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Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome.
- Source :
-
Gastroenterology [Gastroenterology] 2020 Apr; Vol. 158 (5), pp. 1326-1333. Date of Electronic Publication: 2020 Jan 08. - Publication Year :
- 2020
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Abstract
- Background & Aims: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients.<br />Methods: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1.<br />Results: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC.<br />Conclusions: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.<br /> (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenoma diagnosis
Adenoma genetics
Adenomatous Polyposis Coli Protein genetics
Adult
Colonoscopy
Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis genetics
DNA Mismatch Repair
DNA Mutational Analysis
Female
Finland epidemiology
Germany epidemiology
Humans
Male
Middle Aged
Mutation
Netherlands epidemiology
Prospective Studies
beta Catenin genetics
Adenoma epidemiology
Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology
DNA-Binding Proteins genetics
MutL Protein Homolog 1 genetics
MutS Homolog 2 Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 158
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 31926173
- Full Text :
- https://doi.org/10.1053/j.gastro.2019.12.032