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Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0002-2974-2003
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.ORCID iD: 0000-0002-9086-7403
Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..ORCID iD: 0000-0001-6808-4405
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed) Published
Abstract [en]

Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 145, no 2, p. 327-337
Keywords [en]
BRAF, KRAS, colorectal cancer, metabolic factors, microsatellite instability, risk factors
National Category
Cancer and Oncology Nutrition and Dietetics
Identifiers
URN: urn:nbn:se:umu:diva-158782DOI: 10.1002/ijc.32104PubMedID: 30613980Scopus ID: 2-s2.0-85060622510OAI: oai:DiVA.org:umu-158782DiVA, id: diva2:1314324
Note

Originally included in thesis in manuscript form with title [Metabolic factors and colorectal cancer risk by KRAS and BRAF mutation status]

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-06-11Bibliographically approved
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)
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Available from: 2018-09-21 Created: 2018-09-12 Last updated: 2019-05-15Bibliographically approved

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Myte, RobinGylling, BjörnHäggström, JennyHäggström, ChristelZingmark, CarlLöfgren Burström, AnnaPalmqvist, Richardvan Guelpen, Bethany

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