Molecular Genetics Team, LMCB, Faculty of Biological Sciences, University of Science and Technology Houari Boumediene, Algiers, Algeria.
Clinic of Medical Oncology Amine Zirout, University Hospital of Beni-Messous, School of Medicine, University of Algiers-1, Algiers, Algeria.
Ann Hum Genet. 2022 Nov;86(6):328-352. doi: 10.1111/ahg.12482. Epub 2022 Sep 8.
Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.
结直肠癌是阿尔及利亚男女癌症相关死亡的第二大原因。林奇综合征 (LS) 是一种常染色体显性疾病，由错配修复基因 (MMR) 的杂合胚系致病性变异引起，常导致结直肠癌。然而，关于阿尔及利亚患者 MMR 胚系致病性变异的数据有限。这项全国性的首次研究旨在描述疑似 LS 的阿尔及利亚家系的临床病理特征和 MMR 基因的胚系变异。研究了 64 个疑似 LS 的家系。通过 PCR 直接测序对符合阿姆斯特丹标准的 LS 索引病例进行 MMR 基因胚系变异筛查：MLH1（外显子 1、9、10、13、16）、MSH2（外显子 5、6、7、12）、MSH6（外显子 4 和 8）和 PMS2（外显子 6 和 10）。我们选择了这些特定的风险外显子基因，因为它们更有可能携带致病性变异。此外，对两名无关的 LS 患者进行了下一代测序筛查，使用了 30 个遗传性癌症基因的癌症面板。在 19 个（29.68%）家系中发现了 6 个胚系致病性变异和 1 个胚系可能致病性变异（4 个 MLH1、2 个 MSH2 和 1 个 MSH6）。对接受基因检测的索引病例和亲属（n=76）进行分析，发现 30 名（39.47%）有 MMR 致病性基因变异，1 名（0.13%）有 MMR 基因可能致病性变异，3 名有 MMR 变异意义不确定。本研究检测到 2 个 MLH1 胚系致病性变异（2）和 1 个 MSH6 胚系可能致病性变异（1），这两个变异从未在 LS 个体中报道过。在 9 个 LS 家系中发现了反复出现的 MLH1 胚系致病性变异 c.1546C>T，其中 6 个与来自阿尔及利亚四个中北部省份的两个大型家族有关。此外，在 5 个无相关家族史的患者中检测到常见的 MSH2 胚系致病性变异 c.942+3A>T。阿尔及利亚 LS 患者临床病理和遗传特征的累积知识将影响预防和治疗领域的临床管理。
