Medical Policy: 02.04.41
Original Effective Date: July 2012
Reviewed: February 2017
Revised: April 2014
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Some cases of cutaneous malignant melanoma (CMM) are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of disease and in unaffected individuals in a high-risk family.
A genetic predisposition to cutaneous malignant melanoma (CMM) is suspected in specific clinical situations: 1) melanoma has been diagnosed in multiple family members; 2) multiple primary melanomas are identified in a single patient; and 3) in the case of early age of onset. A positive family history of melanoma is the most significant risk factor; it is estimated that approximately 10% of melanoma cases report a first- or second-degree relative with melanoma. While some of the familial risk may be related to shared environmental factors, 3 main genes involved in CMM susceptibility have now been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21, encodes proteins that act as tumor suppressors. Mutations at this site can alter the tumor suppressor function. The second gene, cyclin-dependent kinase 4 (CDK4), is an oncogene located on chromosome 12q13 and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.
The incidence of CDKN2A mutations in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A mutation. Mutations are also infrequent in those with an early age of onset or those with multiple primary melanomas. However, the incidence of CDKN2A mutations increases with a positive family history; CDKN2A mutations will be found in 5% of families with first-degree relatives, rising to 20-40% in kindreds with 3 or more affected first-degree relatives. Mutation detection rates in the CDKN2A gene are generally estimated as 20-25% in hereditary CMM but can vary between 2% and 50%, depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A mutation are available.
Familial CMM has been described as a family in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship. Others have defined familial CMM as having at least 3 (first-, second-, or third-degree) affected members or 2 affected family members in which at least 1 was diagnosed before age 50 years or pancreatic cancer occurred in a first- or second-degree relative, or 1 member had multiple primary melanomas. No widely accepted guidelines for the management of families with hereditary risk of melanoma exist.
Other malignancies associated with familial CMM, specifically those associated with CDKN2A mutations, have been described. The most pronounced associated malignancy is pancreatic cancer, followed by other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be involved in these families. In particular, germline BRCA2 gene mutations have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define since there is no agreement on a standard phenotype, and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A mutations, there were family members with multiple atypical nevi who were noncarriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from noncarriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM but have low to moderate penetrance. One gene of moderate penetrance is the Melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for CMM. This gene is associated with fair complexion, freckles, and red hair; all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A mutations.
Melaris® (Myriad Genetics. Salt Lake City, UT) is commercially available genetic test of the CDKN2A gene.
The evidence for genetic testing in patients who have melanoma and family history of this disease or unaffected individuals in a family at high risk of developing melanoma includes association studies between mutations in certain genes and the risk of developing cutaneous melanoma. Data on the analytic validity of testing are lacking. Limitations with clinical validity include difficulties with mutation variant interpretations, variable penetrance of a given mutation, and residual risk with a negative mutation. Currently, management of patients considered high risk for malignant melanoma focuses on reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. To date the evidence is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. Although research continues in this area, none of the articles identified demonstrate how the presence or absence of the gene mutation would impact clinical care, either for those with melanoma or for those at risk due to family history. Changes in patient management that result from finding a mutation in a patient at risk is unknown. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
In 2010 ASCO updated its policy statement on genetic and genomic testing for cancer suspceptibility. ASCO recommends that "genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials."
The Melanoma Genetics Consortium, comprising of familial melanoma researchers from North America, Europe and Australia, indicated that genetic testing for melanoma susceptibility should not be offered outside the research setting. There is difficulty in interpreting test results and there is potentially limited impact of the results on clinical management.
Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for melanoma include no specific recommendations regarding CDKN2A genetic testing for melanoma.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Melaris® and other CDKN2A tests are laboratory-developed tests (LDTs) and available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.
See also medical policy 02.04.53 Gene Expression Profiling of Melanomas
Genetic molecular testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. Although research continues in this area, none of the articles identified demonstrate how the presence or absence of the gene mutation would impact clinical care, either for those with melanoma or for those at risk due to family history. Changes in patient management that result from finding a mutation in a patient at risk is unknown. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
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