Pathology, University of Leeds, Leeds, UK.
Genetics Laboratory, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
J Clin Pathol. 2019 Jun;72(6):443-447. doi: 10.1136/jclinpath-2018-205687. Epub 2019 Feb 5.
Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/-MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.
结直肠癌（CRC）很常见，其中 3%的病例与林奇综合征（LS）特征性的错配修复途径中的种系突变有关。英国国家卫生与保健优化研究所建议对所有新诊断为 CRC 的患者进行 LS 筛查，无论年龄大小。约克郡癌症研究结直肠癌改善计划为所有新诊断的 CRC 患者提供了一个区域性 LS 筛查服务。在筛查的前 829 例病例中，80 例显示错配修复缺陷（dMMR），其中 4 例免疫组织化学显示所有四种错配修复蛋白的表达缺失。这些病例表现出弥漫性 MLH1 缺失，与 BRAF 突变和 MLH1 启动子高甲基化相关，符合散发性 dMMR，推测存在额外的 MSH2+/-MSH6 双打击突变，而不是潜在的 LS。识别和准确解释这种不寻常的表型很重要，可以防止不必要地向临床遗传学转诊和相关的患者焦虑。
