Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

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 p16(INK4a) and the p53 regulator p14(ARF). The majority of CDKN2A alterations in melanoma selectively target p16(INK4a) or affect the coding sequence of both p16(INK4a) and p14(ARF). There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14(ARF), while not altering the syntenic p16(INK4a) 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.