Risk Factors for Melanoma
Other environmental factors
Personal history of melanoma
Personal history of nonmelanoma skin cancer
Major Genes for Melanoma
CDKN2A/p16 and p14/ARF
Telomerase reverse transcriptase (TERT)
CDK4 and CDK6
DNA repair genes
PTEN and Cowden syndrome
Additional evidence for 9p21 loci
Additional candidate regions for familial melanoma susceptibility
Minor genes (genetic modifiers) for melanoma
Melanoma Risk Assessment
Both 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 mutations in specific susceptibility genes. The frequency with which multiple-case families are ascertained and specific genetic mutations are identified varies significantly between populations and geographic regions. A major population-based study has concluded that the high-penetrance susceptibility gene CDKN2A does not make a significant contribution to the incidence of melanoma.Risk Factors for Melanoma
Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.
While there is no standard measure, sun exposure has generally been classified as intermittent or chronic, and its effects may be considered short-term or cumulative. Intermittent sun exposure is, by definition, sporadic, and is commonly associated with recreational activities, particularly among indoor workers who use weekend or vacation time to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, usually during outdoor work or more extensive recreational activities. Acute sun exposure is obtained over a short time on skin that has not adapted to the sun. Depending on the time of day and the skin type of the individual, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as an injury associated with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. The impact of cumulative sun exposure likely reflects the additive effects of intermittent sun exposure or chronic sun exposure, or both.
Different patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intermittent sun exposure seems to be the most important risk factor for melanoma.[2,3] Analytic epidemiologic studies have shown only modest risks related to sun exposure in melanoma development; three systematic reviews have demonstrated similar estimates for the role of intermittent sun exposure (i.e., odds ratios [ORs] of 1.6 to 1.7).[4-6] Chronic sun exposure, as observed in those occupationally exposed to sunlight, is either protective or without increased risk for the development of melanoma (see Table 5). The biological mechanisms underlying these differences in melanoma risk by sun exposure type have not been fully elucidated.Table 5. Meta-Analysis Results: Intermittent and Chronic Sun Exposure and Melanoma Risk
|Study Citation||Intermittent Sun Exposure (OR, 95% CI)||Chronic Sun Exposure (OR, 95% CI)||Comments|
|CI = confidence interval; OR = odds ratio.|
|Nelemans et al.||1.6 (1.3–1.9)||0.7 (0.6–0.9)||Lack of standardized measures an issue.|
|Elwood et al.||1.7 (1.5–1.9)||0.9 (0.8–0.9)||Mechanisms for the differences in types of sun exposure not understood.|
|Gandini et al.||1.6 (1.3–1.9)||0.9 (0.7–1.0)||None.|
Although these meta-analyses have yielded very similar risk estimates, the measurement of sun exposure is complex; new studies using comparable protocols in different populations with varying levels of sun exposure are needed.
One explanation offered for the rise in melanoma incidence relates to the differential effects of chronic and intermittent sun exposure; as people have replaced outdoor occupations with indoor occupations, they have engaged in more intermittent sun exposure. Data from very different settings seem to suggest that intermittent sun exposure is critical to the risk of developing melanoma.
The evidence relating lifetime cumulative exposure to melanoma risk comes from two sources: migrant studies and studies of lifetime exposure, controlling for intermittent and occupational exposure. Data from Australia and Italy show that individuals who migrate from areas of low exposure to ultraviolet (UV) radiation, such as the United Kingdom, to areas of high exposure, such as Australia or Israel, before they reach age 10 years have a lifetime risk of developing melanoma that is similar to that of people in the new country.[8-10] Alternatively, adolescents or older individuals who migrate from areas of low solar exposure to areas of high solar exposure have a risk that is more similar to that of people from their area of origin than to that of people in the new area. These data have often been cited as indicating that childhood sun exposure is more important than adult sun exposure in melanoma development. However, the data could also be interpreted as suggesting that the length of high-level exposure is more critical than the age at exposure. Thus, people who migrate early in life to a high-insolation region have a longer potential period for intense exposure than do those individuals who migrate later in life.
