Although CDKN2A is well-known as a susceptibility gene for melanoma and pancreatic cancer, germline variants have also been anecdotally associated with a broader range of neoplasms including neural system tumors, head and neck squamous cell carcinomas, breast carcinomas, as well as sarcomas. The CDKN2A gene encodes for two distinct tumor suppressor proteins, p16INK4A and p14ARF, however, the independent association of germline alterations affecting these two proteins with cancer is under-appreciated. Here, we reviewed CDKN2A germline alterations reported among individuals and families with cancer in the literature, specifically addressing the cancer phenotypes in relation to the molecular consequence on p16INK4A and p14ARF. While melanoma is observed to associate with variants affecting both p16INK4A and p14ARF transcripts, it is noted that variants affecting p14ARF are more frequently observed with a heterogenous range of cancers. Finally, we reflected on the implications of this inferred genotype-phenotype association in clinical practice and proposed that clinical management of CDKN2A germline variant carriers should involve dedicated cancer genetics services, with multidisciplinary input from various healthcare professionals.

中文翻译：

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CDKN2A种系的改变与基因型-表型关联在癌症易感性中的相关性

尽管CDKN2A作为黑色素瘤和胰腺癌的易感基因而广为人知，但种系变体也与包括神经系统肿瘤，头颈部鳞状细胞癌，乳腺癌和肉瘤在内的更广泛的肿瘤有关。CDKN2A基因编码两种不同的肿瘤抑制蛋白p16INK4A和p14ARF，但是，影响这两种蛋白的种系改变与癌症之间的独立联系却被人们低估了。在这里，我们回顾了文献中在癌症个体和家庭中报道的CDKN2A生殖系改变，特别是针对与p16INK4A和p14ARF的分子后果相关的癌症表型。虽然观察到黑色素瘤与影响p16INK4A和p14ARF转录本的变体相关，应当指出，影响p14ARF的变体在不同范围的癌症中更频繁地观察到。最后，我们对这种推断的基因型-表型关联在临床实践中的意义进行了反思，并提出CDKN2A种系变异携带者的临床管理应包括专门的癌症遗传学服务，并需要来自各种医疗专业人员的多学科投入。