, Manne SL, Jacobsen PB, et al.: Skin surveillance intentions among family members of patients with melanoma. BMC Public Health 11: 866, 2011. [PUBMED Abstract]
Kasparian NA, McLoone JK, Meiser B, et al.: Skin cancer screening behaviours among individuals with a strong family history of malignant melanoma. Br J Cancer 103 (10): 1502-9, 2010. [PUBMED Abstract]
Bergenmar M, Hansson J, Brandberg Y: Family members' perceptions of genetic testing for malignant melanoma--a prospective interview study. Eur J Oncol Nurs 13 (2): 74-80, 2009. [PUBMED Abstract]
Glanz K, Volpicelli K, Kanetsky PA, et al.: Melanoma genetic testing, counseling, and adherence to skin cancer prevention and detection behaviors. Cancer Epidemiol Biomarkers Prev 22 (4): 607-14, 2013. [PUBMED Abstract]
Aspinwall LG, Leaf SL, Dola ER, et al.: CDKN2A/p16 genetic test reporting improves early detection intentions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev 17 (6): 1510-9, 2008. [PUBMED Abstract]
Aspinwall LG, Leaf SL, Kohlmann W, et al.: Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling. J Am Acad Dermatol 60 (5): 745-57, 2009. [PUBMED Abstract]
Aspinwall LG, Taber JM, Leaf SL, et al.: Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome. Psychooncology 22 (2): 276-89, 2013. [PUBMED Abstract]
Aspinwall LG, Taber JM, Leaf SL, et al.: Melanoma genetic counseling and test reporting improve screening adherence among unaffected carriers 2 years later. Cancer Epidemiol Biomarkers Prev 22 (10): 1687-97, 2013. [PUBMED Abstract]

Changes to This Summary (10/10/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Revised text to state that broadly speaking, there are two large compartments in the skin—the avascular epidermis and the vascular dermis—with many cell types distributed in a connective tissue matrix, largely created by fibroblasts.

Squamous Cell Carcinoma

Added text to state that one study reported a threefold increase in basal cell carcinoma in Japanese individuals who were heterozygous for XPA pathogenic variants (cited Hirai et al. as reference 51).

Melanoma

Added text to state that 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 (cited Eskandarpour et al. as reference 64). However, subsequent studies have found that the rates of the common somatic mutations in melanomas from CDKN2A carriers resemble or are lower than those described in the sporadic melanoma population (cited Zebary et al. and Jovanovic et al. as references 65 and 66, respectively). Of note, melanomas from several patients with CDKN2A variants had coexisting BRAF and NRAS mutations, which is an uncommon occurrence in sporadic melanomas.

Added text to state that 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 (cited Puntervoll et al. as reference 101).

Added text to state that multiple groups have assessed whether MC1R variants are associated with somatic BRAF mutations. Studies indicate that there may be an association between MC1R variants and BRAF V600E somatic mutations (cited Fargnoli et al., Guida et al., Hacker et al., and Thomas et al. as references 179, 180, 181, and 182, respectively). However, it is difficult to determine the impact of pigmentary influences on BRAF somatic mutations versus genetic effects.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of skin cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Skin Cancer are:

Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
Joanne Marie Jeter, MD (The Ohio State University)
Laurence J. Meyer, MD, PhD (Department of Veterans Affairs)
Suzanne M. O'Neill, MS, PhD, CGC
Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
Amanda Ewart Toland, PhD, FACMG (The Ohio State University)
Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
Catharine Wang, PhD, MSc (Boston University School of Public Health)

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Levels of Evidence

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The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Skin Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/skin-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389333]

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