umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Metabolic Risk Factors and Molecular Subtypes of Colorectal Cancer
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
Metabola Riskfaktorer och Molekylära Subtyper av Kolorektalcancer (Svenska)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet , 2018. , s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1975
Nyckelord [en]
Colorectal cancer, risk factors, metabolic syndrome, one-carbon metabolism, molecular subtypes, KRAS, BRAF, MSI, molecular pathological epidemiology
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
cancerepidemiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-151753ISBN: 978-91-7601-939-9 (tryckt)OAI: oai:DiVA.org:umu-151753DiVA, id: diva2:1247566
Disputation
2018-10-12, Sal 260, Norrlands Universitetssjukhus, Målpunkt A21, Byggnad 3A, vån 2., Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-09-21 Skapad: 2018-09-12 Senast uppdaterad: 2019-05-15Bibliografiskt granskad
Delarbeten
1. Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
Öppna denna publikation i ny flik eller fönster >>Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
Visa övriga...
2019 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 2, s. 327-337Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2019
Nyckelord
BRAF, KRAS, colorectal cancer, metabolic factors, microsatellite instability, risk factors
Nationell ämneskategori
Cancer och onkologi Näringslära
Identifikatorer
urn:nbn:se:umu:diva-158782 (URN)10.1002/ijc.32104 (DOI)30613980 (PubMedID)2-s2.0-85060622510 (Scopus ID)
Anmärkning

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

Tillgänglig från: 2019-05-08 Skapad: 2019-05-08 Senast uppdaterad: 2019-06-11Bibliografiskt granskad
2. Metabolic biomarkers and the risk of molecular subtypes of colorectal cancer
Öppna denna publikation i ny flik eller fönster >>Metabolic biomarkers and the risk of molecular subtypes of colorectal cancer
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
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.

Nationell ämneskategori
Cancer och onkologi
Forskningsämne
cancerepidemiologi
Identifikatorer
urn:nbn:se:umu:diva-151751 (URN)
Tillgänglig från: 2018-09-12 Skapad: 2018-09-12 Senast uppdaterad: 2018-09-14
3. Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk
Öppna denna publikation i ny flik eller fönster >>Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk
Visa övriga...
2016 (Engelska)Ingår i: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 27, nr 6, s. 787-796Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.

METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.

RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).

CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk. See Video Abstract at http://links.lww.com/EDE/B83.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-129408 (URN)10.1097/EDE.0000000000000529 (DOI)000390251500006 ()27367522 (PubMedID)
Tillgänglig från: 2016-12-27 Skapad: 2016-12-27 Senast uppdaterad: 2018-09-12Bibliografiskt granskad
4. One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status
Öppna denna publikation i ny flik eller fönster >>One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status
Visa övriga...
2018 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 4, artikel-id e0196233Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2018
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-147822 (URN)10.1371/journal.pone.0196233 (DOI)000430802400077 ()29694444 (PubMedID)
Tillgänglig från: 2018-05-21 Skapad: 2018-05-21 Senast uppdaterad: 2019-11-22Bibliografiskt granskad

Open Access i DiVA

fulltext(4551 kB)161 nedladdningar
Filinformation
Filnamn FULLTEXT02.pdfFilstorlek 4551 kBChecksumma SHA-512
12b32d3de158309d845d87fc957ba7aa8b368d70e777374d86bcd842bd94bdb5c786af5748d1b92f7a44acb0a6dfb167a5ef7a606b8f9d2f11993685c263afd8
Typ fulltextMimetyp application/pdf
spikblad(195 kB)19 nedladdningar
Filinformation
Filnamn SPIKBLAD03.pdfFilstorlek 195 kBChecksumma SHA-512
82d757c7817530060547b58590df6bb936bbd05d49b619149c1f5c575257aa9d846f9445bb58aa295f64a61cb478b91d961c13bef528113915e964df78143a5d
Typ spikbladMimetyp application/pdf

Personposter BETA

Myte, Robin

Sök vidare i DiVA

Av författaren/redaktören
Myte, Robin
Av organisationen
Onkologi
Cancer och onkologi

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 161 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

isbn
urn-nbn

Altmetricpoäng

isbn
urn-nbn
Totalt: 1158 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf