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van Guelpen, BethanyORCID iD iconorcid.org/0000-0002-9692-101X
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Publications (10 of 172) Show all publications
Rontogianni, M. O., Bouras, E., Aglago, E. K., Freisling, H., Murphy, N., Cotterchio, M., . . . Tsilidis, K. K. (2024). Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis. International Journal of Obesity, 48, 709-716
Open this publication in new window or tab >>Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis
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2024 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 48, p. 709-716Article in journal (Refereed) Published
Abstract [en]

Background: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing.

Methods: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia.

Results: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03–1.39) and in women (1.15, 1.06–1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03–1.57; and 1.40, 1.10–1.77, respectively), and with colon cancer in women (1.20, 1.07–1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women.

Conclusions: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cancer and Oncology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-220884 (URN)10.1038/s41366-024-01479-6 (DOI)001155394800003 ()38297030 (PubMedID)2-s2.0-85183703929 (Scopus ID)
Funder
NIH (National Institutes of Health)
Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-06-19Bibliographically approved
Harewood, R., Rothwell, J. A., Bešević, J., Viallon, V., Achaintre, D., Gicquiau, A., . . . Gunter, M. J. (2024). Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). EBioMedicine, 101, Article ID 105024.
Open this publication in new window or tab >>Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC)
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2024 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 101, article id 105024Article in journal (Refereed) Published
Abstract [en]

Background: Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain.

Methods: In a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk.

Findings: Of the 97 assayed lipids, 24 were inversely associated (nominally p < 0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95% CI 0.47–0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95% CI 0.59–0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding the first 5 years of follow-up after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer.

Interpretation: Elevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations. Funding: World Cancer Research Fund (reference: 2013/1002); European Commission (FP7: BBMRI-LPC; reference: 313010).

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Acylcarnitines, Colorectal cancer, Glycerophospholipids, Lipids, Metabolomics, Sphingolipids
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-222579 (URN)10.1016/j.ebiom.2024.105024 (DOI)38412638 (PubMedID)2-s2.0-85187658965 (Scopus ID)
Funder
World Cancer Research Fund International, 2013/1002EU, FP7, Seventh Framework Programme, 313010
Available from: 2024-04-08 Created: 2024-04-08 Last updated: 2024-04-12Bibliographically approved
Sun, M., da Silva, M., Bjørge, T., Fritz, J., Mboya, I. B., Jerkeman, M., . . . Stocks, T. (2024). Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the obesity and disease development Sweden (ODDS) pooled cohort study. The Lancet Regional Health: Europe, 45, Article ID 101034.
Open this publication in new window or tab >>Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the obesity and disease development Sweden (ODDS) pooled cohort study
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2024 (English)In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 45, article id 101034Article in journal (Refereed) Published
Abstract [en]

Background: Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers.

Methods: Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR >1) at an α-level of 0.05 for obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5–24.9 kg/m2) or per 5 kg/m2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related.

Findings: After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5 kg/m2 higher BMI was 1.17 (1.15–1.20) in men and 1.13 (1.11–1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22–1.26) in men and 1.12 (1.11–1.13) in women for established obesity-related cancers (84,384 cases). Interpretation: This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Body mass index, Cancer, Obesity
National Category
Cancer and Oncology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-228809 (URN)10.1016/j.lanepe.2024.101034 (DOI)2-s2.0-85201383782 (Scopus ID)
Projects
ODDSMONICASIMPLERSwedish Twin RegistryWICTORY
Funder
Swedish Research Council, 2017-00650Swedish Research Council, 2017-00644Swedish Research Council, 2021-00160Swedish Research Council, 2021-00180Lund University, STYR 2019/2046).
Available from: 2024-08-28 Created: 2024-08-28 Last updated: 2024-08-28Bibliographically approved
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
Thomas, C. E., Lin, Y., Kim, M., Kawaguchi, E. S., Qu, C., Um, C. Y., . . . Hsu, L. (2024). Characterization of additive gene–environment interactions for colorectal cancer risk. Epidemiology, 36(1), 126-138
Open this publication in new window or tab >>Characterization of additive gene–environment interactions for colorectal cancer risk
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2024 (English)In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 36, no 1, p. 126-138Article in journal (Refereed) Published
Abstract [en]

Background: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure.

Methods: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk.

Results: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility.

