N.N. Petrov Institute of Oncology, Laboratory of Molecular Oncology, St.-Petersburg 197758, Russia.
St.-Petersburg Pediatric Medical University, Department of Medical Genetics, St.-Petersburg 194100, Russia.
Clin Genet. 2018 May;93(5):1015-1021. doi: 10.1111/cge.13228. Epub 2018 Mar 9.
Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs4 [n = 5] and p.Q1062fs [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs6, p.S254Hfs12, p.S1072Kfs9, p.E1547Kfs11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000.
癌症易感性突变的分布表现出显著的种族间差异。本研究旨在评估 APC 和 MUTYH 种系突变在俄罗斯结直肠癌患者中的模式。在 38 名结肠息肉患者中，确定了 26 名 APC 基因缺陷患者（68%）；26 名 APC 突变中有 8 名（31%）与 2 个已知的突变热点相关（p.E1309Dfs4[n=5]和 p.Q1062fs[n=3]），而 6 名（23%）突变是新的（p.K73Nfs6、p.S254Hfs12、p.S1072Kfs9、p.E1547Kfs11、p.L1564X 和 p.C1263Wfs*22）。在 12 名仍有息肉的 MUTYH 基因双等位基因突变患者中，在 90 名携带 KRAS p.G12C 取代的结直肠癌（CRC）患者中有 6 名（6.7%），但在 231 名 KRAS p.G12C 等位基因阴性的早发性 CRC 病例中没有。除了已知的欧洲创始等位基因 p.Y179C 和 p.G396D 外，本研究还揭示了 MUTYH p.R245H 种系突变的反复特征。此外，还发现了 3 种新的致病性 MUTYH 等位基因（p.L111P、p.R245S 和 p.Q293X）。对 7 个 APC/MUTYH 突变阴性 DNA 样本的靶向下一代测序，在 1 名患者中发现了新的潜在致病性 POLD1 变体（p.L460R），在 3 名患者中发现了已知的低外显率与癌症相关的 CHEK2 p.I157T 等位基因。对 1120 名健康受试者的分析显示，15 名 MUTYH 突变的杂合携带者，因此俄罗斯 MUTYH 相关息肉的预期发病率可能为 1:23000。
