Metabolomics and transcriptomics identify pathway differences between visceral and subcutaneous adipose tissue in colorectal cancer patients: the ColoCare study

Liesenfeld, David B.; Grapov, Dmitry; Fahrmann, Johannes F.; Salou, Mariam; Scherer, Dominique; Tóth, Réka; Habermann, Nina; Böhm, Jürgen; Schrotz‐King, Petra; Gigic, Biljana; Schneider, Martin; Ulrich, Alexis; Herpel, Esther; Schirmacher, Peter; Fiehn, Oliver; Lampe, Johanna W.; Ulrich, Cornelia M.

doi:10.3945/ajcn.114.103804

Cited by 116 publications

(124 citation statements)

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“…Further, variants near FAR1 (fatty acyl-CoA reductase 1) have been previously associated with bone mineral density in Hispanic children [25], and BCL9 has recently been identified with type 2 diabetes in aboriginal Australians [60]. FAR1 has also been shown to be expressed differently between visceral and subcutaneous adipose tissue in colorectal cancer patients [61]. Of these GPGE association results, BARX1 , ZNF169 and FAR1 were all significant in brain regions, which is consistent with a popular hypothesis that the central nervous system regulation of energy balance plays a major role in the development of obesity [62–65].…”

Section: Discussionmentioning

confidence: 99%

Association of gene coding variation and resting metabolic rate in a multi-ethnic sample of children and adults

et al. 2017

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BackgroundResting metabolic rates (RMR) vary across individuals. Understanding the determinants of RMR could provide biological insight into obesity and its metabolic consequences such as type 2 diabetes and cardiovascular diseases.MethodsThe present study measured RMR using reference standard indirect calorimetry and evaluated genetic variations from an exome array in a sample of children and adults (N = 262) predominantly of African and European ancestry with a wide range of ages (10 – 67 years old) and body mass indices (BMI; 16.9 – 56.3 kg/m2 for adults, 15.1 – 40.6 kg/m2 for children).ResultsSingle variant analysis for RMR identified suggestive loci on chromosomes 15 (rs74010762, TRPM1, p-value = 2.7 × 10−6), 1 (rs2358728 and rs2358729, SH3D21, p-values < 5.8x10−5), 17 (AX-82990792, DHX33, 5.5 × 10−5) and 5 (rs115795863 and rs35433829, C5orf33 and RANBP3L, p-values < 8.2 × 10−5). To evaluate the effect of low frequency variations with RMR, we performed gene-based association tests. Our most significant locus was SH3D21 (p-value 2.01 × 10−4), which also contained suggestive results from single-variant analyses. A further investigation of all variants within the reported genes for all obesity-related loci from the GWAS catalog found nominal evidence for association of body mass index (BMI- kg/m2)-associated loci with RMR, with the most significant p-value at rs35433754 (TNKS, p-value = 0.0017).ConclusionsThese nominal associations were robust to adjustment for BMI. The most significant variants were also evaluated using phenome-wide association to evaluate pleiotropy, and genetically predicted gene expression using the summary statistics implicated loci related to in obesity and body composition. These results merit further examination in larger cohorts of children and adults.Electronic supplementary materialThe online version of this article (doi:10.1186/s40608-017-0145-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Association of gene coding variation and resting metabolic rate in a multi-ethnic sample of children and adults

et al. 2017

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“…Several lines of evidence indicate that LM plays a crucial role in carcinogenesis [11, 12, 17]. Accordingly, expression levels of several related genes have been found to display prognostic and predictive value in CC patients [11, 12, 18].…”

Section: Discussionmentioning

confidence: 99%

3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

et al. 2016

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Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3’-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69–5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a “risk genotype” of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC.

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“…While BAT and beige adipose tissue have been associated with thermoregulation, WAT is considered the key site for energy storage in the form of triacylglycerides (7). WAT can be further divided into distinct body compartments, which have differential impact on disease risk (8). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are characterized by differences in cellular structure, molecular composition, and secretome, each of which may be altered by the degree of adiposity itself (8).…”

Section: Introductionmentioning

confidence: 99%

Signals from the Adipose Microenvironment and the Obesity–Cancer Link—A Systematic Review

Himbert

Delphan

Scherer

et al. 2017

Cancer Prevention Research

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Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiological, clinical, and preclinical data suggest that within the growth-promoting, pro-inflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity-associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct “crosstalk” between adipose tissue and carcinomas in humans. We identified 4,641 articles with n=20 human clinical studies which are summarized as: (a) breast (n=7), (b) colorectal (n=4), (c) esophageal (n=2), (d) esophageal/colorectal (n=1), (e) endometrial (n=1), (f) prostate (n=4), and (g) ear-nose-throat (ENT) cancer (n=1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL-6, TNF-alpha and other mechanisms. Moreover, visceral white adipose tissue (VAT) plays a more central role as it is more bio-energetically active and is associated with a more pro-cancer secretome than subcutaneous adipose tissue (SAT). Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers.

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Metabolomics and transcriptomics identify pathway differences between visceral and subcutaneous adipose tissue in colorectal cancer patients: the ColoCare study

Cited by 116 publications

References 40 publications

Association of gene coding variation and resting metabolic rate in a multi-ethnic sample of children and adults

Association of gene coding variation and resting metabolic rate in a multi-ethnic sample of children and adults

3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

Signals from the Adipose Microenvironment and the Obesity–Cancer Link—A Systematic Review

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