Data from Connecticut have shown that cumulative lifetime exposure to ultraviolet-B (UVB) radiation does not differ between melanoma cases and controls; rather, intermittent sun exposure is the more important risk factor. The risks related to intermittent sun exposure are even greater if this pattern is experienced both early in life and later in life. These data can also be interpreted as suggesting that sun exposure patterns are rather consistent and stable throughout one's lifetime (i.e., that individuals who receive a great deal of intermittent sun exposure during early life are also likely to receive a great deal of intermittent sun exposure during later life). Nonetheless, an intermittent pattern of sun exposure over many years appears to significantly increase melanoma risk.
The relationship between sun exposure, sunscreen use, and the development of skin cancer is also 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.[12,13]Other environmental factors
There are a number of additional environmental factors that are important to melanoma development (see Table 6).Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa
|Study Citation||Subjects||Time and/or Place||Point Estimate|
|Wennborg et al.||Cohort (N = 23,718)||1970–1994; Sweden||RR, 2.7 (95% CI, 1.1–5.6)|
|Ron et al.||Various cohorts (N = 80,000)||Hiroshima, Japan||Excess RR per sievert, 2.1 (95% CI, <0.01–12)|
|Sigurdson et al.||U.S. Radiologic Technologists cohort (N = 90,305)||United States||SIR, 1.59 (95% CI, 1.38–1.80)|
|Telle-Lamberton et al.||French Atomic Energy Commission workers (N = 58,320)||France||SMR, 1.50 (90% CI, 1.04–2.11) among males|
|Sont et al.||(N = 3,737)||Canada||SIR, 1.16 (90% CI, 1.04–1.30)|
|Airline Flight Crews|
|Pukkala et al.||Male pilots (N = 10,032)||Scandinavia||SIR, 2.3 (95% CI, 1.7–3.0)|
|Tynes et al.||(N = 807 cases, 1,614 controls)||1980–1996; Norway||OR, 1.87 (95% CI, 1.23–2.83)|
|Lundberg et al.||Men in PVC processing plants (N = 717)||Sweden||SMR, 3.4 (95% CI, 1.1–7.9)|
|Landgård et al.||Workers exposed to PVC (N = 428)||Norway||SIR, 2.06 (95% CI, 1.36–6.96)|
|Loomis et al.||Occupational cohort of men exposed to PCBs (N = 138,905)||United States||RR, 1.29 (95% CI, 0.96–1.82); 5% increase per 2,000 h of exposure|
|Cl = confidence interval; OR = odds ratio; PCB = polychlorinated biphenyls; PVC = polyvinyl chloride; RR = relative risk; SIR = standardized incidence ratio; SMR = standard mortality rate.|
|aAdapted from Gruber et al.|
Occupational exposure for airline flight personnel, particularly pilots and flight attendants, appears to be particularly significant.[20,25-32] Since the risk of internal cancers is not consistently elevated in these very large cohort studies, most investigators think that the excess melanoma cancers observed are caused by lifestyle factors such as excessive intermittent sun exposure (i.e., UV radiation that does not penetrate beyond the surface of the skin) rather than cosmic (i.e., ionizing) radiation, which would be expected to increase the risk of radiation-related solid tumors.
Other occupational exposures have been variously and inconsistently associated with melanoma risk. If these reports are genuine, these exposures are likely to account for only a small fraction of cases.[33-35]
Arsenic exposure (both from drinking water and from exposure to combustion products) has been consistently associated with nonmelanoma skin cancer and has more recently been linked to melanoma.[34,36-38] Heavy metals bind to melanin, and occupational studies show that printers and lithographers have increased melanoma risk.[34,40-43] Further clarification of the occupational exposures associated with the development of melanoma in people employed in the printing/lithography trade has been difficult because of the small numbers of workers; the exposure of workers to numerous chemicals, solvents, pigments, and dyes; the extended latency of disease presentation; and changing work practices and environments over the past 50 years. Five studies have shown increased risk of melanoma among electronics workers.[24,43-46] However, more persuasive evidence of metal-related melanoma risk has been documented in the long-term follow-up of individuals with metal-on-metal hip replacements.[47-49]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. Darker-skinned ethnic groups (blacks, darker Hispanics, Asians) have a very low risk of melanoma; however, individuals in these groups develop melanoma on less-pigmented acral surfaces (palms, soles, nail beds). Among relatively light-skinned individuals, skin color is modified by genetics and behavior. MC1R is one of the major genes controlling pigmentation (see below); other pigmentation genes are under investigation.
