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

by 1,2, 1,2 and 1,2,*
1
Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
2
Melanoma Institute Australia, Sydney, NSW 2065, Australia
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(10), 1447; https://doi.org/10.3390/biom10101447
Received: 1 September 2020 / Revised: 11 October 2020 / Accepted: 12 October 2020 / Published: 15 October 2020
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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. View Full-Text
Keywords: p16INK4a; p14ARF; CDKN2A; INK4a/ARF; melanoma; tumor suppressor proteins p16INK4a; p14ARF; CDKN2A; INK4a/ARF; melanoma; tumor suppressor proteins
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Ming, Z.; Lim, S.Y.; Rizos, H. Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression. Biomolecules 2020, 10, 1447.

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