The spectrum of Lynch syndrome-associated germ-line mutations in Russia

• Published in: European journal of medical genetics Vol. 63; no. 3; p. 103753
• Main Authors: Yanus, Grigoriy A., Akhapkina, Tatiana A., Iyevleva, Aglaya G., Kornilov, Alexandr V., Suspitsin, Evgeny N., Kuligina, Ekaterina Sh, Ivantsov, Alexandr O., Aleksakhina, Svetlana N., Sokolova, Tatiana N., Sokolenko, Anna P., Togo, Alexandr V., Imyanitov, Evgeny N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.03.2020
• Subjects: Colorectal cancer; DNA mismatch repair; Founder effect; Hereditary cancer syndromes; Lynch syndrome; Hereditary cancer syndromes; Founder effect; DNA mismatch repair; Colorectal cancer; Lynch syndrome
• ISSN: 1769-7212; 1878-0849; 1878-0849
• DOI: 10.1016/j.ejmg.2019.103753

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.