Grindedal Eli Marie, Møller Pål, Eeles Ros, Stormorken Astrid Tenden, Bowitz-Lothe Inger Marie, Landrø Stefan Magnus, Clark Neal, Kvåle Rune, Shanley Susan, Maehle Lovise
Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet University Hospital, N-0310 Oslo, Norway.
Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2460-7. doi: 10.1158/1055-9965.EPI-09-0058. Epub 2009 Sep 1.
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.
前列腺癌的遗传易感性包括多个低外显率的常见变异（单核苷酸多态性）和高外显率的罕见变异。错配修复（MMR）基因MLH1、MSH2、MSH6和PMS2与林奇综合征相关，在该综合征中，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中的种系突变是否可能与前列腺癌相关。我们确定了106名MMR突变的男性携带者或必然携带者。其中9人患了前列腺癌。对这9例肿瘤中8例的肿瘤组织进行了免疫组织化学分析。将观察到的发病率、60岁和70岁时的累积风险、发病年龄和 Gleason评分与基于人群系列评估的预期值进行比较。在8个肿瘤中的7个中发现了突变的MMR基因的基因产物缺失。前列腺癌的预期病例数为1.52例，而观察到的为9例（P < 0.01）。前列腺癌的平均发病年龄为60.4岁，而预期为66.6岁（P = 0.006）；Gleason评分为8至10分的男性人数显著高于预期（P < 0.00001）。Kaplan-Meier分析表明，MMR突变携带者到70岁时的累积风险可能为30%（标准误，0.088），而一般人群为8.0%。这与BRCA2突变相关的高风险相似。据我们所知，本研究首次表明，MMR基因可能是罕见的遗传变异之一，突变时会赋予前列腺癌高风险。
