Ming Zizhen, Lim Su Yin, Rizos Helen
Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Melanoma Institute Australia, Sydney, NSW 2065, Australia.
Biomolecules. 2020 Oct 15;10(10):1447. doi: 10.3390/biom10101447.
Genetic alterations in the (or ) 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 and the p53 regulator p14. The majority of CDKN2A alterations in melanoma selectively target p16 or affect the coding sequence of both p16 and p14. There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14, while not altering the syntenic p16 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.
在许多癌症类型中都报道过（或）基因座的基因改变，包括黑色素瘤、头颈部鳞状细胞癌、肺癌、乳腺癌和胰腺癌。在黑色素瘤中，约50%的原发性黑色素瘤、超过75%的转移性黑色素瘤以及40%有皮肤黑色素瘤易感性的家族系谱中都发现了功能缺失的CDKN2A改变。CDKN2A基因座编码两种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和p53调节蛋白p14。黑色素瘤中大多数CDKN2A改变选择性地靶向p16或影响p16和p14的编码序列。也有一部分不太常见的体细胞和种系INK4a/ARF改变影响p14，而不改变同线性p16编码区。在本综述中，我们描述了影响黑色素瘤中CDKN2A基因座的体细胞改变的频率和类型以及家族性黑色素瘤中的种系CDKN2A改变，及其在黑色素瘤发生发展中的功能后果。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。