Conclusions: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Place, publisher, year, edition, pages
Wolters Kluwer, 2024
Keywords
additive interaction, colorectal cancer, genetic epidemiology, GxE, multiplicative interaction
National Category
Medical Genetics and Genomics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-230961 (URN)10.1097/EDE.0000000000001795 (DOI)39316822 (PubMedID)2-s2.0-85205921385 (Scopus ID)
Funder
Swedish Research CouncilSwedish Cancer SocietyRegion SkåneRegion VästerbottenKarolinska Institute
Available from: 2024-10-29 Created: 2024-10-29 Last updated: 2025-02-10Bibliographically approved
da Silva, M., Fritz, J., Mboya, I. B., Sun, M., Wahlström, J., van Guelpen, B., . . . Stocks, T. (2024). Cohort profile: the Obesity and Disease Development Sweden (ODDS) study, a pooled cohort. BMJ Open, 14(7), Article ID e084836.
Open this publication in new window or tab >>Cohort profile: the Obesity and Disease Development Sweden (ODDS) study, a pooled cohort
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2024 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 14, no 7, article id e084836Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality.

PARTICIPANTS: ODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17-103 years in 1963-2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019-2021, varying between the registers.

FINDINGS TO DATE: Among all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977-1994) in men and 2001 (1991-2010) in women, age 19 (18-40) years in men and 30 (26-36) years in women and BMI 22.9 (20.9-25.4) kg/m2 in men and 23.2 (21.2-26.1) kg/m2 in women. Normal weight (BMI 18.5-24.9 kg/m2) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m2) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8-40.8) years in men and 19.6 (9.3-29.0) years in women. During follow-up, 283 244 men and 123 457 women died.

FUTURE PLANS: The large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2024
Keywords
Body Mass Index, EPIDEMIOLOGY, Obesity, Weight Gain
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-228073 (URN)10.1136/bmjopen-2024-084836 (DOI)001306358600001 ()39013647 (PubMedID)2-s2.0-85199015805 (Scopus ID)
Funder
Swedish Research Council, 2021-01934Swedish Cancer Society, 230633 SIAMrs. Berta Kamprad's Cancer Foundation, FBKS-2021-12-343The Crafoord Foundation, 20210628 20220572 20230547Swedish Cancer Society, 232767 Pj
Available from: 2024-07-31 Created: 2024-07-31 Last updated: 2024-10-30Bibliographically 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: 2025-02-11Bibliographically approved
Thomas, C. E., Georgeson, P., Qu, C., Steinfelder, R. S., Buchanan, D. D., Song, M., . . . Phipps, A. I. (2024). Epidemiologic factors in relation to colorectal cancer risk and survival by genotoxic colibactin mutational signature. Cancer Epidemiology, Biomarkers and Prevention, 33(4), 534-546
Open this publication in new window or tab >>Epidemiologic factors in relation to colorectal cancer risk and survival by genotoxic colibactin mutational signature
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2024 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 33, no 4, p. 534-546Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88.

METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases).

RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066).

CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available.

IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2024
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-223486 (URN)10.1158/1055-9965.EPI-23-0600 (DOI)001200133000005 ()38252034 (PubMedID)2-s2.0-85189863522 (Scopus ID)
Funder
Swedish Cancer Society
Available from: 2024-04-19 Created: 2024-04-19 Last updated: 2024-10-28Bibliographically approved
Chen, Z., Guo, X., Tao, R., Huyghe, J. R., Law, P. J., Fernandez-Rozadilla, C., . . . Zheng, W. (2024). Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes. Nature Communications, 15(1), Article ID 3557.
Open this publication in new window or tab >>Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 3557Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:umu:diva-224181 (URN)10.1038/s41467-024-47399-x (DOI)38670944 (PubMedID)2-s2.0-85191635301 (Scopus ID)
Funder
NIH (National Institutes of Health), R01CA188214NIH (National Institutes of Health), R37CA227130NIH (National Institutes of Health), R01CA269589
Available from: 2024-05-17 Created: 2024-05-17 Last updated: 2025-02-10Bibliographically approved
Aglago, E. K., Qu, C., Harlid, S., Phipps, A. I., Steinfelder, R. S., Ogino, S., . . . Peters, U. (2024). Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing. American Journal of Clinical Nutrition, 120(3), 664-673
Open this publication in new window or tab >>Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing
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2024 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 120, no 3, p. 664-673Article in journal (Refereed) Published
Abstract [en]

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.

Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.

Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.

Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways.

Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
colorectal cancer, folate, folic acid, molecular subtypes, somatic mutations, tumor
National Category
Cancer and Oncology Medical Genetics and Genomics
Identifiers
urn:nbn:se:umu:diva-228475 (URN)10.1016/j.ajcnut.2024.07.012 (DOI)001331131100001 ()39025327 (PubMedID)2-s2.0-85200746168 (Scopus ID)
Available from: 2024-08-16 Created: 2024-08-16 Last updated: 2025-02-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9692-101X

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