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.

中文翻译：

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INK4a / ARF基因座中的遗传改变：对黑素瘤发展和进展的影响。

据报道，INK4a / ARF（或CDKN2A）基因座的遗传改变在包括黑色素瘤在内的许多癌症类型中均存在。头颈部鳞状细胞癌；肺癌，乳腺癌和胰腺癌。在黑色素瘤中，已经在大约50％的原发性黑色素瘤，超过75％的转移性黑色素瘤以及40％易患皮肤黑色素瘤的家庭的生殖系中鉴定出功能性CDKN2A改变。CDKN2A基因座编码两个关键的肿瘤抑制蛋白，即细胞周期蛋白依赖性激酶抑制剂p16 ^INK4a和p53调节剂p14 ^ARF。黑色素瘤中的大多数CDKN2A改变选择性靶向p16 ^INK4a或影响两个p16 ^INK4a的编码序列和p14 ^ARF。还有一些不常见的体细胞和种系INK4a / ARF改变会影响p14 ^ARF，而不会改变同系的p16 ^INK4a编码区。在这篇综述中，我们描述了影响黑色素瘤CDKN2A基因座和家族性黑色素瘤种系CDKN2A基因改变的体细胞改变的频率和类型，以及它们在黑色素瘤发展中的功能性后果。我们讨论了CDKN2A失活改变的临床意义及其对治疗反应和耐药性的影响。