Ghiorzo Paola, Gargiulo Sara, Pastorino Lorenza, Nasti Sabina, Cusano Roberto, Bruno William, Gliori Sara, Sertoli Mario R, Burroni Anna, Savarino Vincenzo, Gensini Francesca, Sestini Roberta, Queirolo Paola, Goldstein Alisa M, Scarrà Giovanna Bianchi
Department of Oncology, Biology and Genetics/Medical Genetics Service, University of Genoa, and Dermatology Unit, San Martino Hospital, Italy.
Hum Mol Genet. 2006 Sep 15;15(18):2682-9. doi: 10.1093/hmg/ddl199. Epub 2006 Aug 7.
Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
在特定人群中，多达50%的黑色素瘤家族中，CDKN2A基因的突变是黑色素瘤易感性的基础，并且已经描述了几种CDKN2A的始祖突变。已发现CDKN2A的遗传突变与其他非黑色素瘤癌症有关，包括胰腺癌（PC）和神经系统肿瘤（NST）。在此，我们报告了CDKN2A基因第1外显子中的一种新型种系突变E27X，该突变最初是在居住于意大利西北部与利古里亚接壤的一个小地理区域或原籍于此的黑色素瘤患者中检测到的。该突变呈阳性的一部分黑色素瘤家族显示出患有胰腺癌和神经母细胞瘤。E27X产生一个过早的终止密码子，导致p16蛋白水平显著降低，而p14ARF未发生改变。由于胰腺癌和神经系统肿瘤据推测优先与位于第2外显子的CDKN2A突变和/或单独影响p14ARF的突变相关，E27X在第1α外显子中的位置为阐明CDKN2A/ARF基因座参与癌症易感性的机制提供了有趣的见解。
