A high colorectal cancer (CRC) incidence is observed in Tunisia, with a relatively high proportion of patients developing CRC before the age of 40. While this suggests a genetic susceptibility, only a few Tunisian Lynch Syndrome families have been described. In this study we aimed to identify the underlying genetic cause in 32 patients with early onset CRC and/or a positive family history. Of twenty-four patients’ tumor or biopsies could be analyzed with immunohistochemical staining to detect loss of expression of one of the MMR proteins. Ten tumors showed loss of expression, of which one tumor was from a patient where a germline pathogenic MSH2 variant was detected previously with Sanger sequencing. Next generation sequencing of the MMR, POLE and POLD1 genes was performed in leukocyte and tumor DNA of the remaining nine patients, as well as in two patients with MMR-proficient tumors, but with severe family history. In six of 11 patients a germline variant was detected in MLH1 (n = 5) or MSH2 (n = 1). Two of six patients were from the same family and both were found to carry a novel in-frame MLH1 deletion, predicted to affect MLH1 function. All MLH1 variant carriers had loss of heterozygosity with retention of the variant in the tumors, while a somatic pathogenic variant was detected in the patient with the germline MSH2 variant.

中文翻译：

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突尼斯人群中Lynch综合征的靶向下一代测序筛查。

在突尼斯观察到大肠癌（CRC）发生率很高，在40岁之前罹患CRC的患者比例相对较高。尽管这表明有遗传易感性，但仅描述了少数突尼斯林奇综合征家族。在这项研究中，我们旨在确定32例早期CRC和/或阳性家族史患者的潜在遗传原因。二十四例患者的肿瘤或活检可以用免疫组织化学染色进行分析，以检测一种MMR蛋白的表达缺失。十个肿瘤表现出表达缺失，其中一个肿瘤来自患者，该患者先前通过Sanger测序检测到种系致病性MSH2变体。MMR，POLE和POLD1的下一代测序在其余9例患者的白细胞和肿瘤DNA中以及在2例具有MMR精通肿瘤但有严重家族史的患者中进行了基因检测。11名患者中有6名在MLH1（n = 5）或MSH2（n = 1）中检测到种系变异。6名患者中有2名来自同一家庭，均被发现携带新的框内MLH1缺失，预计会影响MLH1功能。所有MLH1变异体携带者均具有杂合性丧失，且保留在肿瘤中，而在生殖系MSH2变异体患者中检测到体细胞致病变异体。