Genetic Testing for Melanoma

Introduction

Approximately 10% of melanomas present in familial clusters ( Fig. 30.1 ). Aggregation of melanoma in a family may occur due to a combination of shared environmental exposure and genetic factors. Melanoma risk factors are summarized in Table 30.1 . A recent study has found that approximately 40% of risk in families is due to shared variants in genes associated with pigmentation. While shared phenotypic features and environmental exposures accounts for a significant amount of familial melanoma risk, rare families harbor mutations in highly penetrant cancer predisposition genes. Patients who have inherited predisposition for melanoma are at 30–70-fold higher risk of developing melanoma than the general population.

To date, two high penetrance genes definitively associated with hereditary melanoma, cyclin-dependent kinase inhibitor 2A ( CDKN2A) on chromosome 19p21 and cyclin-dependent kinase 4 ( CDK4 ) on chromosome 12q14, have been identified. Mutations in CDKN2A account for approximately 20–40% of hereditary melanoma, and 0.2–1% of all melanomas ( Fig. 30.1 ). Mutations in CDK4 are rare and have been reported in fewer than fifteen families worldwide, leaving CDKN2A as the most significant melanoma predisposition gene identified thus far.

An efficient method for identifying this subset of particularly high-risk patients is needed so that additional clinical resources can be devoted to their care, even in fast-paced outpatient practices. Genetic testing is one mechanism by which high-risk patients and their families can be quickly identified. While CDKN2A was identified in 1994, incorporation of hereditary melanoma genetic testing into clinical practice has lagged behind that of other cancer predisposition genes such as BRCA1/BRCA2 (hereditary breast/ovarian cancer) and MSH2/MLH1 (Lynch syndrome – hereditary colon cancer). Recent studies suggest a strong interest in genetic testing among families with a history of melanoma, and that receiving genetic test results with appropriate education and counseling may help promote positive screening and behavioral changes among high-risk individuals. In order to address this growing demand for genetic services for hereditary melanoma, an international consortium recently published guidelines for appropriately identifying patients who are candidates for genetic counseling and testing for hereditary melanoma. In this chapter we will summarize current information about CDKN2A , the process of identifying high-risk families and incorporating genetic testing into clinical practice.

Gene identification

CDKN2A is a tumor suppressor gene that regulates cellular proliferation and growth by inhibiting RB (retinoblastoma protein) phosphorylation and entry into the cell cycle. CDKN2A produces two protein products, p16 ^INK4a , which is transcribed from exons 1α, 2, and 3, and p14 ^ARF , which is transcribed from an alternate reading frame and includes exons 1β, 2, and 3. Depending on the location, mutations in CDKN2A may disrupt one or both of the proteins produced by this gene. Most mutations that have been found to cause a risk for melanoma affect p16 ^INK4a , and at least one study has suggested that mutations which affect both proteins may be more penetrant. However, rare mutations which only affect p14 ^ARF have also been reported to segregate with the melanoma diagnoses in families, establishing it as an independent bona fide melanoma predisposition gene. Inheriting a deleterious mutation in one copy of CDKN2A is sufficient to cause an individual to have a melanoma predisposition. Parents who have a mutation in the CDKN2A gene will have a 50% chance of passing on the mutated allele and a 50% chance of passing on the functional copy of the gene with each offspring.

CDKN2A mutation penetrance estimates vary between populations and geographic regions due to gene–gene and gene–environment interactions. Studies of families ascertained on the basis of multiple cases have demonstrated penetrance estimates of 91%, 76%, and 58% in Australia, the United States, and Europe, respectively. Penetrance estimates are greatest in areas with high background rates of melanoma. This is likely because there are additional factors such as high ultraviolet radiation (UV) intensity and other shared genetic factors which work synergistically with the CDKN2A gene to increase melanoma risk. One of the best-studied genetic interactions is between CDKN2A and MC1R . Box et al. found the penetrance of CDKN2A mutations increased from 50% to 84% when inherited with a MCIR variant. Other genetic factors that contribute to incomplete penetrance have not yet been well defined. Yang et al. conducted an association study looking for potential CDKN2A interactions with 152 genes associated with pigmentation, DNA repair, apoptosis, and immune response. The only significant association identified was with IL9 (a gene involved with Th1:Th2 immune pathway), but several other candidate genes showed possible interactions that may become more evident with a larger sample size. Further studies are needed to characterize the gene–environment interactions that contribute to the differing melanoma risk estimates. Population-based studies have resulted in lower, but still significant, risk estimates. Begg et al. estimated a 28% risk for melanoma to age 80 in a population-based sample. However, for patients presenting in a clinical setting, penetrance estimates based on multiple case families are likely to be the most appropriate estimates to use for counseling when they are referred based on family history.

In addition to predisposing to melanoma, CDKN2A mutations are also associated with an increased risk for pancreatic cancer in some families. GenoMEL, an international melanoma genetics consortium, found that 28% of CDKN2A families had diagnoses of pancreatic cancer, compared to 6% of families without mutations. However, when data were evaluated by country, no excess risk of pancreatic cancer was seen in Australian families. Therefore, the nature of the association between CDKN2A and pancreatic cancer is still incompletely understood. Studies of families with CDKN2A mutations exhibiting pancreatic cancer have found that the risk to age 80 may be as high as 25%.

Genetic testing in clinical practice

There are several required steps for incorporating genetic testing into clinical practice, including identification of high-risk patients, providing genetic counseling, appropriately ordering genetic testing, interpreting results and incorporating findings into management recommendations. All of these steps can be time-intensive and referral to a local genetic counseling resource may be the most efficient approach for providing patients with these services. Table 30.2 provides a list of online resources for identifying cancer genetic services.