Pastorino L, Bonelli L, Ghiorzo P, Queirolo P, Battistuzzi L, Balleari E, Nasti S, Gargiulo S, Gliori S, Savoia P, Abate Osella S, Bernengo M G, Bianchi Scarrà G
Department of Oncology, Biology and Genetics/Medical Genetics Service, University of Genoa, Genoa, Italy.
Pigment Cell Melanoma Res. 2008 Dec;21(6):700-9. doi: 10.1111/j.1755-148X.2008.00512.x. Epub 2008 Oct 22.
We evaluated the contribution of germline CDKN2A mutations and MC1R variants to the development of melanoma in a hospital-based study of single (SPM, n = 398) and multiple primary melanoma (MPM, n = 95). The overall frequency of CDKN2A mutations was 15.2%, and four-fold higher in MPM than in SPM cases (OR = 4.27; 95% CI 2.43-7.53). The likelihood of identifying a CDKN2A mutation increased with family history of melanoma and younger age at diagnosis in MPM cases. Compared to SPM patients, the risk of harboring a CDKN2A mutation rose as the number of primary melanomas increased and was not influenced by family history. The G101W and E27X founder mutations were the most common. Several other mutations (W15X, Q50X, R58X, A68L, A127P and H142R) were detected for the first time in Italian patients. One novel mutation, T77A, was identified. Several non-coding variants with unknown functional significance were also found (5'UTR -25C > T, -21C > T, -67G > C, IVS1 +37G > C); the novel 5'UTR -21C > T variant was not detected in controls. The CDKN2A A148T polymorphism was more frequent in MPM patients than in the control population (15.7% versus 6.6%). Compared to the SPM patients, MPM cases had a 2-fold increased probability of being MC1R variant carriers and a higher probability of carrying two or more variants. No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM. We observed no interaction between CDKN2A status and the presence of MC1R variants. The high frequency of CDKN2A mutations in our MPM cases, independent of their family history, is of relevance to genetic counseling and testing in our population.
在一项基于医院的单发性原发性黑色素瘤（SPM，n = 398）和多发性原发性黑色素瘤（MPM，n = 95）研究中，我们评估了种系CDKN2A突变和MC1R变异对黑色素瘤发生发展的影响。CDKN2A突变的总体频率为15.2%，在MPM中比在SPM病例中高四倍（OR = 4.27；95% CI 2.43 - 7.53）。在MPM病例中，发现CDKN2A突变的可能性随着黑色素瘤家族史以及诊断时年龄较小而增加。与SPM患者相比，携带CDKN2A突变的风险随着原发性黑色素瘤数量的增加而上升，且不受家族史影响。G101W和E27X始祖突变最为常见。在意大利患者中首次检测到其他几种突变（W15X、Q50X、R58X、A68L、A127P和H142R）。鉴定出一种新突变T77A。还发现了几种功能意义未知的非编码变异（5'UTR -25C > T、-21C > T、-67G > C、IVS1 +37G > C）；新的5'UTR -21C > T变异在对照组中未检测到。CDKN2A A148T多态性在MPM患者中比在对照人群中更常见（15.7% 对6.6%）。与SPM患者相比，MPM病例成为MC1R变异携带者的概率增加两倍，且携带两个或更多变异的概率更高。未观察到变异类型与黑色素瘤数量之间的特定关联，这表明MC1R变异的数量而非类型增加了MPM的风险。我们未观察到CDKN2A状态与MC1R变异存在之间的相互作用。我们的MPM病例中CDKN2A突变的高频率，无论其家族史如何，对于我们人群的遗传咨询和检测都具有重要意义。