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.
- Type I: Extremely fair skin, always burns, never tans.
- Type II: Fair skin, always burns, sometimes tans.
- Type III: Medium skin, sometimes burns, always tans.
- Type IV: Olive skin, rarely burns, always tans.
- Type V: Moderately pigmented brown skin, never burns, always tans.
- Type VI: Markedly pigmented black skin, never burns, always tans.
- Number of nevi or nevus density.
- Abnormal or atypical nevi.
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.[52-55] 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. 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.Immunosuppression
Melanoma is 1.6 to 2.5 times more common among recipients of organ transplants than in the general population, an excess that has generally been attributed to the effects of immunosuppressive therapy administered to avoid allograft rejection.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 of 2.62 for offspring of individuals with melanoma and 2.94 for siblings. 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, 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. The major hereditary melanoma susceptibility gene, CDKN2A, is found to be mutated 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 mutation.[62,63] 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.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 mutation 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.[64-67]Personal history of nonmelanoma skin cancer
Having a personal history of BCC or SCC is also associated with an increase in risk of a subsequent melanoma.[68-70] Depending on the study, this risk ranges from a nonsignificant increase for melanoma with a previous SCC of 1.04 (95% confidence interval [CI], 0.13–8.18) to a highly significant risk of 7.94 (95% CI, 4.11–15.35).[71,72] 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.
Mutations in CDKN2A account for 35% to 40% of familial melanomas. A large case series from Britain found that CDKN2A mutations 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. A similar study of Greek individuals with melanoma found CDKN2A mutations in 3.3% of single melanoma cases, 22% of familial melanoma cases, and 57% of individuals with multiple primary melanomas. The frequency of CDKN2A mutations 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 multiple primary melanomas. Many mutations reported among families consist of founder mutations, which are unique to specific populations and the geographic areas from which they originate.[75-81]
Depending on the study design and target population, melanoma penetrance related to deleterious CDKN2A mutations 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. 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 mutation 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. 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. 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 melanocortin 1 receptor (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. (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 to reach statistical significance, suggesting that other minor risk factors may interact with major risk loci.[85,86]
A comparison of clinical features from 182 patients with CDKN2A mutations and 7,513 individuals without mutations found that individuals with CDKN2A mutations had a statistically significant younger age at diagnosis (mean age at diagnosis: 39.0 years vs. 54.3 years; P < .001). There was also a 5-year cumulative incidence of a second melanoma of 23.4% in mutation carriers and a rate of 2.3% in mutation-negative controls. An Italian study performed genotype-phenotype correlations in 100 families with familial melanoma to determine clinical features predictive of the identification of a CDKN2A mutation. Probands with multiple primary melanomas, 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 mutation; probands with none of these features had less than a 1% likelihood of having a CDKN2A mutation. The most predictive feature was multiple primary melanomas. Results from the Genes, Environment, and Melanoma study showed that first-degree relatives of CDKN2A mutation carriers with melanoma had an approximately 50% increased risk of cancers other than melanoma, compared with first-degree relatives of other melanoma patients. Cancers with increased risk in this population included gastrointestinal cancers (relative risk [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).
CDKN2A exon 1ß mutations (p14ARF) have been identified in a small percentage of families negative for p16INK4a mutations. In a study of 94 Italian families with two or more cases of melanoma, 3.2% of families had mutations in p14ARF. At this time, testing for p14ARF is not commercially available.Melanoma and pancreatic cancer
A subset of CDKN2A mutation carrier families also displays an increased risk of pancreatic cancer.[91,92] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%. The RR has been reported as high as 47.8. Although at least 18 different mutations in p16 have been identified in such families, specific mutations appear to have a particularly elevated risk of pancreatic cancer.[62,95] Mutations 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 mutation is a 19-base pair deletion in CDKN2A exon 2 and is a founder mutation 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. However, other reports indicate that the average age at diagnosis is 5.8 years earlier for these mutation carriers than for those with sporadic pancreatic cancer. Geographic variation may play a role in determining pancreatic risk in these mutation carrier families. In a multicontinent study of the features of germline CDKN2A mutations, Australian families carrying these mutations did not have an increased risk of pancreatic cancer. It was also reported that similar CDKN2A mutations were involved in families with and without pancreatic cancer; therefore, there must be additional factors involved in the development of melanoma and pancreatic cancer. Some families with CDKN2A mutations may have a pattern of site-specific pancreatic cancer only.[100,101] Conversely, melanoma-prone families that do not have a CDKN2A mutation have not been shown to have an increased risk of pancreatic cancer.
