Identification of Lynch syndrome risk variants in the Romanian population

• DOI: 10.1111/jcmm.13881
• Publication Date: 2018-10-16T07:58:40Z
• Authors: Paul D. Iordache; Dana Mates; Bjarni Gunnarsson; Hannes P. Eggertsson; Patrick Sulem; Stefania Benonisd...; Irma Eva Csiki; Stefan Rascu; Daniel Radavoi; Radu Ursu; Catalin Staicu; Violeta Calota; Angelica Voinoiu; Mariana Jinga; Gabriel Rosoga; Razvan Danau; Sorin Cristian Sima; Daniel Badescu; Nicoleta Suciu; Viorica Radoi; Ioan Nicolae Mates; Mihai Dobra; Camelia Nicolae; Sigrun Kristjansd...; Jon G. Jonasson; Andrei Manolescu; Gudny Arnadottir; Brynjar Jensson; Aslaug Jonasdottir; Asgeir Sigurdsson; Louise le Roux; Hrefna Johannsdottir; Thorunn Rafnar; Bjarni V. Halldor...; Viorel Jinga; Kari Stefansson
• Keywords: Adult; Male; 0301 basic medicine; Romania; Original Articles; DNA Methylation; Middle Aged; 16. Peace & justice; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Glycosylases; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; MutS Homolog 2 Protein; Adenomatous Polyposis Coli; Risk Factors; Mutation; Humans; Female; Genetic Predisposition to Disease; MutL Protein Homolog 1; Aged; Mismatch Repair Endonuclease PMS2

AbstractTwo familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high‐risk CRC mutations in the Romanian population. We performed whole‐genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559‐1G>C).