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Metabolic biomarkers and the risk of molecular subtypes of colorectal cancer
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0001-8540-6891
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Body fatness measured as high body mass index (BMI) increase the risk for colorectal cancer (CRC). The mechanisms behind the relationship are not fully understood, but might include insulin resistance and changes in adipokine concentrations produced by adipose tissue. Yet, associations between circulating biomarkers related to these mechanisms and CRC risk have been somewhat inconsistent, possibly due to CRC heterogeneity. To better understand the role of insulin resistance and adipokines in CRC development, we therefore investigated circulating biomarkers related to these mechanisms in relation to molecular subtypes of CRC.

Methods: This was a prospective case-control study of 1010 cases and 1:1 matched controls nested within the population-based Northern Sweden Health and Disease Study (NSHDS). Concentrations of insulin, C-peptide, adiponectin, and leptin were quantified in prediagnostic plasma using immunoassays and related to CRC and CRC subtypes defined by mutations in BRAF and KRAS, and microsatellite instability (MSI) status analyzed in tumor tissue. Odds ratios (ORs) and 95% confidence intervals (CIs) for CRC by metabolic biomarker levels were calculated with conditional logistic regression.

Results: Higher C-peptide and lower adiponectin were associated with an increased CRC risk (ORs per 1 standard deviation increase (95% CI): 1.11 (1.01, 1.23) and 0.91 (0.83, 1.00), respectively). The associations were attenuated when adjusting for BMI (ORs (95% CI): 1.07 (0.96, 1.19) and 0.93 (0.84, 1.03), respectively), with the potential exception of the association of C-peptide in women. Circulating insulin and leptin were not associated with CRC risk. We found no clear differences in the association between any biomarkers and CRC risk by molecular subtypes defined by KRAS and BRAF mutation status (Pheterogeneity>0.6), or MSI status (Pheterogeneity>0.3).

Conclusion: Circulating biomarkers of insulin resistance and adipokines were not associated with CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status.

National Category
Cancer and Oncology
Research subject
Cancer Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-151751OAI: oai:DiVA.org:umu-151751DiVA, id: diva2:1247560
Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2018-09-14
In thesis
1. Metabolic Risk Factors and Molecular Subtypes of Colorectal Cancer
Open this publication in new window or tab >>Metabolic Risk Factors and Molecular Subtypes of Colorectal Cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Metabola Riskfaktorer och Molekylära Subtyper av Kolorektalcancer
Abstract [en]

Background: Colorectal cancer (CRC) is a heterogeneous disease developing from distinct pathways, resulting in tumor subtypes with large differences in clinical and molecular characteristics. Molecular characteristics are increasingly being used clinically to guide therapy. However, whether molecular subtypes of CRC differ in etiology or risk factors is not clear. Clarifying such potential differences may lead to an improved understanding of CRC etiology, with implications for CRC prevention and screening.

Aim: The aim of this thesis was to investigate whether risk factors related to energy metabolism, such as body fatness, and one-carbon metabolism, such as circulating B-vitamin status, were associated with specific subtypes of CRC defined by molecular characteristics of the tumor. 

Methods: These prospective studies are based on data and blood samples from cohorts within the population-based Northern Sweden Health and Disease Study (NSHDS). Prospective CRC cases with available archived tumor tissue were analyzed for key molecular features (KRAS and BRAF mutation status, Microsatellite instability (MSI) status, and CpG Island Methylator Phenotype (CIMP) status). Paper I was a cohort study of metabolic factors related to the metabolic syndrome (117 687 participants). Paper II was a nested-case control study on circulating insulin resistance-markers and adipokines (1010 cases and 1010 matched controls). Papers III and IV were nested case-control studies of one-carbon metabolism biomarkers and genetic variants (613 cases and 1190 matched controls).

Results: In paper I, we observed associations between metabolic factors, such as BMI, blood pressure, and blood lipids, and CRC risk consistent with previous studies. These associations were similar regardless of tumor KRAS and BRAF mutation status. In paper II, circulating biomarkers of insulin resistance and adipokines were not associated with the risk of CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status. In paper III, higher circulating levels of metabolites involved in the methionine cycle (namely, betaine and methionine) were associated with a lower CRC risk. In paper IV, we found no support for clear subtype-specific roles of any circulating one-carbon metabolism biomarker or genetic variants in CRC development.

Conclusions: The result of these prospective studies suggests that metabolic factors related to energy metabolism and one-carbon metabolism are generally associated with the risk of CRC, regardless of major subtypes defined by key molecular tumor features. If causal, metabolic risk factors likely influence the risk of colorectal cancer through more than one carcinogenic pathway.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2018. p. 70
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1975
Keywords
Colorectal cancer, risk factors, metabolic syndrome, one-carbon metabolism, molecular subtypes, KRAS, BRAF, MSI, molecular pathological epidemiology
National Category
Cancer and Oncology
Research subject
Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-151753 (URN)978-91-7601-939-9 (ISBN)
Public defence
2018-10-12, Sal 260, Norrlands Universitetssjukhus, Målpunkt A21, Byggnad 3A, vån 2., Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-21 Created: 2018-09-12 Last updated: 2019-05-15Bibliographically approved

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Myte, RobinHarlid, SophiaSundkvist, AnneliGylling, BjörnHäggström, JennyZingmark, CarlLöfgren Burström, AnnaPalmqvist, Richardvan Guelpen, Bethany

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