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- Stepien, M., et al.
(författare)
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Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study
- 2021
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:3, s. 609-625
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed forN1-acetylspermidine, isatin,p-hydroxyphenyllactic acid, tyrosine, sphingosine,l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, gamma-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
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| 2. |
- Duell, E. J., et al.
(författare)
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Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:4, s. 880-893
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Tidskriftsartikel (refereegranskat)abstract
- ABO blood serotype A is known to be associated with risk of gastric cancer (GC), but little is known how ABO alleles and the fucosyltransferase (FUT) enzymes and genes which are involved in Lewis antigen formation [and in Helicobacter pylori (H. pylori) binding and pathogenicity] may be related to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group A (AO+AA, odds ratio=1.84, 95%CI=1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes) in FUT2 (Se), FUT3 (Le) and FUT6 with intestinal-type GC. Further, one variant in ABO, two in FUT3 and two in FUT6 were associated with H. pylori infection status in controls, and two of these (in FUT3 and FUT6) were weakly associated with intestinal-type GC risk. None of the individual variants surpassed a Bonferroni corrected p-value cutoff of 0.0016; however, after a gene-based permutation test, two loci [FUT3(Le)/FUT5/FUT6 and FUT2(Se)] were significantly associated with diffuse- and intestinal-type GC, respectively. Replication and functional studies are therefore recommended to clarify the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis. What's New? Blood type A indicates a higher risk of gastric cancer, but why? This study examined the relationship between blood group genes and cancer. The authors investigated 32 variants among not only the ABO alleles, but also including the genes involved in producing the Lewis blood group antigens. They confirmed blood group A as a risk factor for diffuse-type gastric cancer, and also detected an association between certain Lewis antigen alleles and intestinal-type gastric cancer. Interestingly, these alleles also popped up among controls who harbored H. pylori infection. These associations certainly warrant further investigation into their role in gastric cancer.
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| 3. |
- Durães, C., et al.
(författare)
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Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations
- 2014
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Ingår i: International Journal of Cancer. - : Wiley-Liss Inc.. - 0020-7136 .- 1097-0215. ; 135:6, s. 1343-1355
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Tidskriftsartikel (refereegranskat)abstract
- The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. Eighty-seven SNPs were genotyped in a Portuguese case-control study (358 cases, 1,485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC-EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p=0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p=3.1 × 10-5) and non cardia localisation (p=4.6 × 10-3). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations. What's new? Genetic susceptibility to gastric cancer lurks in the region of the interleukin 1 gene cluster, but no one yet knows just how genetic variation contributes to risk. These authors searched for other variants within this genetic neighborhood by assessing linkage disequilibrium. There they found several small nucleotide polymorphisms (SNPs), mainly in the IL1A gene region, that associated with gastric carcinoma, particularly the intestinal subtype. By identifying these SNPs, they hope to shed more light on how the disease develops or help identify people who are at risk. © 2014 UICC.
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