BackgroundPathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients.MethodsConsecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2.ResultsEight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected.ConclusionPathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

中文翻译：

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巴基斯坦结直肠癌患者中 MLH1、MSH2 和 MSH6 致病性种系变异的患病率和谱

背景 MLH1、MSH2 和 MSH6 基因的致病性种系变异占林奇综合征 (LS) 的大部分。在来自巴基斯坦的第一份报告中，我们调查了结直肠癌 (CRC) 患者中致病性 MLH1/MSH2/MSH6 变异的患病率。方法在 Shaukat Khanum 纪念癌症医院和研究中心 (SKMCH&RC) 招募了连续病例 (n = 212)， 2007 年 11 月至 2011 年 3 月期间。具有 > 3 种或 2 种 HNPCC 相关癌症家族史的患者分别被分类为 HNPCC (n = 9) 或疑似 HNPCC (n = 20)（第 1 组；n = 29）。无家族史的病例被指定为非 HNPCC（第 2 组；n = 183）。在第 1 组中全面筛选 MLH1/MSH2/MSH6 基因。随后在第 2 组中评估第 1 组中确定的致病性/可能致病性变异。结果在第 1 组中发现了 8 个不同的致病性/可能致病性 MLH1/MSH2 变异（10/29；34.5） %），属于 HNPCC（5/9；55.6%）和疑似 HNPCC（5/20；25%）家庭，以及属于非 HNPCC 的第 2 组（2/183；1.1%）。总体而言，三种复发性变异（MSH2 c.943-1G > C、MLH1 c.1358dup 和 c.2041G > A）占所有携带致病性/可能致病性 MLH1/MSH2 变异的家族的 58.3% (7/12)。未检测到致病性 MSH6 变异。结论 致病性/可能致病性 MLH1/MSH2 变异在巴基斯坦患有 HNPCC/疑似 HNPCC 的 CRC 患者中占很大比例。我们的研究结果表明，在对该人群进行全面基因筛查之前，应对 HNPCC/疑似 HNPCC 家族进行这些复发性变异检测。