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 following diagnosis of a first primary melanoma is approximately 5% and is greater for males and older patients.[63,64,65,66]
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.[67,68,69] 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).[70,71] 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 for 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 prior to 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.