University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, UK.
University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, UK.
Gynecol Oncol. 2014 Feb;132(2):506-12. doi: 10.1016/j.ygyno.2013.12.003. Epub 2013 Dec 10.
DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.
DNA 错配修复 (MMR) 缺陷与多种癌症风险增加相关，是 BRCA1 和 BRCA2 突变后遗传性卵巢癌的最常见原因。虽然已经对结直肠癌中的 MMR 缺陷进行了广泛研究，但卵巢癌中的 MMR 相对研究较少。本综述总结了 MMR 的机制，MMR 缺陷如何一般促进致癌作用，然后评估关于卵巢癌中 MMR 缺陷的现有研究，特别强调对疾病发生率和治疗的影响。卵巢癌中种系 MMR 基因突变的发生率仅为 2%，但其他基因失活机制意味着七种主要基因（MSH2、MSH3、MSH6、MLH1、MLH3、PMS1 和 PMS2）中的一个的表达缺失发生在高达 29%的病例中。突变和表达数据均表明，MMR 缺陷在非浆液性卵巢癌中更为常见。一些研究表明，与历史对照相比，MMR 缺陷患者的生存率有所提高，但这些研究并未考虑到非浆液性肿瘤的优势。一些体外研究表明，MMR 缺陷是铂类耐药的原因。迄今为止，这在临床上尚未得到明确证明。需要进行更大规模的研究，考虑到临床表现和免疫组织化学亚型，以评估 MMR 缺陷对生存率和化疗敏感性的影响。对结直肠癌中 MMR 相关合成致死性的研究已经确定了二氢叶酸还原酶、DNA 聚合酶 β 和 DNA 聚合酶 γ 以及 PTEN 诱导的假定激酶 1，通过引起氧化 DNA 损伤的积累，对某些 MMR 缺陷具有合成致死性。这些合成致死性靶标需要进行测试，并且应该在 MMR 缺陷的卵巢癌背景下寻找其他靶标，试图为这些患者提供新的治疗策略。
