Lim P C, Tester D, Cliby W, Ziesmer S C, Roche P C, Hartmann L, Thibodeau S N, Podratz K C, Jenkins R B
Departments of Gynecologic Oncology Surgery, Laboratory Medicine & Pathology, Anatomical Pathology, and Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Clin Cancer Res. 1996 Nov;2(11):1907-11.
DNA mismatch repair genes have been reported to play a role in the pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). Mutations of DNA mismatch repair genes have accounted for 90% of HNPCC-related colon and endometrial tumors. These mutations have been associated with microsatellite instability (MIN). Because endometrial cancer (EC) is the most common extracolonic malignancy associated with HNPCC, we hypothesized that similar molecular alterations may occur in sporadic endometrial tumors exhibiting MIN. Mutational analysis of the MSH2 and MLH1 genes was undertaken in sporadic EC that demonstrate MIN to determine the role of these genes in the pathogenesis of sporadic ECs. Established microsatellite markers were used to determine the incidence of MIN from 28 patients with sporadic EC. MIN was observed in 32% (9 of 28) of the tumor specimens analyzed. Mutational analysis of MSH2 and MLH1 genes was performed by immunohistochemical analysis and direct sequencing of tumor specimens that exhibited MIN. All 28 tumor specimens exhibited strong nuclear staining with both MSH2 and MLH1 antibodies, suggesting the absence of mutations. Sequencing of all exons of both the MSH2 and MLH1 genes in the nine MIN-positive tumor specimens demonstrated no mutations. We conclude that the MSH2 and MLH1 genes do not play a role in the pathogenesis of sporadic endometrial cancer.
据报道，DNA错配修复基因在遗传性非息肉病性结直肠癌（HNPCC）的发病机制中起作用。DNA错配修复基因的突变占HNPCC相关结肠癌和子宫内膜癌肿瘤的90%。这些突变与微卫星不稳定性（MIN）有关。由于子宫内膜癌（EC）是与HNPCC相关的最常见的结肠外恶性肿瘤，我们推测在表现出MIN的散发性子宫内膜肿瘤中可能发生类似的分子改变。对表现出MIN的散发性EC进行MSH2和MLH1基因的突变分析，以确定这些基因在散发性EC发病机制中的作用。使用已建立的微卫星标记来确定28例散发性EC患者中MIN的发生率。在分析的肿瘤标本中，32%（28例中的9例）观察到MIN。通过免疫组织化学分析和对表现出MIN的肿瘤标本进行直接测序，对MSH2和MLH1基因进行突变分析。所有28个肿瘤标本均显示MSH2和MLH1抗体均有强核染色，提示无突变。对9个MIN阳性肿瘤标本中的MSH2和MLH1基因的所有外显子进行测序，未发现突变。我们得出结论，MSH2和MLH1基因在散发性子宫内膜癌的发病机制中不起作用。
