Germ-Line Mutations in Mismatch Repair Genes Associated with Prostate Cancer
Germ-Line Mutations in Mismatch Repair Genes Associated with Prostate Cancer
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DOI：
10.1158/1055-9965.epi-09-0058
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发表时间：
2009-09-01
影响因子：
3.8
通讯作者：
Maehle, Lovise
中科院分区：
文献类型：
--
作者：
Grindedal, Eli Marie;Moller, Pal;Maehle, Lovise
前列腺癌的遗传易感性包括多种常见的外显性低的变异(单核苷酸多态)和罕见的高外显性的变异。错配修复(MMR)基因MLH1、MSH2、MSH6和PMS2与Lynch综合征有关，其中结肠癌和子宫内膜癌是主要的表型。我们研究的目的是调查这些基因的胚系突变是否可能与前列腺癌有关。共鉴定出106例男性MMR突变携带者或专性携带者。其中9人罹患前列腺癌。对9个肿瘤中的8个肿瘤组织进行免疫组织化学分析。观察发病率、60岁和70岁时的累积风险、发病年龄和Gleason评分与基于人群的系列评估的预期结果进行比较。在8个肿瘤中有7个发现突变的MMR基因没有基因产物。预期前列腺癌病例数为1.52例，而实际观察病例数为9例(P<；0.01)。前列腺癌的平均发病年龄为60.4岁，高于预期的66.6岁(P=0.006)；Gleason评分在8到10之间的男性数量显著高于预期(P<；0.00001)。Kaplan-Meier分析表明，MMR突变携带者70年的累积风险可能为30%(SE，0.088)，而普通人群为8.0%。这与BRCA2突变相关的高风险相似。据我们所知，这项研究首次表明，MMR基因可能是罕见的基因变异之一，当突变时，会导致前列腺癌的高风险。(癌症流行病学生物标记物2009；18(9)：2460-7)
Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2460-7)