Fatty acids in habitual diet, plasma phospholipids, and tumour and normal colonic biopsies in young colorectal cancer patients

Fatty acid metabolism is altered in colorectal cancer (CRC). We aimed to investigate incorporation of dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) into plasma phospholipids (PLs), tumour tissue, and normal mucosa in young CRC patients. We also aimed to study differences in PUFA composition between tumour and normal mucosa, and PUFA status associated with cancer stage. Sixty-five CRC patients younger than 55 years were included in a multicenter study. We assessed dietary fatty acid composition by food-frequency questionnaire. Fatty acid composition in plasma PL (n = 65) and tumour and normal colonic biopsies (n = 32) were analysed by gas chromatography. We observed a significant correlation for docosahexaenoic acid (DHA) between dietary intake and concentration in plasma PL (weight%) (r = 0.42; P = 0.001), but not for any n-6 PUFA. Tissue concentrations of arachidonic acid, eicosapentaenoic acid, and DHA (weight%) were 1.7–2.5 times higher in tumour than normal mucosa (P ≤ 0.001). Concentrations of n-3 and n-6 PUFA in plasma PL and tissues were not related to Duke’s stage, although patients with more severe cancer stage reported higher intake of n-3 PUFA. In conclusion, we found accumulation of the longchained n-3 and n-6 PUFA in tumour tissue in young CRC patient

Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci

<p>Abstract</p> <p>Background</p> <p>Estimates suggest that up to 30% of colorectal cancers (CRC) may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV) (Roche NimbleGen, 385 000 oligo CGH array) in microsatellite stable (MSS) tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53) and 17 elderly patients with median age 79 years (range: 69-87). Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list.</p> <p>Results</p> <p>The total fraction of the genome with aberrant copy number, the overall genomic profile and the <it>TP53 </it>mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, <it>CLC, EIF4E</it>, <it>LTBP4, PLA2G12A, PPAT</it>, <it>RG9MTD2</it>, and <it>ZNF574</it>, had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups.</p> <p>Conclusions</p> <p>Ten genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late onset CRC. Integration of genome and transcriptome data identifies seven novel candidate genes with the potential to identify an increased risk for CRC.</p

Mutational Characterization of the Bile Acid Receptor TGR5 in Primary Sclerosing Cholangitis

TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases

DNA Sequence Profiles of the Colorectal Cancer Critical Gene Set KRAS-BRAF-PIK3CA-PTEN-TP53 Related to Age at Disease Onset

The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients

Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis

Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC). Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992-2006] and n = 138 [2008-2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100). Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p <0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p <0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF (R)) test and Mayo risk score proved to be stronger predictors of transplant-free survival. Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC. Lay summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway

Background Incidence and prevalence of ulcerative colitis follow a north–south (latitudinal) gradient and increases northwards at the northern hemisphere or southwards at the southern hemisphere. The disease has increased during the last decades. The temporal trend has been explained by the hygiene hypothesis, but few parallel explanations exist for the spatial variability. Many factors are linked to latitude such as climate. Our purpose was to investigate the association between variables governing the climate and prospectively identified patients. Methods In this study, we used a subset of the population-based Cohort of Norway (n = 80412) where 370 prevalent cases of ulcerative colitis were identified through self-reported medication. The meteorological and climatic variables temperature, precipitation, and altitude were recorded from weather stations of the Norwegian Meteorological Institute. Summer temperature was used to capture environmental temperature. Results Summer temperature was significantly related to the prevalence of ulcerative colitis. For each one-degree increase in temperature the odds for ulcerative colitis decreased with about 9% (95% CI: 3%-15%). None of the other climatic factors were significantly associated to the risk of ulcerative colitis. Contextual variables did not change the association to the prevalence of ulcerative colitis. Conclusions The present results show that the prevalence of ulcerative colitis is associated to summer temperature. Our speculation is that summer temperature works as an instrumental variable for the effect of microbial species richness on the development of ulcerative colitis. Environmental temperature is one of the main forces governing microbial species richness and the microbial composition of the commensal gut flora is known to be an important part in the process leading to ulcerative colitis

Inflammatory bowel disease

Scandinavian researchers have contributed to the present understanding of inflammatory bowel disease (IBD). Important epidemiological data and family risk factors have been reported from all the Nordic countries, original twin studies mainly from Denmark and Sweden, and relationships to cancer and surgery mostly from Sweden. In collaboration with the industry, development of medical compounds was for a long time in the front line of international research, and the Scandinavian countries participated in the clinical breakthrough of biologic treatment. At present, many Nordic centers are working in the forefront of IBD research. An increasing number of young investigators have entered the scene along with the extended distribution of University clinics and research laboratories in these countries. This presentation of IBD gives a brief overview in the fields of clinical epidemiology and molecular biology. Many areas are covered by International collaborations with partners from Nordic centers. IBD was a topic focused by the founders of Scandinavian Journal of Gastroenterology. After 50 years one may state that the journal’s history reflects important pieces of scientific knowledge within these diseases. The early scope of Johannes Myren for IBD was shown through his work in the original World Association of Gastroenterology (OMG), and after 50 years we can clearly support the view that global perspectives in IBD are increasingly important