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Papadimitriou, N., Qu, C., Harrison, T. A., Bever, A. M., Martin, R. M., Tsilidis, K. K., . . . Murphy, N. (2024). Body size and risk of colorectal cancer molecular defined subtypes and pathways: mendelian randomization analyses. EBioMedicine, 101, Article ID 105010.
Open this publication in new window or tab >>Body size and risk of colorectal cancer molecular defined subtypes and pathways: mendelian randomization analyses
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2024 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 101, article id 105010Article in journal (Refereed) Published
Abstract [en]

Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain.

Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO).

Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03).

Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4).

Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Colorectal cancer, Mendelian randomization, Molecular subtypes, Obesity
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-222809 (URN)10.1016/j.ebiom.2024.105010 (DOI)38350331 (PubMedID)2-s2.0-85184797654 (Scopus ID)
Funder
Swedish Research Council, VR 2017-00650Swedish Research Council, VR 2017-01737Knut and Alice Wallenberg Foundation, VLL-765961
Available from: 2024-04-11 Created: 2024-04-11 Last updated: 2024-04-11Bibliographically approved
Bodén, S., Zheng, R., Ribbenstedt, A., Landberg, R., Harlid, S., Vidman, L., . . . Brunius, C. (2024). Dietary patterns, untargeted metabolite profiles and their association with colorectal cancer risk. Scientific Reports, 14(1), Article ID 2244.
Open this publication in new window or tab >>Dietary patterns, untargeted metabolite profiles and their association with colorectal cancer risk
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2024 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, no 1, article id 2244Article in journal (Refereed) Published
Abstract [en]

We investigated data-driven and hypothesis-driven dietary patterns and their association to plasma metabolite profiles and subsequent colorectal cancer (CRC) risk in 680 CRC cases and individually matched controls. Dietary patterns were identified from combined exploratory/confirmatory factor analysis. We assessed association to LC–MS metabolic profiles by random forest regression and to CRC risk by multivariable conditional logistic regression. Principal component analysis was used on metabolite features selected to reflect dietary exposures. Component scores were associated to CRC risk and dietary exposures using partial Spearman correlation. We identified 12 data-driven dietary patterns, of which a breakfast food pattern showed an inverse association with CRC risk (OR per standard deviation increase 0.89, 95% CI 0.80–1.00, p = 0.04). This pattern was also inversely associated with risk of distal colon cancer (0.75, 0.61–0.96, p = 0.01) and was more pronounced in women (0.69, 0.49–0.96, p = 0.03). Associations between meat, fast-food, fruit soup/rice patterns and CRC risk were modified by tumor location in women. Alcohol as well as fruit and vegetables associated with metabolite profiles (Q2 0.22 and 0.26, respectively). One metabolite reflecting alcohol intake associated with increased CRC risk, whereas three metabolites reflecting fiber, wholegrain, and fruit and vegetables associated with decreased CRC risk.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Nutrition and Dietetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-220475 (URN)10.1038/s41598-023-50567-6 (DOI)001152222400046 ()38278865 (PubMedID)2-s2.0-85183347182 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion VästerbottenIngaBritt and Arne Lundberg’s Research Foundation
Available from: 2024-02-16 Created: 2024-02-16 Last updated: 2024-02-16Bibliographically approved
Aglago, E. K., Kim, A., Lin, Y., Qu, C., Evangelou, M., Ren, Y., . . . Campbell, P. T. (2023). A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk. Cancer Research, 83(15), 2572-2583
Open this publication in new window or tab >>A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
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2023 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 83, no 15, p. 2572-2583Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.

SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2023
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-212758 (URN)10.1158/0008-5472.CAN-22-3713 (DOI)37249599 (PubMedID)2-s2.0-85166391630 (Scopus ID)
Available from: 2023-08-10 Created: 2023-08-10 Last updated: 2023-08-10Bibliographically approved
Harbs, J., Rinaldi, S., Keski-Rahkonen, P., Liu, X., Palmqvist, R., van Guelpen, B. & Harlid, S. (2023). An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples. Epigenetics, 18(1), Article ID 2196759.
Open this publication in new window or tab >>An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples
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2023 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 18, no 1, article id 2196759Article in journal (Refereed) Published
Abstract [en]

Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2023
Keywords
Sex hormones, sex hormone binding globulin, DNA methylation, men, NSHDS
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-205420 (URN)10.1080/15592294.2023.2196759 (DOI)000961068800001 ()36994855 (PubMedID)2-s2.0-85151198554 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, AMP 17-866Cancerforskningsfonden i Norrland, AMP 17-856Cancerforskningsfonden i Norrland, AMP 18-915Cancerforskningsfonden i Norrland, AMP 19-967Region Västerbotten, VLL-547711Region Västerbotten, VLL-680921Region Västerbotten, VLL58269Umeå University
Note

Originally included in thesis in manuscript form. 

