Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, APHP, IFR02, Université Paris, Henri Huchard, 75018 Paris, France.
Eur J Cancer. 2009 Dec;45(18):3228-36. doi: 10.1016/j.ejca.2009.04.034. Epub 2009 May 26.
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.
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).
Overall, the c.1783G, p.595V 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 [1.29-2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects.
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.
色素性干皮病变异型（XPV）是一种罕见的常染色体隐性遗传皮肤疾病，易导致多种早期皮肤癌，包括黑色素瘤。XPV 是由于 POLH 基因突变所致，该基因编码一种 DNA 跨损伤聚合酶。在这项研究中，我们检验了一个假设，即 POLH 变体可能与黑色素瘤风险相关。
我们在法国的 1075 名黑色素瘤患者和 1091 名匹配的对照者中，对一个常见的非同义 POLH 变体 c.1783A>G p.M595V 进行了基因分型。此外，我们通过对 201 名有家族性黑色素瘤病史（n=123）、散发多发性黑色素瘤（n=65）和黑色素瘤伴皮肤癌病史（n=13）的患者进行整个编码序列测序，寻找罕见的 POLH 变体。
总体而言，c.1783G，p.595V 等位基因与黑色素瘤呈统计学相关（相应的等位基因频率分别为 0.040 与 0.022，P 值=1.17 x 10(-3)，比值比（OR）=1.86 [1.27-2.71]），这一结果在包括 274 名意大利患者和 174 名匹配对照者的一项荟萃分析中得到进一步证实（P 值=7.7 x 10(-4)，OR=1.84 [1.29-2.63]）。有趣的是，在 3 名患者（c.295G>A p.V99M、c.815T>C p.I272T 和 c.1745C>T p.S582L）中发现了 3 个非同义 POLH 变体，而在 352 名健康受试者的染色体对照中未见这些变体。
除了严重影响跨损伤合成的缺陷，这是皮肤癌和黑色素瘤的主要风险因素外，功能较弱的 POLH 变体可能作为低外显率的黑色素瘤易感等位基因。目前正在寻找与皮肤癌易感性相关的遗传标志物，这可能有助于确定高危人群作为临床随访的目标。其他人群的复制研究正在进行中，以评估这些数据。
