Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

Porkka N, Valo S, Nieminen TT, Olkinuora A, Mäki-Nevala S, Eldfors S and Peltomäki P

Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively. Genes harboring mutations with allele frequency 25 % or higher in at least 31 % of tumors were regarded to be possible drivers. Among 72 and 10 such genes identified in colorectal and ovarian tumors, respectively, the most frequently mutated genes BRD4 and MLL2 (62 % of colorectal tumors) and ARID1A (50 % of ovarian carcinomas) are involved in epigenetic regulation. The total number of somatic mutations or mutant genes per tumor were significantly associated with CIMP. Our results suggest that even in an inherited disease, tumor type-specific epigenetic changes are significant and may result from regulatory changes (CIMP) or structural events (mutations of epigenetic regulatory genes). The findings are clinically relevant since many of the affected pathways can be therapeutically targeted.

Oncotarget, 2017

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=22445&path%5B%5D=70979

eLS: Mismatch Repair Genes

Kansikas M, Nyström M & Peltomäki P.

The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post-replicative MMR is strand-specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non-canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti-mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers.

 

Link to updated article. eLS, 2017.

 

InSiGHT 2017, Florence, Italy

The 7th biennial International Society for Gastrointestinal Hereditary tumors Incorporated (InSIGHT) meeting was organized in Florence, Italy on 5-8th of July.

Both Prof. Minna Nyström’s and Prof. Päivi Peltomäki’s groups were represented in the meeting.

PhD, Marjaana Pussila (Prof. Nyström’s group)

M.Sc, Mariann Kasela (Prof. Nyström’s group)

M.Sc, Anni Niskakoski (Prof. Peltomäki’s group)

PhD, Satu Mäki-Nevala (Prof. Peltomäki’s group) (study based on PhD Satu Valo’s work)

M.Sc, Noora Porkka (Prof. Peltomäki’s group)

 

Cancer-preceding Gene Expression Changes in Mouse Colon Mucosa

Public PhD defence on 16th of June 2017, at 12 noon

Biocenter 2, Lecture hall 2041

Author: M.Sc. Marjaana Pussila
University of Helsinki, Faculty of Biological and Environmental Sciences, Department of Biosciences, perinnöllisyystiede

Opponent: Professor Theodore Fotsis, MD, PhD
Foundation for Research & Technology-Hellas (FORTH)
Institute of Molecular Biology and Biotechnology (IMBB)
Department of Biomedical Research (Ioannina)

Prof. Theodore Fotsis, M.Sc Marjaana Pussila and Prof. Minna Nyström

Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon

Dermadi D, Valo S, Ollila S, Soliymani R, Sipari N, Pussila M, Sarantaus L, Linden J, Baumann M and Nyström M

Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risk of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation.

Cancer Res; 77(12); 3352–63. ©2017 AACR.

PMID: 28416481

Annual National HNPCC Meeting

The Annual Meeting of the Finnish collaborative HNPCC reseach groups was organized in Jyväskylä on 9-10th of March.

Prof. Päivi Pelomäki gave an overview of the on-going research projects including 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. Satu Valo, PhD, and Noora Porkka, M.Sc, presented projects related to epigenetic and genetic characterization of Lynch syndrome related cancer. Minttu Kansikas, PhD, and Mariann Kasela, M.Sc, from Prof. Minna Nyström’s research group 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 PMS2 gene function on MMR repair efficiency.

Prof. Päivi Peltomäki

 

 

 

 

 

 

 

 

 

PhD, Satu Valo

 

 

 

 

 

 

 

 

 

M.Sc, Noora Porkka

Review in Duodecim: Disorders of DNA repair mechanisms and their clinical significance

Kansikas M, Nyström M & Peltomäki P.

DNA repair mechanisms maintain genome stability by preventing the multiplication of genetic errors, caused by environmental factors and intracellular processes during cell division. Unrepaired damage may permanently alter the genome and cell functions, and even minor changes in DNA strand may initiate malignant transformation of the cell. Up to 25 000 changes in DNA occur daily in a single actively dividing cell, and these changes are continuously repaired. If DNA repair mechanisms are impaired, errors will accumulate into the genome. As numerous factors of different nature can cause genetic errors, several different DNA repair mechanisms are necessary to ensure genomic stability.

DNA:n korjausmekanismit pitävät yllä perimän vakautta estämällä ympäristön ja solujen sisäisten prosessien aiheuttamien vaurioiden monistumisen solunjakautumisten yhteydessä. Korjaamatta jääneet vauriot voivat muuttaa perimän ja solun toimintaa pysyvästi. Jo pienikin DNA:n emäsjuosteessa tapahtuva muutos voi aloittaa solun muuttumisen syöpäsoluksi. Yhdessä aktiivisesti jakautuvassa solussa on arvioitu päivittäin tapahtuvan jopa 25 000 DNA:n muutosta, joita koko ajan korjataan. Mikäli DNA:n korjausmekanismien toiminta häiriintyy, alkaa perimään nopeasti kasautua virheitä. Koska virheitä aiheuttavat monet eri tekijät, jotka ovat luonteeltaan erilaisia, tarvitaan myös useita DNA:n korjausmekanismeja. Näiden mekanismien selvittäminen on ollut tärkeää, ja siinä uraauurtavaa työtä tehneet tutkijat palkittiin vuoden 2015 Nobelin kemianpalkinnolla.

Duodecim, 2017.

http://www.duodecimlehti.fi/lehti/2017/3/duo13542 (in Finnish)

Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity.

Niku M, Pajari AM, Sarantaus L, Päivärinta E, Storvik M, Heiman-Lindh A, Suokas S, Nyström M, Mutanen M.

Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of ApcMin/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε+ T lymphocytes and of mucosal FoxP3+ regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene.

J Nutr Biochem. 2016