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

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)

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

Itkonen HM, Kantelinen J, Vaara M, Parkkinen S, Schlott B, Grosse F, Nyström M, Syväoja JE, Pospiech H.

The high fidelity of genome duplication is ensured by cooperation of the proofreading and mismatch repair (MMR) activities of DNA polymerases. Here, we show that human mismatch recognizing proteins MutS homologue 2 (MSH2) and MSH6 co-purify and interact with replicative Pol α, the replicative primase which replicates DNA with poor fidelity. We show that MSH2 associates with known human replication origins with different dynamics than Pol α. Furthermore, we explored the potential functional role of Pol α in the mismatch repair reaction by using an in vitro mismatch repair assay and observed that Pol α promotes mismatch repair. Taken together, we show that human Pol α interacts with MSH2-MSH6 complex and propose that this interaction occurs during the mismatch repair reaction.

FEBS Letters, 2016

Tricarico R, Kasela M, Mareni C, Thompson BA, Drouet A, Staderini L, Gorelli G, Crucianelli F, Ingrosso V, Kantelinen J, Papi L, De Angioletti M, Berardi M, Gaildrat P, Soukarieh O, Turchetti D, Martins A, Spurdle AB, Nyström M, Genuardi; InSiGHT Variant Interpretation Committee.

Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as “likely pathogenic” or “likely nonpathogenic.” This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting.

Hum Mutat. 2016