Bertram Chandra G, Gaut Rupert M, Barrett Jennifer H, Pinney Elizabeth, Whitaker Linda, Turner Faye, Bataille Veronique, Dos Santos Silva Isabel, J Swerdlow Anthony, Bishop D Timothy, Newton Bishop Julia A
Division of Genetic Epidemiology, Cancer Research UK Clinical Center in Leeds, St. James's University Hospital, Leeds, U.K.
J Invest Dermatol. 2002 Oct;119(4):961-5. doi: 10.1046/j.1523-1747.2002.01825.x.
Melanocytic nevi are the most potent risk factors for melanoma yet identified. Variation in the nevus phenotype within a population is predominantly genetically determined. Genes that determine nevus expression may therefore act as low penetrance melanoma susceptibility genes. Rare germline mutations in CDKN2A predispose to melanoma and appear to be nevogenic, although the correlation between nevus phenotype and mutation status is poor. It is plausible that more common CDKN2A variants may influence both melanoma susceptibility and nevus susceptibility. Ala148Thr is a G to A missense polymorphism of CDKN2A, which is found in 4%-6% of the general population. We have investigated the role of Ala148Thr as a low penetrance melanoma or nevus susceptibility allele in two separate groups of individuals. The first was a sample of 488 adults recruited from 179 families of patients with the atypical nevus phenotype and/or a family history of melanoma, and the second was a population-based sample of 599 women. Similar prevalences of Ala148Thr (4.9% and 5.2%) were found in both samples but significant variation in the prevalence of the polymorphism was seen across geographic areas within England. There was no association between Ala148Thr status and nevus number or history of melanoma, and therefore the results did not support the hypothesis that the Ala148Thr variant is a low penetrance melanoma or nevus susceptibility allele. A significant protective role of Ala148Thr on the number of atypical nevi was observed in the family sample (mean of 1 atypical nevus in those with the allele and 3.5 nevi in those without, p = 0.02). After allowing for potential confounders this was not evident in the population-based sample.
黑素细胞痣是目前已确定的黑色素瘤最主要的危险因素。人群中痣表型的差异主要由基因决定。因此，决定痣表达的基因可能作为低外显率的黑色素瘤易感基因。CDKN2A基因的罕见种系突变易患黑色素瘤，且似乎具有痣形成倾向，尽管痣表型与突变状态之间的相关性较差。更常见的CDKN2A变异可能同时影响黑色素瘤易感性和痣易感性，这是有道理的。Ala148Thr是CDKN2A基因的一种G到A的错义多态性，在普通人群中发现率为4%-6%。我们在两组不同的个体中研究了Ala148Thr作为低外显率黑色素瘤或痣易感等位基因的作用。第一组是从179个具有非典型痣表型和/或黑色素瘤家族史的患者家庭中招募的488名成年人样本，第二组是599名女性的基于人群的样本。在两个样本中发现Ala148Thr的患病率相似（分别为4.9%和5.2%），但在英格兰不同地理区域，该多态性的患病率存在显著差异。Ala148Thr状态与痣数量或黑色素瘤病史之间没有关联，因此结果不支持Ala148Thr变异是低外显率黑色素瘤或痣易感等位基因的假设。在家族样本中观察到Ala148Thr对非典型痣数量有显著的保护作用（携带该等位基因者平均有1个非典型痣，未携带者平均有3.5个痣，p=0.02）。在考虑潜在混杂因素后，在基于人群的样本中这一现象并不明显。