In a review of 110 families with multiple cases of pancreatic cancer, 18 showed an association between pancreatic cancer and melanoma. 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 mutations in CDKN2A; mutations 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 mutations in CDKN2A. The possible existence of this disorder was first described in 1993. 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. 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.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. Sequencing demonstrated a mutation in the promoter region of a subunit of TERT, which in construct assays demonstrated increased promoter activity. This mutation cosegregated with melanoma and other cancers, including ovarian, renal, bladder, and bronchial, 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. A separate study reported mutations that also increased promoter activity in the same TERT promoter region in 50 of 70 sporadic melanomas.  Similar mutations were seen in 16% of a diverse set of established cancer cell lines, suggesting this might be a common activation mutation in multiple cancer types. The frequency of this mutation in melanoma families has not yet been investigated.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 mutations are very rare, being found in only a handful of melanoma kindreds.[108-110] All described families demonstrated a substitution of amino acid 24, suggesting this position as a mutation hotspot within the CDK4 gene. Mutation of CDK4 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 mutations was similar to the risk seen in families with CDKN2A mutations. (Refer to the CDKN2A/p16 and p14/ARF section of this summary for more information.)
Despite its functional similarity to CDK4, germline mutations in CDK6 have not been identified in any melanoma kindreds.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. The anatomic site distribution of melanomas in XP patients is similar to that of the general population.[114,115]
Genetic polymorphisms associated with DNA repair genes have been associated with mildly increased melanoma risk in the general population.PTEN and Cowden syndrome
Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS) is a rare syndrome that is associated with an increase in benign lesions and cancers, with the most commonly associated cancers being those of the breast, endometrium, and thyroid. (Refer to the PDQ summaries on Genetics of Colorectal Cancer and Genetics of Breast and Ovarian Cancer for more information about Cowden syndrome/PHTS.) A study assessed whether 154 individuals with PHTS and pathogenic mutations in PTEN were at an increased risk of other cancers. More cases of melanoma than expected were found. Four women and four men were diagnosed with melanoma and less than one case was expected, for a standardized incidence ratio of 28.3 for women (95% CI, 7.6–35.4) and 39.4 for men (95% CI, 10.6–100.9) (P < .001).Additional evidence for 9p21 loci
When the first data linking CDKN2A mutations to melanoma risk became available, it was clear that these mutations 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. The specific genes involved have remained elusive but are still under intense investigation.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 mutation-negative for CDKN2A and CDK4. 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 mutations in the genes tested thus far. A genome-wide association study of individuals from 34 high-risk melanoma families revealed three single nucleotide polymorphisms (SNPs) on 10q25.1 associated with melanoma risk. 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. A genome-wide linkage study of 35 Swedish families identified evidence of linkage on chromosomal regions 17p11-12 and 18q22. No causitive genes have been confirmed, but candidates map to all of the loci. None of these loci have been confirmed in independent studies.Minor genes (genetic modifiers) for melanoma
The MC1R gene, otherwise known as the alpha melanocyte-stimulating hormone receptor, is located on chromosome 8. Partial loss-of-function mutations are associated not only with red hair, fair skin, and poor tanning, but also with increased skin cancer risk independent of cutaneous pigmentation.[124-126] A comprehensive meta-analysis of over 8,000 cases and 50,000 controls showed the highest risk of melanoma in individuals with MC1R variants associated with red hair. However, this association remains controversial. Another meta-analysis showed that melanoma risk was highest in individuals who carry MC1R variants and have phenotypes generally considered protective for melanoma, including good tanning ability, darker hair, and darker skin. 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. 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.[129,130]
MC1R variants can also modify melanoma risk in individuals with CDKN2A mutations. A study consisting of 815 CDKN2A mutation carriers 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. 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 mutations 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. In contrast, a large consortium study did not show as large a decrease in age at onset of melanoma. Another study of Norwegian melanoma cases and controls showed that CDKN2A mutation carriers had an increased risk of melanoma when they carried either the Arg160Trp or Asp84Glu MC1R variants. However, MC1R status may play a prognostic role in melanoma patients. Pooled analyses of cohorts of melanoma patients with MC1R variants suggest that the presence of one or more variants conveys an overall survival benefit (hazard ratio = 0.78; 95% CI, 0.65–0.94).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. The E318K variant was found in three of seven melanoma cases tested in this family and was present at a much higher frequency in melanoma cases than controls. Six additional families out of 182 families negative for CDKN2A and CDK4 mutations were found to carry the variant. Population-based studies show a twofold increased risk of melanoma in carriers of the E318K variant. These data suggest that the E318K variant may be a moderate-risk allele for melanoma. MITF is a transcription factor that has been shown to regulate multiple genes important in melanocyte function.BRCA2
