Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk
Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk
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DOI：
10.1016/j.ejca.2009.04.034
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发表时间：
2009-12-01
影响因子：
8.4
通讯作者：
Soufir, Nadem
中科院分区：
文献类型：
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作者：
Di Lucca, Julie;Guedj, Mickael;Soufir, Nadem
目的：着色性干皮变异体（XPV）是一种罕见的隐性常染色体遗传性皮肤病，易导致多种早发性皮肤癌，包括黑色素瘤。XPV是由编码DNA翻译聚合酶的POLH基因突变引起的。在这项工作中，我们验证了POLH变异可能与黑色素瘤风险相关的假设。实验设计：对来自法国的1075名黑色素瘤患者和1091名种族匹配的对照者进行基因分型，研究一种常见的非同义POLH变体c.1783A>G . p.M595v。此外，我们通过对201例黑色素瘤（n = 123）、散发性多发性黑色素瘤（n = 65）和黑色素瘤合并皮肤癌（n = 13）家族史患者的整个编码序列进行测序，寻找罕见的POLH变异。结果：总体而言，c.1783G、p.59SV等位基因与黑色素瘤存在统计学相关性(等位基因频率分别为0.040 vs 0.022， p值= 1.17 × 10(-3)，优势比(OR) = 1.86[1.27-2.71])，一项包括274名意大利患者和174名匹配对照的meta分析进一步证实了这一点（p值= 7.7 × 10(-4), OR = 1.84[1.29-2.631]）。有趣的是，在3名患者中发现了3种非同义的POLH变异（C . 295g >A p.V99M, C . 815t >C . 1272t和C . 1745c >T p.S582L），而这些变异在352名健康受试者的染色体对照中不存在。结论：除了翻译合成严重缺陷是皮肤癌和黑色素瘤的主要危险因素外，毒性较小的POLH变异可能是低外显率黑色素瘤的易感等位基因。正在进行的皮肤癌易感性遗传标记的鉴定可以帮助确定高风险受试者作为临床随访的目标。等待其他人群的重复研究来评估这些数据。(C) 2009年Elsevier Ltd.出版
Purpose: Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. in this work, we tested the hypothesis that POLH variants could be associated with melanoma risk.Experimental design: A common non-synonymous POLH variant, c.1783A>G p.M595v, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma (n = 123), sporadic multiple melanomas (n = 65) and a melanoma associated with a skin carcinoma (n = 13).Results: Overall, the c.1783G, p.59SV allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P-value = 1.17 x 10(-3), odds ratio (OR) = 1.86 [1.27-2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy (P-value = 7.7 x 10(-4), OR = 1.84 [1.29-2.631). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.1272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects.Conclusions: Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data. (C) 2009 Published by Elsevier Ltd.