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RESEARCH PRODUCT
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
Reinhard BüttnerPäivi PeltomäkiMonique E. Van LeerdamAlexandra M. J. LangersMarkus LoefflerWouter T. De Vos Tot Nederveen CappelRobert HüneburgChristoph EngelDeepak VangalaStefan AretzStefan AretzChristian P. StrassburgLaura Renkonen-sinisaloLaura Renkonen-sinisaloAlbrecht StenzingerVolker EndrisPaul C. Van De MeebergMaarten A J M JacobsToni T. SeppäläToni T. SeppäläToni T. SeppäläHendrik BläkerAnna LepistöAnna LepistöAysel AhadovaAysel AhadovaElke Holinski-federNils RahnerJukka-pekka MecklinMonika MorakMariëtte C.a. Van KouwenMatthias KloorMatthias KloorVerena Steinke-langeMagnus Von Knebel DoeberitzMagnus Von Knebel DoeberitzMarie Louise VerhulstKarolin BuckschGabriela MösleinJürgen WeitzHans F. A. VasenStefanie HolzapfelStefanie HolzapfelJan J. KoornstraSilke ZachariaeMarloes Bigirwamungu-bargemanKarsten SchulmannKirsi PylvänäinenJuda Vechtsubject
0301 basic medicineOncologyMaleColorectal cancerDNA Mutational Analysisgenetic analysisHEREDITARYcancer riskGUIDELINESDNA Mismatch Repair0302 clinical medicineGermanyTumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]Prospective Studiesprognostic factorFinlandbeta CateninNetherlandsOutcomePrognostic FactorGastroenterologyGenetic AnalysisColonoscopyMiddle AgedCANCERLynch syndromeCancer Risk3. Good healthDNA-Binding ProteinsDEFICIENCYMutS Homolog 2 Proteinsyöpägeenitoutcome030211 gastroenterology & hepatologyDNA mismatch repairFemaleMutL Protein Homolog 1geenitutkimusAdenomaAdultmedicine.medical_specialtycongenital hereditary and neonatal diseases and abnormalitiesAdenoma3122 CancersAdenomatous Polyposis Coli ProteinINSTABILITYSOCIETYMLH103 medical and health sciencesInternal medicinemedicineMANAGEMENTHumansLynchin oireyhtymäneoplasmspaksusuolisyöpäHepatologybusiness.industryCancernutritional and metabolic diseasesennusteetmedicine.diseaseColorectal Neoplasms Hereditary Nonpolyposisdigestive system diseasesMSH6030104 developmental biologyMSH2Mutationbusinessdescription
Contains fulltext : 220040.pdf (Publisher’s version ) (Closed access) 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. 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. 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. 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-04-01 |