The Annual Meeting of the Finnish collaborative HNPCC reseach groups was organized in Haikko, Porvoo on 9th of June 2018.
Prof. Päivi Pelomäki gave an overview of the on-going research projects including an overview of the current status of the collaborative project initiated together with Prof. Jukka-Pekka Mecklin and Prof. Minna Nyström funded by Jane and Aatos Erkko Foundation in aim to recognize molecular mechanisms of colon cancer susceptibility. Noora Porkka, M.Sc and Satu Mäki-Nevala, PhD, presented projects related to epigenetic and genetic characterization of Lynch and Lynch-like syndrome cancer. Minttu Kansikas, PhD, and Marjaana Pussila, PhD, from Prof. Minna Nyströms lab presented on-going projects related to the development and validation of a non-invasive test to detect Lynch syndrome (http://www.lscancerdiag.com/) and assessment of the effects of MLH1 gene deficiency in normal colon mucosa on colon cancer chromosome stability.
M.Sc, Noora Porkka
PhD, Satu Mäki-Nevala
PhD, Minttu Kansikas
Pussila M, Törönen P, Einarsdottir E, Katayama S, Krjutškov K, Holm L, Kere J, Peltomäki P, Mäkinen MJ, Linden J, Nyström M.
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.
Carcinogenesis. 2018 May 28;39(6):788-797.