Available from: 2023-03-06 Created: 2023-03-06 Last updated: 2023-09-05Bibliographically approved
Fritz, J., Jochems, S. H. J., Bjørge, T., Wood, A. M., Häggström, C., Ulmer, H., . . . Stocks, T. (2023). Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts. British Journal of Cancer
Open this publication in new window or tab >>Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts
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2023 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited.

Methods: We included 259,884 men from eight European cohorts, with 11,760 incident PCa’s and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index.

Results: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01–1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14–1.35, of which 28%; 4%–52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death.

Conclusions: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.

Place, publisher, year, edition, pages
Nature Publishing Group, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-218306 (URN)10.1038/s41416-023-02526-1 (DOI)2-s2.0-85179305097 (Scopus ID)
Funder
World Cancer Research Fund InternationalSwedish Cancer Society, 20 1033 PjFSwedish Cancer Society, CAN 2017/1019Swedish Research Council, 2018-02825ProstatacancerförbundetThe Crafoord Foundation, 20200546
Available from: 2023-12-21 Created: 2023-12-21 Last updated: 2023-12-21
Botteri, E., Peveri, G., Berstad, P., Bagnardi, V., Chen, S. L. .., Sandanger, T. M., . . . Ferrari, P. (2023). Changes in lifestyle and risk of colorectal cancer in the european prospective investigation into cancer and nutrition. American Journal of Gastroenterology, 118(4), 702-711
Open this publication in new window or tab >>Changes in lifestyle and risk of colorectal cancer in the european prospective investigation into cancer and nutrition
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2023 (English)In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 118, no 4, p. 702-711Article in journal (Refereed) Published
Abstract [en]

Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort.

Methods: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI).

Results: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile.

Discussion: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

National Category
Public Health, Global Health, Social Medicine and Epidemiology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-206527 (URN)10.14309/ajg.0000000000002065 (DOI)001005701300001 ()36227801 (PubMedID)2-s2.0-85151312824 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2023-04-11 Created: 2023-04-11 Last updated: 2023-09-05Bibliographically approved
Bodén, S., Harbs, J., Sundkvist, A., Fuchs, K., Myte, R., Gylling, B., . . . van Guelpen, B. (2023). Plasma concentrations of gut hormones acyl ghrelin and peptide YY and subsequent risk of colorectal cancer and molecular tumor subtypes. Cancer Prevention Research, 16(2), 75-87
Open this publication in new window or tab >>Plasma concentrations of gut hormones acyl ghrelin and peptide YY and subsequent risk of colorectal cancer and molecular tumor subtypes
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2023 (English)In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 16, no 2, p. 75-87Article in journal (Refereed) Published
Abstract [en]

Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We investigated whether circulating levels of the gut hormones ghrelin (analyzed as acyl ghrelin) and Peptide YY (PYY) were associated with subsequent colorectal cancer risk, including clinical and molecular tumor subtypes. We also provide descriptive data on these hormones in relation to background participant characteristics and metabolic biomarkers. This population-based study included 1,010 matched case-control pairs with a median of 12.3 years of follow-up. Acyl ghrelin and PYY were measured by multiplex immunoassay. Data on KRAS and BRAF mutations and microsatellite instability (MSI) status were available for 704 and 708 cases, respectively. Conditional logistic regression models estimated association to colorectal cancer risk. Partial correlation and linear regression were used to investigate relationships between background and metabolic variables and variation in plasma gut hormone concentrations. Acyl ghrelin was not clearly associated with colorectal cancer risk (multivariable OR per 1 SD increase: 1.11; 95% CI, 1.00-1.23). Positive associations were observed for specific subtypes, in particular BRAF-mutated colorectal cancer and right-sided colon cancer, although with nonsignificant heterogeneity. PYY was not related to colorectal cancer risk (multivariable OR per 1 SD: 1.04; 95% CI, 0.95-1.14) or any tumor subtype. In the control participants, ghrelin was inversely correlated with BMI, and PYY was positively correlated with C-peptide and insulin levels. These findings provide limited support for a possible role for ghrelin in colorectal cancer development, primarily in specific anatomical and molecular tumor subtypes.

PREVENTION RELEVANCE: The findings of this study do not support a major role for the metabolic gut hormones ghrelin and PYY in colorectal cancer development but suggest the possibility of an involvement for ghrelin in specific tumor subtypes. Elucidating subtype-specific risk factors and mechanisms of carcinogenesis may have implications for precision prevention.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-204740 (URN)10.1158/1940-6207.CAPR-22-0325 (DOI)000928164800001 ()36367526 (PubMedID)2-s2.0-85147457884 (Scopus ID)
Funder
Region VästerbottenUmeå UniversitySwedish Cancer Society, 2017/ 581Swedish Cancer Society, 2014/780Swedish Cancer Society, 2012/0501Cancerforskningsfonden i Norrland, AMP 21-1039Cancerforskningsfonden i Norrland, AMP 20-1015Cancerforskningsfonden i Norrland, AMP 19-984Knut and Alice Wallenberg Foundation
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2023-09-05Bibliographically approved
Lu, S. S., Rutegård, M., Ahmed, M., Häggström, C., Gylfe, Å., Harlid, S. & van Guelpen, B. (2023). Prediagnostic prescription antibiotics use and survival in patients with colorectal cancer: a swedish national register-based study. Cancer Epidemiology, Biomarkers and Prevention, 32(10), 1391-1401
Open this publication in new window or tab >>Prediagnostic prescription antibiotics use and survival in patients with colorectal cancer: a swedish national register-based study
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2023 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 32, no 10, p. 1391-1401Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Antibiotics use is associated with higher colorectal cancer risk, but little is known regarding any potential effects on survival.

