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Publications (10 of 84) Show all publications
Fritz, J., Jochems, S. H. J., Bjørge, T., Wood, A. M., Häggström, C., Ulmer, H., . . . Stocks, T. (2024). Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts. British Journal of Cancer, 130, 308-316
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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2024 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 130, p. 308-316Article in journal (Refereed) Published
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, 2024
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-218306 (URN)10.1038/s41416-023-02526-1 (DOI)001124661600001 ()38087039 (PubMedID)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: 2024-04-26Bibliographically 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
Edlund, J., Sdougkou, K., Papazian, S., Wu, W.-Y. Y., Martin, J. W. & Harlid, S. (2024). Chemical exposomics in biobanked plasma samples and associations with breast cancer risk factors. Paper presented at 36th Annual Conference of the International Society for Environmental Epidemiology, Santiago, Chile, August 25–28, 2024. Journal of Exposure Science and Environmental Epidemiology, Article ID 117703.
Open this publication in new window or tab >>Chemical exposomics in biobanked plasma samples and associations with breast cancer risk factors
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2024 (English)In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, article id 117703Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: The chemical exposome includes exposure to numerous environmental and endogenous molecules, many of which have been linked to reproductive outcomes due to their endocrine-disrupting properties. As several breast cancer risk factors, including age and parity, are related to reproduction, it is imperative to investigate the interplay between such factors and the chemical exposome prior to conducting large scale exposome-based breast cancer studies.

Objective: This pilot study aimed to provide an overview of the chemical exposome in plasma samples from healthy women and identify associations between environmental exposures and three risk factors for breast cancer: age, parity, and age at menarche.

Material and methods: Plasma samples (n = 161), were selected based on reproductive history from 100 women participating in the Northern Sweden Health and Disease Study, between 1987 and 2006. Samples were analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) for 77 priority target analytes including contaminants and hormones, with simultaneous untargeted profiling of the chemical exposome and metabolome. Linear mixed effects models were applied to test associations between risk factors and chemical levels.

Results: Fifty-five target analytes were detected in at least one individual and over 94,000 untargeted features were detected across all samples. Among untargeted features, 430 could be annotated and were broadly classified as environmental (246), endogenous (167) or ambiguous (17). Applying mixed effect models to features detected in at least 70% of the samples (16,778), we found seven targeted analytes (including caffeine and various per- and poly-fluoroalkyl substances) and 38 untargeted features, positively associated with age. The directionality of these associations reversed for parity, decreasing with increasing births. Seven separate targeted analytes were associated with age at menarche.

Significance: This study demonstrates how a comprehensive chemical exposome approach can be used to inform future research prioritization regarding associations between known and unknown substances, reproduction, and breast cancer risk.

Impact statement: This study illustrates how chemical exposomics of long-term stored blood samples offers valuable insights to discover chemical exposures and their potential links to disease in humans, particularly those related to reproduction and breast cancer risk factors.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Breast cancer, Chemical exposome, High-resolution mass spectrometry, Liquid chromatography, Plasma
National Category
Occupational Health and Environmental Health Public Health, Global Health, Social Medicine and Epidemiology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-233782 (URN)10.1038/s41370-024-00736-0 (DOI)001371134900001 ()39643621 (PubMedID)2-s2.0-85211505106 (Scopus ID)
Conference
36th Annual Conference of the International Society for Environmental Epidemiology, Santiago, Chile, August 25–28, 2024
Funder
Swedish Cancer Society, 21 1531 PjLions Cancerforskningsfond i Norr, LP 23-2339Lions Cancerforskningsfond i Norr, LP 22-2310Cancerforskningsfonden i NorrlandScience for Life Laboratory, SciLifeLab
Available from: 2025-01-10 Created: 2025-01-10 Last updated: 2025-01-10
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
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
Tian, Y., Lin, Y., Qu, C., Arndt, V., Baurley, J. W., Berndt, S. I., . . . Chang-Claude, J. (2024). Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk. British Journal of Cancer, 130(10), 1687-1696
Open this publication in new window or tab >>Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
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2024 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 130, no 10, p. 1687-1696Article in journal (Refereed) Published
Abstract [en]

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.

Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.

Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.

Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-223079 (URN)10.1038/s41416-024-02638-2 (DOI)001195111400001 ()38561434 (PubMedID)2-s2.0-85189134864 (Scopus ID)
Funder
NIH (National Institutes of Health)
Available from: 2024-04-17 Created: 2024-04-17 Last updated: 2024-06-20Bibliographically approved
Yeung, E., Biedrzycki, R. J., Gómez Herrera, L. C., Issarapu, P., Dou, J., Marques, I. F., . . . Guan, W. (2024). Maternal age is related to offspring DNA methylation: a meta-analysis of results from the pace consortium. Aging Cell, 23(8), Article ID e14194.
Open this publication in new window or tab >>Maternal age is related to offspring DNA methylation: a meta-analysis of results from the pace consortium
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2024 (English)In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 23, no 8, article id e14194Article in journal (Refereed) Published
Abstract [en]

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
aging, child, DNA methylation, melatonin, receptor
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-225931 (URN)10.1111/acel.14194 (DOI)001234420300001 ()38808605 (PubMedID)2-s2.0-85194821046 (Scopus ID)
Available from: 2024-06-12 Created: 2024-06-12 Last updated: 2024-08-20Bibliographically approved
Lu, S. S., Rutegård, M., Häggström, C., Gylfe, Å., Harlid, S. & van Guelpen, B. (2024). Prior antibiotics exposure is associated with an elevated risk of surgical site infections, including anastomotic leakage, after colon cancer but not rectal cancer surgery: A register-based study of 38,839 patients. International Journal of Cancer
Open this publication in new window or tab >>Prior antibiotics exposure is associated with an elevated risk of surgical site infections, including anastomotic leakage, after colon cancer but not rectal cancer surgery: A register-based study of 38,839 patients
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2024 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Gut microbiota composition has been implicated in surgical site complications after colorectal cancer surgery. Antibiotics affect gut microbiota, but evidence for a role in surgical site complications is inconclusive. We aimed to investigate use of prescription antibiotics during the years before surgery in relation to the risk of surgical site infections, including anastomotic leakage, within 30 days after surgery. Cardiovascular/neurological complications and the urinary antiseptic methenamine hippurate, for which there is no clear link with the microbiota, were used as negative controls. We conducted a patient cohort study using complete population data from Swedish national registers between 2005 and 2020. The final study population comprised 26,527 colon cancer and 12,312 rectal cancer cases with a 4.5 year exposure window. In colon cancer patients, antibiotics use was associated with a higher risk of surgical site infections (adjusted odds ratio (aOR) for any versus no use = 1.20, 95% confidence interval (CI) 1.10–1.33) and anastomotic leakage in particular (aOR =1.19, 95% CI 1.03–1.36), both with dose–response relationships for increasing cumulative antibiotics use (Ptrend = <0.001 and Ptrend = 0.047, respectively). Conversely, associations in rectal cancer patients, as well as for the negative controls cardiovascular/neurological complications and methenamine hippurate, were null. In conclusion, prescription antibiotics use up to 4.5 years before colorectal cancer surgery is associated with a higher risk of surgical site infections, including anastomotic leakage, after colon cancer but not rectal cancer surgery. These findings support a role for antibiotics-induced intestinal dysbiosis in surgical site infections.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
anastomotic leakage, antimicrobials, colorectal cancer surgery, gut microbiome, postoperative complications, surgical site infections
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-232763 (URN)10.1002/ijc.35269 (DOI)39600222 (PubMedID)2-s2.0-85210363197 (Scopus ID)
Funder
Region Västerbotten, RV-932777Lions Cancerforskningsfond i Norr, LP 17-2154Knut and Alice Wallenberg Foundation
Available from: 2024-12-19 Created: 2024-12-19 Last updated: 2024-12-19
Drew, D. A., Kim, A. E., Lin, Y., Qu, C., Morrison, J., Lewinger, J. P., . . . Gauderman, W. J. (2024). Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer. Science Advances, 10(22), Article ID eadk3121.
Open this publication in new window or tab >>Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
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2024 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 10, no 22, article id eadk3121Article in journal (Refereed) Published
Abstract [en]

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2024
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:umu:diva-225944 (URN)10.1126/sciadv.adk3121 (DOI)001235968800024 ()38809988 (PubMedID)2-s2.0-85194884675 (Scopus ID)
Available from: 2024-06-12 Created: 2024-06-12 Last updated: 2025-02-10Bibliographically 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 and Genomics
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: 2025-02-10Bibliographically 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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