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

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.

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer

“…Nevertheless, CDKN2A is not directly involved in DDR; rather, its main products, p16INK4a and p14ARF, are tumor suppressors involved in cell cycle regulation. Indeed, p16INK4a interacts with CDK4 and CDK6, inhibiting their interaction with cyclin D and pRb phosphorylation, thus preventing transition from G1 to S phase; p14ARF induces cell cycle arrest by activating p53 through the inhibition of its negative regulator MDM2 [ 39 ]. Therefore, given that our aim was to investigate DDR-related genes rather than genes merely involved in cancer susceptibility syndromes, we considered the SOPHiA HCS as a valid tool for this task.…”

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…An important downstream target of KDM6B is p16 INK4A which is found to be upregulated in cells expressing E7 [186]. Even though p16 INK4A is considered a tumor suppressor and isdownregulated in different cancers [187][188][189], its expression seems to be required in HPV induced tumors. Specifically, E7 can induce proteasome-mediated degradation of pRb by interacting with the cullin 2 ubiquitin ligase complex [190].…”

Individualized Treatment Strategy for Cutaneous Melanoma: Where Are We Now and Where Are We Going?

“…Alterations in CDKN2A in melanoma mainly target p16INK4a or affect both p16INK4a and p14ARF. Additionally, there is a subgroup of less frequent somatic and germline INK4a/ARF alterations that impact p14ARF but not p16INK4a ( 17 ). Bi-allelic loss of CDKN2A is correlated with aggressive initiation of melanoma.…”