MELANOMA AND GENETICS
By Gary M. White, MD
- 10% of cutaneous melanoma (CM) are gene susceptibility-related.
- The most common susceptibility gene is CDKN2A.
- The most common somatic mutations in CM are BRAF and NRAS.
- Approximately 50% of CM are BRAF mutation-positive.
- Approximately 20% of CM are NRAS positive.
- The same frequencies of BRAF and NRAS mutations are found in CDKN2A-related melanoma vs. sporadic CM [JID 2014;134;287].
- See rule of 3 below.
Two Distinct Types Of Testing
- Germline testing--test the family
- Somatic testing--test the cancer tissue
Melanoma Familial Genes
- Cyclin-Dependent Kinase Inhibitor 2A Mutation
- Found in 10% of families with 2 cases of melanoma
- Found in 30-40% of families with 3+ cases of melanoma
- Preliminary evidence of preferential histologic pattern, e.g., non-spindle cell morphology, dense pigmentation and high pagetoid scatter [JAAD 2015;72;496]
- Increased risk of lung, pancreatic, and breast cancer [JAAD 2014;71:888-95]
- Screen for other tumors routinely, e.g., pancreatic
- Only documented in a small number of melanoma families
- There may be an increased incidence of pancreatic cancer
- Increased risk of breast and ovarian cancer
- Several studies suggest that BRCA2 mutation carriers are 2.5-2.7 times more likely to develop melanoma compared to the general population
BAP1 Tumor Syndrome
- Uveal melanoma
- Cutaneous melanoma
- Only 15% of BAP1 mutation carriers have CM, suggesting that it is a medium-penetrance risk gene for CM
- Renal cell carcinoma
- Possible association with BCCs
When Should Germline Testing Be Considered?
- This is controversial. The American Society of Clinical Oncology has stated that screening tests for CDKN2A and CDK4 have not yet been shown to be of medical benefit.
- Three (or more) related individuals affected with melanoma (1st or 2nd degree)--controversial.
- Individuals with three or more multiple primary melanomas??
- Presence of pancreatic cancer and melanoma in one family (1st or 2nd degree)--controversial.
A large French study recommended the use of the rule of 3 for patients over the age of 40 and the rule of 2 for patients when the melanoma developed before the age of 40 [JAMA Derm 2017;153;1122]. The rule of 3 is met when there are 3 or more primary melanomas or genetically related cancers in the patient or first or second degree relatives. Genetically related cancers include exocrine pancreas adenocarcinoma, renal clear cell carcinoma, CNS tumors, mesothelioma and ocular melanoma.
Somatic Testing--Why Do It?
- Diagnostic, e.g., FISH, Gene expression profiling
- Therapeutic, e.g., BRAF
- Prognosis, gene expression profiling
- Sensitive detection of the BRAF V600E mutation
- Approximately 50% of melanomas are BRAF mutation-positive
- May also detect other mutations such as V600D, V600K, V600R
- V600E/K mutations confer increased sensitivity to BRAF inhibitors (vemurafenib, dabrafenib)
- Used on formalin-fixed, paraffin-embedded tissue, so biopsy specimens sent for routine histopathology are used
Somatic Mutation-Based Therapy
- BRAF V600E/K -> BRAF and/or MEK inhibitor
- NRAS -> MEK inhibitor
- KIT -> imatinib, dasatinib
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