Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers.,In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma.,The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF.,The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF.,There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions.,In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development.,We discuss the clinical implications of CDKN2A inactivating alterations and their influence on treatment response and resistance.
Familial melanoma is associated with point mutations in the cyclin-dependent kinase (CDK) inhibitor p16INK4A (p16).,We recently reported that p16 regulates intracellular oxidative stress in a cell cycle-independent manner.,Here, we constructed 12 different familial melanoma-associated point mutants spanning the p16 coding region and analyzed their capacity to regulate cell-cycle phase and suppress reactive oxygen species (ROS).,Compared to wild-type p16 which fully restored both functions in p16-deficient fibroblasts, various p16 mutants differed in their capacity to normalize ROS and cell cycle profiles.,While some mutations did not impair either function, others impaired both.,Interestingly, several impaired cell-cycle (R24Q, R99P, V126D) or oxidative function (A36P, A57V, P114S) selectively, indicating that these two functions of p16 can be uncoupled.,Similar activities were confirmed with selected mutants in human melanoma cells.,Many mutations impairing both cell-cycle and oxidative functions, or only cell cycle function, localize to the third ankyrin repeat of the p16 molecule.,Alternatively, most mutations impairing oxidative but not cell-cycle function, or those not impairing either function, lie outside this region.,These results demonstrate that particular familial melanoma-associated mutations in p16 can selectively compromise these two independent tumor-suppressor functions, which may be mediated by distinct regions of the protein.