*Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR †Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
Adv Anat Pathol. 2017 Nov;24(6):372-378. doi: 10.1097/PAP.0000000000000169.
Lynch syndrome (LS) is a hereditary cancer syndrome caused by a germline mutation in a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common cancers associated with LS are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with LS-associated endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same cancers. Germline testing of all endometrial cancer patients is not cost effective, and screening using young age of cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective. Therefore, most groups now advocate for tumor tissue testing to screen for LS, with germline testing targeted to women with abnormal tissue testing results. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is used in many clinical laboratories for this tumor screening step, as immunohistochemistry is relatively inexpensive and is technically more accessible for smaller clinical labs. PCR-based tissue testing, whereas technically more challenging, does play an important role in the identification of these patients. MLH1 methylation analysis identifies women with tumor MLH1 loss who likely have sporadic endometrial cancer and do not need heightened cancer prevention surveillance. High levels of microsatellite instability have been identified in tumors with retained positive expression of mismatch repair proteins. Somatic sequencing of mismatch repair genes from tumor DNA, whereas not currently available in most clinical laboratories, is helpful in resolution of cases in which germline sequencing fails to identify a mutation in a mismatch repair gene. The tumor tissue testing approach can help to identify most women at-risk for germline mutations in a LS gene, but not all patients will be captured using this approach. Clinical suspicion can still play a pivotal role in accurately identifying a subset of these patients.
林奇综合征（LS）是一种遗传性癌症综合征，由 DNA 错配修复基因（通常为 MLH1、MSH2、MSH6 或 PMS2）的种系突变引起。与 LS 相关的最常见癌症是结直肠癌和子宫内膜癌。识别具有 LS 相关子宫内膜癌的女性很重要，因为这些女性及其受影响的兄弟姐妹和子女有患这些相同癌症的风险。对所有子宫内膜癌患者进行种系测试并不具有成本效益，并且使用癌症诊断年龄较小和/或存在综合征相关家族史进行筛查的效果不佳且效率低下。因此，大多数组织现在主张对肿瘤组织进行检测以筛查 LS，对组织检测结果异常的女性进行种系检测。MLH1、MSH2、MSH6 和 PMS2 的免疫组织化学在许多临床实验室中用于这种肿瘤筛查步骤，因为免疫组织化学相对便宜，并且对于较小的临床实验室来说在技术上更容易实现。基于 PCR 的组织检测虽然在技术上更具挑战性，但在识别这些患者方面发挥着重要作用。肿瘤 MLH1 失活的女性可能患有散发性子宫内膜癌，无需加强癌症预防监测，通过 MLH1 甲基化分析可以识别出来。在错配修复蛋白表达阳性的肿瘤中发现了高水平的微卫星不稳定性。肿瘤 DNA 中错配修复基因的体细胞测序虽然目前在大多数临床实验室中不可用，但有助于解决种系测序未能识别错配修复基因中的突变的情况。肿瘤组织检测方法有助于识别大多数存在 LS 基因突变风险的女性，但并非所有患者都可以通过这种方法检测到。临床怀疑仍然可以在准确识别这些患者的亚组中发挥关键作用。