METHODS: We conducted a nationwide cohort study, using complete-population data from Swedish national registers between 2005 and 2020, to investigate prediagnostic prescription antibiotics use in relation to survival in colorectal cancer patients.

RESULTS: We identified 36,061 stage I-III and 11,242 stage IV colorectal cancer cases diagnosed between 2010 and 2019. For stage I-III, any antibiotics use (binary yes/no variable) was not associated with overall or cancer-specific survival. Compared with no use, moderate antibiotics use (total 11-60 days) was associated with slightly better cancer-specific survival [adjusted HR (aHR) = 0.93; 95% confidence interval (CI), 0.86-0.99)], whereas very high use (>180 days) was associated with worse survival [overall survival (OS) aHR = 1.42; 95% CI, 1.26-1.60, cancer-specific survival aHR = 1.31; 95% CI, 1.10-1.55]. In analyses by different antibiotic types, although not statistically significant, worse survival outcomes were generally observed across several antibiotics, particularly macrolides and/or lincosamides. In stage IV colorectal cancer, inverse relationships between antibiotics use and survival were noted.

CONCLUSIONS: Overall, our findings do not support any substantial detrimental effects of prediagnostic prescription antibiotics use on cancer-specific survival after colorectal cancer diagnosis, with the possible exception of very high use in stage I-III colorectal cancer. Further investigation is warranted to confirm and understand these results.

IMPACT: Although the study findings require confirmation, physicians probably do not need to factor in prediagnostic prescription antibiotics use in prognosticating patients with colorectal cancer.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215390 (URN)10.1158/1055-9965.EPI-23-0340 (DOI)37490284 (PubMedID)2-s2.0-85173563887 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, LP17–2154Cancerforskningsfonden i Norrland, LP21-2275Region Västerbotten, RV-932777
Available from: 2023-10-27 Created: 2023-10-27 Last updated: 2024-02-20Bibliographically approved
Mao, Z., Baker, J. R., Takeuchi, M., Hyogo, H., Tjønneland, A., Eriksen, A. K., . . . Fedirko, V. (2023). Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients. International Journal of Cancer, 152(11), 2257-2268
Open this publication in new window or tab >>Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients
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2023 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 152, no 11, p. 2257-2268Article in journal (Refereed) Published
Abstract [en]

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1 = 1.53, 95% CI: 1.04-2.25, Ptrend =.002) and all-cause (HRQ5 vs Q1 = 1.62, 95% CI: 1.16-2.26, Ptrend <.001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon = 1.02, 95% CI: 0.74-1.42; HRdistal colon = 1.51, 95% CI: 1.20-1.91; Peffect modification =.02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
advanced glycation end products, colorectal cancer, glyceraldehyde-derived advanced glycation end products, mortality, prospective study
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-206343 (URN)10.1002/ijc.34449 (DOI)000956441500001 ()36715363 (PubMedID)2-s2.0-85150753434 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion SkåneRegion Västerbotten
Available from: 2023-04-28 Created: 2023-04-28 Last updated: 2023-09-05Bibliographically approved
Ugai, T., Akimoto, N., Haruki, K., Harrison, T. A., Cao, Y., Qu, C., . . . Ogino, S. (2023). Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases. Journal of gastroenterology, 58, 229-245
Open this publication in new window or tab >>Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases
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2023 (English)In: Journal of gastroenterology, ISSN 0944-1174, E-ISSN 1435-5922, Vol. 58, p. 229-245Article in journal (Refereed) Published
Abstract [en]

Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics.

Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation.

Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages.

Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Biogeography, Epigenetics, Mismatch repair, Molecular pathological epidemiology, Young-onset cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-204064 (URN)10.1007/s00535-023-01955-2 (DOI)000928167600001 ()36648535 (PubMedID)2-s2.0-85146393347 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion SkåneRegion VästerbottenCancerforskningsfonden i Norrland
Available from: 2023-02-02 Created: 2023-02-02 Last updated: 2023-09-05Bibliographically approved
Projects
The fetal exposome and DNA methylation in cord blood – early prediction of childhood asthma and allergy? – A study in the prospective birth cohort NorthPop [2019-01187_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8540-6891

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