University of Oulu

Marjaana Pussila, Petri Törönen, Elisabet Einarsdottir, Shintaro Katayama, Kaarel Krjutškov, Liisa Holm, Juha Kere, Päivi Peltomäki, Markus J Mäkinen, Jere Linden, Minna Nyström; Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer, Carcinogenesis, Volume 39, Issue 6, 28 May 2018, Pages 788–797, https://doi.org/10.1093/carcin/bgy056

Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

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Author: Pussila, Marjaana1; Törönen, Petri2; Einarsdottir, Elisabet3,4;
Organizations: 1Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme and
2Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland
3Department of Biosciences and Nutrition, Karolinska Institutet, SE-14183 Huddinge, Sweden
4Folkhälsan Institute of Genetics, Molecular Neurology Research Program, University of Helsinki, FI-00014 Helsinki, Finland
5Competence Centre on Health Technologies, 50410 Tartu, Estonia
6Department of Genetics and Molecular Medicine, King’s College London, London SE1 9RT, UK
7Medicum, Department of Medical and Clinical Genetics, University of Helsinki, FI-00014 Helsinki, Finland
8Cancer and Translational Medicine Research Unit, Department of Pathology, University of Oulu, FI-90014 Oulu, Finland
9Medical Research Center Oulu, Oulu University Hospital, University of Oulu, FI-90014 Oulu, Finland
10Department of Basic Veterinary Sciences, FCLAP, University of Helsinki, FI-00014 Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6.8 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018090634750
Language: English
Published: Oxford University Press, 2018
Publish Date: 2018-09-06
Description:

Abstract

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/−) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.

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Series: Carcinogenesis
ISSN: 0143-3334
ISSN-E: 1460-2180
ISSN-L: 0143-3334
Volume: 39
Issue: 6
Pages: 788 - 797
DOI: 10.1093/carcin/bgy056
OADOI: https://oadoi.org/10.1093/carcin/bgy056
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This study was supported by grants from Jane and Aatos Erkko Foundation (M.N.), and Helsinki Institute of Life Science (P.T.).
Copyright information: © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
  https://creativecommons.org/licenses/by-nc/4.0/