6533b7d5fe1ef96bd1263d8e

RESEARCH PRODUCT

DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression

Satu Mäki-nevalaMinna NyströmVirinder Kaur SarhadiSakari KnuutilaAnna LepistöJukka-pekka MecklinAri RistimäkiLaura Renkonen-sinisaloPäivi PeltomäkiSatu Valo

subject

0301 basic medicineMaleResearch paperMICROSATELLITE INSTABILITYHYPOMETHYLATIONDNA mismatch repairPHENOTYPEmedicine.disease_causeEpigenesis Genetic0302 clinical medicineCOLORECTAL ADENOMASCDKN2APromoter Regions Geneticcolorectal adenomaDNA methylationLINE-1 methylationTumor suppressorGeneral MedicineMethylationMiddle AgedCANCERTUMORSLynch syndromeDNA-metylaatio3. Good healthDEFICIENCY030220 oncology & carcinogenesisDNA methylationsyöpätauditFemaleColorectal adenomaAdultcongenital hereditary and neonatal diseases and abnormalitiesAdenomatumor suppressorsuolistosyövätColorectal adenomaBiologycomplex mixturesGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesBRAF MUTATIONmedicineHumansLynchin oireyhtymäAgedTumor Suppressor ProteinsMicrosatellite instabilityDNAUNE-1 methylationta3122medicine.diseaseGENEColorectal Neoplasms Hereditary Nonpolyposisdigestive system diseasestumorigenesisCOPY NUMBER030104 developmental biologyLynch syndromeLong Interspersed Nucleotide Elements3121 General medicine internal medicine and other clinical medicineMutationTumorigenesisCancer research3111 BiomedicineTumotigenesismutationCarcinogenesis

description

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. Peer reviewed

yearjournalcountryeditionlanguage
2018-12-01EBioMedicine
10.1016/j.ebiom.2018.12.018http://europepmc.org/articles/PMC6355728