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Identification of Lynch syndrome risk variants in the Romanian population

Identification of Lynch syndrome risk variants in the Romanian population

Title: Identification of Lynch syndrome risk variants in the Romanian population
Author: Iordache, Paul   orcid.org/0000-0003-2248-8927
Mates, Dana
Gunnarsson, Bjarni
Eggertsson, Hannes   orcid.org/0000-0002-1674-9978
sulem, patrick   orcid.org/0000-0001-7123-6123
Benonisdottir, Stefania   orcid.org/0000-0001-5019-514X
Csiki, Irma Eva
Rascu, Stefan
Radavoi, Daniel
Ursu, Radu
... 26 more authors Show all authors
Date: 2018-10-16
Language: English
Scope: 6068-6076
University/Institute: Háskólinn í Reykjavík
Reykjavik University
Háskóli Íslands
University of Iceland
School: Tækni- og verkfræðideild (HR)
School of Science and Engineering (RU)
Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Journal of Cellular and Molecular Medicine;22(12)
ISSN: 1582-1838
1582-4934 (eISSN)
DOI: 10.1111/jcmm.13881
Subject: Colorectal cancer; Lynch syndrome; Romania; Endaþarmskrabbamein; Lynch heilkenni; Rúmenía
URI: https://hdl.handle.net/20.500.11815/1301

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Iordache, PD, Mates, D, Gunnarsson, B, et al. Identification of Lynch syndrome risk variants in the Romanian population. J Cell Mol Med. 2018; 22: 6068– 6076. https://doi.org/10.1111/jcmm.13881


Two 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).


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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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