Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer
Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer
复制标题
DOI：
10.1200/jco.2005.04.671
复制
发表时间：
2005-09-20
影响因子：
45.3
通讯作者：
Hopper, JL
中科院分区：
文献类型：
--
作者：
Southey, MC;Jenkins, MA;Hopper, JL
目的 错配修复 (MMR) 蛋白表达、微卫星不稳定性 (MSI)、家族史和种系 MMR 基因突变状态之间的关系尚未在人群基础上进行研究。 方法 我们研究了 131 名未选择的、诊断年龄小于 45 岁的结直肠癌患者。对于 105 个可用肿瘤，使用免疫组织化学 (IHC) 和 MSI 测量了 MLH1、MSH2、MSH6 和 PMS2 蛋白表达。对以下患者的种系 DNA 进行了 hMLH1、hMSH2、hMSH6 和 hPMS2 突变筛查：所有患者均来自符合遗传性非息肉病性结直肠癌 (HNPCC) 阿姆斯特丹标准的家庭；所有肿瘤均具有高 MSI、低 MSI 或缺乏任何 MMR 蛋白表达；以及 23 名表达所有 MMR 蛋白的 MS 稳定肿瘤的随机样本。结果 在 18 名患者中发现种系突变（9 名 hMLH1、4 名 hMSH2、4 名 hMSH6 和 1 名 hPMS2）；所有肿瘤均表现出 MMR 蛋白表达缺失，除一个外，所有肿瘤均为高 MSI 或低 MSI，其中 9 个肿瘤来自符合阿姆斯特丹标准的家族。 IHC 检测、MSI（高或低）和阿姆斯特丹标准对 MMR 基因突变的敏感性分别为 100%、94% 和 50%。相应的阳性预测值为 69%、50% 和 75%。 结论 四种 MMR 蛋白的肿瘤 IHC 分析和 MSI 检测为识别携带 MMR 基因突变的早发结直肠癌患者提供了高度敏感的策略，仅使用阿姆斯特丹标准就会漏掉其中一半的患者。基于肿瘤的方法对早发性结直肠癌患者进行 MMR 基因突变检测，无论其家族史如何，似乎是 HNPCC 的有效筛查策略。
Purpose The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis.Methods We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins.Results Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%.Conclusions Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.