Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors

Arjen R Mensenkamp; Ingrid P Vogelaar; Wendy A G van Zelst-Stams; Monique Goossens; Hicham Ouchene; Sandra J B Hendriks-Cornelissen; Michael P Kwint; Nicoline Hoogerbrugge; Iris D Nagtegaal; Marjolijn J L Ligtenberg

doi:10.1053/j.gastro.2013.12.002

Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors

Gastroenterology. 2014 Mar;146(3):643-646.e8. doi: 10.1053/j.gastro.2013.12.002. Epub 2013 Dec 10.

Affiliations

¹ Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: arjen.mensenkamp@radboudumc.nl.
² Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
³ Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
⁴ Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.

PMID: 24333619
DOI: 10.1053/j.gastro.2013.12.002

Abstract

Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes. Tumors are characterized by microsatellite instability (MSI). However, a considerable number of MSI-positive tumors have no known molecular mechanism of development. By using Sanger and ion semiconductor sequencing, 25 MSI-positive tumors were screened for somatic mutations and loss of heterozygosity in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutations in these genes. We conclude that 2 acquired events explain the MMR-deficiency in more than 50% of the MMR-deficient tumors without causal germline mutations or promoter methylation.

Keywords: Colorectal Cancer; Genetic; Lynch-Like Syndrome; Mismatch Repair Deficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adolescent
Adult
Aged
Brain Neoplasms / epidemiology
Brain Neoplasms / genetics*
Cohort Studies
Colorectal Neoplasms / epidemiology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
Comorbidity
DNA Methylation / genetics
DNA Mismatch Repair / genetics
Germ-Line Mutation / genetics*
Humans
Microsatellite Instability
Middle Aged
MutL Protein Homolog 1
MutS Homolog 2 Protein / genetics*
Neoplastic Syndromes, Hereditary / epidemiology
Neoplastic Syndromes, Hereditary / genetics*
Nuclear Proteins / genetics*
Promoter Regions, Genetic / genetics
Retrospective Studies
Young Adult

Substances

Adaptor Proteins, Signal Transducing
MLH1 protein, human
Nuclear Proteins
MSH2 protein, human
MutL Protein Homolog 1
MutS Homolog 2 Protein

Supplementary concepts

Turcot syndrome