Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing
Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing
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DOI：
10.1200/jco.2013.51.2129
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发表时间：
2014-01-10
影响因子：
45.3
通讯作者：
Spurdle, Amanda B.
中科院分区：
文献类型：
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作者：
Buchanan, Daniel D.;Tan, Yen Y.;Spurdle, Amanda B.
目的 对来自基于人群的子宫内膜癌队列（未选择年龄或家族史）的临床病理数据进行分析，以确定识别生殖系错配修复 (MMR) 基因突变患者的最佳方案。 患者和方法 使用免疫组织化学 (IHC) 检测纳入澳大利亚国家子宫内膜癌研究 (ANECS) 的 702 名患者的子宫内膜癌的 MMR 蛋白表达和 MLH1 基因启动子甲基化。 MLH1 缺陷病例。对 MMR 蛋白缺陷肿瘤患者的种系 DNA 进行 MMR 突变检测。将肿瘤特征、诊断时年龄和各种临床标准（阿姆斯特丹、贝塞斯达、妇科肿瘤学会、ANECS）的组合对种系突变状态的预测进行比较。结果 702 例中有 170 例 (24%) 检测到肿瘤 MMR 蛋白缺陷。对 158 个 MMR 缺陷病例的种系测试发现了 22 个截短突变（占所有病例的 3%）和 4 个未分类的变异。 111 例 MLH1/PMS2 IHC 缺失的病例中，99 例 (89%) 检测到肿瘤 MLH1 甲基化；全部均为种系 MLH1 突变阴性。在诊断时年龄小于 60 岁的女性中，MMR IHC 加 MLH1 甲基化检测的组合为识别突变携带者提供了最高的阳性预测值，分别为 46% 和其他考虑标准的 41%。结论 通过逐步检测 60 岁以下患者的肿瘤 MMR IHC 缺失、MLH1 IHC 缺失个体的肿瘤 MLH1 甲基化和种系，可以优化 MMR 突变阳性子宫内膜癌患者的群体水平识别。表现出 MSH6、MSH2 或 PMS2 缺失或 MLH1/PMS2 缺失但不存在 MLH1 甲基化的患者的突变。
Purpose Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.Patients and Methods Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).Results Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus 41% for any other criteria considered.Conclusion Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.