Mäki-Nevala , S , Valo , S , Ristimaki , A , Sarhadi , V , Knuutila , S , Nyström , M , Renkonen-Sinisalo , L , Lepistö , A , Mecklin , J-P & Peltomäki , P 2019 , ' DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression ' , EBioMedicine , vol. 39 , pp. 280-291 . https://doi.org/10.1016/j.ebiom.2018.12.018
Title: | DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression |
Author: | Mäki-Nevala, Satu; Valo, Satu; Ristimaki, Ari; Sarhadi, Virinder; Knuutila, Sakari; Nyström, Minna; Renkonen-Sinisalo, Laura; Lepistö, Anna; Mecklin, Jukka-Pekka; Peltomäki, Päivi |
Contributor organization: | Department of Medical and Clinical Genetics Medicum University of Helsinki Department of Pathology HUSLAB Genome-Scale Biology (GSB) Research Program Clinicum Research Programs Unit Molecular and Integrative Biosciences Research Programme Doctoral Programme in Integrative Life Science Minna Nyström / Principal Investigator Genetics Biosciences Department of Surgery II kirurgian klinikka HUS Abdominal Center |
Date: | 2019-01 |
Language: | eng |
Number of pages: | 12 |
Belongs to series: | EBioMedicine |
ISSN: | 2352-3964 |
DOI: | https://doi.org/10.1016/j.ebiom.2018.12.018 |
URI: | http://hdl.handle.net/10138/298910 |
Abstract: | Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n 49) and MMR-proficient (MMR-P, n 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (1612, NEUROGI,CRABP1, and CDKN2A) and TSGs (SERPI and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid juselius Foundation, and HiL1FE. (C) 2019 Published by Elsevier B.V. |
Subject: |
Lynch syndrome
Colorectal adenoma DNA methylation DNA mismatch repair UNE-1 methylation Mutation Tumotigenesis Tumor suppressor MICROSATELLITE INSTABILITY COLORECTAL ADENOMAS BRAF MUTATION COPY NUMBER CANCER GENE DEFICIENCY PHENOTYPE TUMORS HYPOMETHYLATION 3111 Biomedicine 3121 General medicine, internal medicine and other clinical medicine |
Peer reviewed: | Yes |
Rights: | cc_by_nc_nd |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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