Abstract
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.
Highlights
Melanoma is an aggressive and highly metastatic form of skin cancer that causes nearly 60,000 deaths globally each year [1]
Many CDKN2A genetic and epigenetic changes impact both the p16INK4a and p14ARF protein products encoded by this locus, and early studies confirmed the major contribution of p16INK4a in CDKN2A-associated melanoma, there is significant evidence that p14ARF plays an important and additional role in melanomagenesis
CDKN2A loss is associated with histological features predictive of poor prognosis in melanoma and correlates with diminished patient response to treatment, with loss of CDKN2A associated with poor response to BRAF/MEK inhibitors and chemotherapy but potentially improved responses to immune checkpoint inhibitors
Summary
Melanoma is an aggressive and highly metastatic form of skin cancer that causes nearly 60,000 deaths globally each year [1]. Melanoma originates from neural-crest-derived pigment-producing cells known as melanocytes. These specialized, dendritic cells are predominantly located in the basal layer of the epidermis, and are found in the vascular uvea of the eye and in mucosal membranes [2]. The CDKN2A locus is located on chromosome band 9p21 and is referred to as the INK4a/ARF locus. This is one of the most commonly altered sequences in cancer and is mutated, deleted, or methylated in 40–70% of sporadic melanomas [8]. Despite sharing largely overlapping DNA sequences, the functional impact of CDKN2A alterations is complex and can be difficult to predict. We discuss the impact of CDKN2A on the response of melanoma patients to current therapies
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