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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)

Pathogenic pseudoexons in APC mutation-negative FAP

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Nieminen TT, Pavicic W, Porkka N, Kankainen M, Järvinen HJ, Lepistö A, Peltomäki P.

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.

Oncotarget, 2016

Western diet and genetic predisposition as risk factors of colon cancer

Public PhD defence on 1st of July 2016, at 12 noon.

Biomedicum Helsinki, Lecture hall 2

Author: M.Sc. Satu Valo
Division of Genetics, Department of Biosciences, University of Helsinki
Department of Medical and Clinical Genetics, University of Helsinki

Opponent: Prof. Karl Heinimann, MD, PhD
Department of Medical Genetics, University Hospital of Basel, Switzerland

Prof. Päivi Peltomäki, Prof. Minna Nyström, M.Sc Satu Valo and Prof. Karl Heinimann

Prof. Päivi Peltomäki, Prof. Minna Nyström, M.Sc Satu Valo and Prof. Karl Heinimann

PhD defence

PhD defence

Annual National HNPCC Meeting

The Annual Meeting of the Finnish collaborative HNPCC reseach groups took place at Hämeenkylän Kartano in Vantaa on 4th of March.

In her presentation, Prof. Minna Nyström introduced DiagMMR™ a new tool for Lynch syndrome carrier diagnosis (http://www.lscancerdiag.com/). Other members of Prof. Päivi Peltomäki’s and Prof. Minna Nyström’s research groups gave presentations regarding some of the recent projects related to the Western diet effects on colon cancer predisposition (MSc. Marjaana Pussila, MSc. Satu Valo and BSc. Pauliina Paloviita) and promoter specific alterations of APC in FAP (PhD Taina Nieminen).

MSc. Satu Valo

HNPCC Taina3

PhD. Taina Nieminen

 

 

Characteristics of colorectal tumors with inactive Wnt signaling

The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription

Abdel-Rahman WM, Lotsari-Salomaa JE, Kaur S, Niskakoski A, Knuutila S, Järvinen H, Mecklin JP and Peltomäki P.

All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.

Gastroenterol Res Pract. 2016

Update on Lynch syndrome genomics

Peltomäki P.

Four main DNA mismatch repair (MMR) genes have been identified, MLH1, MSH2, MSH6, and PMS2, which when mutated cause susceptibility to Lynch syndrome (LS). LS is one of the most prevalent hereditary cancer syndromes in man and accounts for 1-3 % of unselected colorectal carcinomas and some 15 % of those with microsatellite instability and/or absent MMR protein. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) maintains a database for LS-associated mutations since 1996. The database was recently reorganized to efficiently gather published and unpublished data and to classify the variants according to a five-tiered scheme linked to clinical recommendations. This review provides an update of germline mutations causing susceptibility to LS based on information available in the InSiGHT database and the latest literature. MMR gene mutation profiles, correlations between genotype and phenotype, and possible mechanisms leading to the characteristic spectrum of tumors in LS are discussed in light of the different functions of MMR proteins, many of which directly serve cancer avoidance.

Review in Fam cancer, 2016.

Fig. Distributions of the types of germline variants across each MMR gene (Peltomäki  P, Fam Cancer 2016).

Fig. Distributions of the types of germline variants across each MMR gene (Peltomäki P, Fam Cancer 2016).

Jane and Aatos Erkko Foundation Awards 1.25 million for Hereditary Cancer Research

Prof. Päivi Peltomäki (PI) together with Prof. Minna Nyström (Co-PI) and Prof. Jukka-Pekka Mecklin (Co-PI) were nominated by Jane and Aatos Erkko Foundation to receive a grant of 1.25 million euro for their joint interdisciplinary research to recognize molecular mechanisms of hereditary cancer susceptibility in association with lifestyle and diet in aim to improve diagnosis and cancer prevention.

Announcement in Finnish:

Perinnöllinen syöpä (Lynchin oireyhtymä) syövänkehityksen ja -ehkäisyn mallina

Jane ja Aatos Erkon Säätiö on myöntänyt merkittävän (1.25 miljoonan euron) apurahan professorien Päivi Peltomäen, Minna Nyströmin ja Jukka-Pekka Mecklinin johtamalle poikkitieteelliselle hankkeelle.

Syövän synty nähdään pääsääntöisesti joko elintavoista tai synnynnäisestä alttiudesta johtuvaksi. Elintapatekijöiden vaikutusta on edelleenkin vaikea tutkimuksellisesti konkretisoida. Tuoreet tutkimuslöydöksemme kuitenkin paljastivat, että elintapatekijät kuten ravinto ja liikunta näyttävät vaikuttavan myös perinnöllisen syövän syntyyn. Tässä tutkimuksessa pyritään yhdistämään eri lähestymistapoja ja käyttämään pitkään tunnettua periytyvää suolisyöpäalttiutta syövän syntymekanismien ja ehkäisyn mallina ja vertaamaan havaintoja niihin suolisyöpiin, joiden ajatellaan syntyvän ei-periytyvästi.

Tutkimusprojekti selvittää, miksi alttius sairastua paksusuolisyöpään vaihtelee yksilöllisesti, mitkä ovat kasvaimen molekyyli- ja kudostason syntymekanismit ja miten kehittyminen syöväksi voidaan estää. Tieteellisten tavoitteiden ohella tutkimuksella on tärkeä kansanterveydellinen päämäärä: tehostaa paksusuolisyövän ehkäisyä alttiuden varhaisen tunnistamisen ja omien elintapavalintojen kautta.

Erkko2016