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dc.contributor.authorMäki-Nevala, Satu
dc.contributor.authorValo, Satu
dc.contributor.authorRistimäki, Ari
dc.contributor.authorSarhadi, Virinder
dc.contributor.authorKnuutila, Sakari
dc.contributor.authorNyström, Minna
dc.contributor.authorRenkonen-Sinisalo, Laura
dc.contributor.authorLepistö, Anna
dc.contributor.authorMecklin, Jukka-Pekka
dc.contributor.authorPeltomäki, Päivi
dc.date.accessioned2019-02-12T12:22:01Z
dc.date.available2019-02-12T12:22:01Z
dc.date.issued2019
dc.identifier.citationMäki-Nevala, S., Valo, S., Ristimäki, 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. <i>EBioMedicine</i>, <i>39</i>, 280-291. <a href="https://doi.org/10.1016/j.ebiom.2018.12.018" target="_blank">https://doi.org/10.1016/j.ebiom.2018.12.018</a>
dc.identifier.otherCONVID_28803842
dc.identifier.otherTUTKAID_79997
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/62761
dc.description.abstractBackground 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 (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 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 HiLIFE.fi
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherElsevier BV
dc.relation.ispartofseriesEBioMedicine
dc.rightsCC BY-NC-ND 4.0
dc.subject.othercolorectal adenoma
dc.subject.otherDNA mismatch repair
dc.subject.otherLINE-1 methylation
dc.subject.othermutation
dc.subject.othertumorigenesis
dc.subject.othertumor suppressor
dc.titleDNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201901281341
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2019-01-28T13:15:20Z
dc.description.reviewstatuspeerReviewed
dc.format.pagerange280-291
dc.relation.issn2352-3964
dc.relation.numberinseries0
dc.relation.volume39
dc.type.versionpublishedVersion
dc.rights.copyright© 2019 Published by Elsevier B.V.
dc.rights.accesslevelopenAccessfi
dc.subject.ysosyöpätaudit
dc.subject.ysoDNA
dc.subject.ysoLynchin oireyhtymä
dc.subject.ysosuolistosyövät
dc.subject.ysoDNA-metylaatio
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p678
jyx.subject.urihttp://www.yso.fi/onto/yso/p7690
jyx.subject.urihttp://www.yso.fi/onto/yso/p23697
jyx.subject.urihttp://www.yso.fi/onto/yso/p25845
jyx.subject.urihttp://www.yso.fi/onto/yso/p38350
dc.rights.urlhttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.relation.doi10.1016/j.ebiom.2018.12.018


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