The Breast Cancer Linkage Consortium found that mutations in BRCA2 were associated with a relative risk of melanoma of 2.58 (95% CI, 1.3–5.2). A second study reported a similar increase in risk, although the result fell short of statistical significance. In contrast, another large cohort study of BRCA2 mutation carriers 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. Ashkenazi Jewish melanoma patients have not been shown to have an increased prevalence of the three founder mutations in BRCA1 and BRCA2 that are commonly found in this population. Overall, the evidence for increased risk of melanoma in the BRCA2 population is inconsistent at this time.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 multiple primary melanomas 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. 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. 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. 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. 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 nonmelanoma skin cancer. 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.
Two models have been developed to predict the probability of identifying germline CDKN2A mutations in individuals or families for research purposes (Table 7). MelPREDICT  uses logistic regression and MelaPRO  uses a Mendelian modeling algorithm to estimate the chance of an individual carrying a mutation in CDKN2A.Table 7. Characteristics of Common Models for Estimating the Likelihood of a CDKN2A Mutation
|MelaPRO ||MelPREDICT |
|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|
|Does not take into account domain-specific penetrances or geographical differences in penetrance|
Clinical testing is available to identify germline mutations 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, see GeneTests: Laboratory Directory.
Expert opinion regarding testing for germline mutations 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 mutation, and the reassurance of a negative testing result in individuals in a mutation-carrying family. However, a negative test result in a family that does not have a known mutation is uninformative; the genetic cause of disease in these patients must still be identified. It should also be noted that members of CDKN2A mutation–carrying families who do not carry the mutation themselves remain at increased risk of melanoma. At this time, identification of a CDKN2A mutation 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.
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
Management of members of melanoma-prone families
High-risk individuals, including first-degree family members in melanoma-prone families should be educated about sun safety and warning signs of melanoma. 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. 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.[147,148] A cost-utility analysis has demonstrated the benefits of screening in the high-risk population.
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.
At present, chemoprevention of melanoma in high-risk individuals remains an area of active investigation; however, no medications are recommended for melanoma risk reduction at this time.Pancreatic cancer screening in CDKN2A mutation carriers
Screening for pancreatic cancer remains an area of investigation and controversy for carriers of CDKN2A mutations. 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  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.
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 the CDKN2A mutation carrier population 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 CDKN2A mutations carriers only if there is a family history of pancreatic cancer and, even then, only in the context of a clinical trial.General population
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.
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. 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. 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.[156-158] As survival is inversely correlated with Breslow depth for melanoma, early diagnosis leads to better prognosis.Primary prevention
Primary prevention for melanoma consists of avoiding intense intermittent exposure to UV radiation, both solar and nonsolar. It should be stressed that the dose-response levels for such exposure are not defined, but that large, sporadic doses of UV radiation on skin are those epidemiologically most associated with later development of melanoma. Sunburn is a marker of that exposure, so that the amount of time spent in the sun should be calculated to avoid sunburn if at all possible. Tanning beds should be avoided, as studies suggest that they increase the risk of melanoma.[160,161]
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.[162,163] However, regular sunscreen use has been shown to reduce melanoma incidence in a prospective, randomized controlled trial.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. Our 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.References
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