Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.
Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.
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DOI：
10.1200/jco.2015.63.9518
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发表时间：
2015-12-20
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影响因子：
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通讯作者：
Mutch D
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作者：
Goodfellow PJ;Billingsley CC;Lankes HA;Ali S;Cohn DE;Broaddus RJ;Ramirez N;Pritchard CC;Hampel H;Chassen AS;Simmons LV;Schmidt AP;Gao F;Brinton LA;Backes F;Landrum LM;Geller MA;DiSilvestro PA;Pearl ML;Lele SB;Powell MA;Zaino RJ;Mutch D
子宫内膜癌（EC）中Lynch综合征（LS）的最佳筛查实践仍然未知。我们试图确定肿瘤微卫星不稳定性（MSI）分型沿着免疫组织化学（IHC）和MLH 1甲基化分析是否有助于识别LS女性。评估GOG 210患者的EC的MSI、MLH 1甲基化和错配修复（MMR）蛋白表达。每个肿瘤被分类为具有正常MMR、与MLH 1甲基化相关的缺陷MMR或可能的MMR突变（即，缺陷MMR但无甲基化）。比较三组的癌症家族史、人口统计学和临床特征。林奇突变测试进行了一个子集的妇女。对1,002个EC的分析表明，11.8%的肿瘤可能存在MMR突变。在肿瘤被归类为可能的MMR突变的女性中，有LS家族史的患者数量最多（P = 0.001）。Lynch突变在41%的被归类为可能突变的患者病例中被鉴定（51个测试病例中的21个）。在一名肿瘤中有完整MSH 6表达的患者中鉴定出MSH 6 Lynch突变之一。突变携带者诊断时的年龄比非携带者年轻（54.3 v62.3岁; P <0.01），其中5名携带者诊断时的年龄> 60岁。结合MSI，甲基化，和IHC分析可能被证明是有用的林奇筛选EC。24%的突变携带者在年龄> 60岁时出现EC，一名携带者有MSI阳性肿瘤，没有IHC缺陷。将Lynch检测限制在年龄< 60岁或有IHC缺陷的女性中，可能会导致遗漏相当一部分遗传疾病。
The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.