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Wilson, L. E., Xu, Z., Harlid, S., White, A. J., Troester, M. A., Sandler, D. P. & Taylor, J. A. (2019). Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue. American Journal of Epidemiology, 188(6), 1055-1065
Open this publication in new window or tab >>Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue
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2019 (English)In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 6, p. 1055-1065Article in journal (Refereed) Published
Abstract [en]

The biological mechanisms driving associations between alcohol consumption and chronic diseases might include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, California) array data on blood DNA methylation was examined in a discovery set of 2,878 non-Hispanic white women from the Sister Study (United States, 2004-2015) who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (false discovery rate of Q < 0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 cytosine-phosphate-guanine (CpG) sites. Associations were replicated (P < 0.05) for 677 CpGs in an independent set of 187 blood DNA samples from the Sister Study and for 628 CpGs in an independent set of 171 normal breast DNA samples; 1,207 CpGs were replicated in either blood or normal breast, with 98 CpGs replicated in both tissues. Individual gene effects were notable for phosphoglycerate dehydrogenase (PGHDH), peptidyl-prolyl cis-trans isomerase (PPIF), solute carrier 15 (SLC15), solute carrier family 43 member 1 (SLC43A1), and solute carrier family 7 member 11 (SLC7A11). We also found that high alcohol consumption was associated with significantly lower global methylation as measured by the average of CpGs on the entire array.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
alcohol consumption, breast cancer, DNA methylation, epigenome-wide association study
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-161732 (URN)10.1093/aje/kwz032 (DOI)000473760200008 ()30938765 (PubMedID)
Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved
Fedirko, V., Jenab, M., Meplan, C., Jones, J. S., Zhu, W., Schomburg, L., . . . Hughes, D. J. (2019). Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status. Nutrients, 11(4), Article ID 935.
Open this publication in new window or tab >>Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status
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2019 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 4, article id 935Article in journal (Refereed) Published
Abstract [en]

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengateassays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
selenium, selenium status, selenoprotein gene variation, selenium pathway, colorectal neoplasms, selenoprotein P, prospective cohort, colorectal cancer risk, genetic epidemiology, biomarkers
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-159879 (URN)10.3390/nu11040935 (DOI)000467749800228 ()31027226 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion SkåneVästerbotten County Council
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., . . . Tsilidis, K. K. (2019). Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer
Open this publication in new window or tab >>Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

Keywords
Europe, association, cancer, cohort, epidemiology, hypertension, morphology, risk factors
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162707 (URN)10.1002/ijc.32576 (DOI)31319002 (PubMedID)
Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-08-27
Myte, R., Sundkvist, A., van Guelpen, B. & Harlid, S. (2019). Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort. Epigenetics, 14(7), 649-659
Open this publication in new window or tab >>Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort
2019 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed) Published
Abstract [en]

DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
DNA methylation, inflammation, biomarkers, C, reactive protein, colorectal cancer, risk factors, epigenetics, proteomics
National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-160622 (URN)10.1080/15592294.2019.1603962 (DOI)000470485500001 ()31033411 (PubMedID)
Funder
Västerbotten County Council, VLL-547711Västerbotten County Council, VLL-680921Västerbotten County Council
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Smith, T., Muller, D. C., Moons, K. G. M., Cross, A. J., Johansson, M., Ferrari, P., . . . Tzoulaki, I. (2019). Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies. Gut, 68, 672-683
Open this publication in new window or tab >>Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies
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2019 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, p. 672-683Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.

DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).

RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.

CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
cancer prevention, colorectal cancer, colorectal cancer screening, epidemiology, medical statistics
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-146375 (URN)10.1136/gutjnl-2017-315730 (DOI)000471830300013 ()29615487 (PubMedID)
Funder
NordForskSwedish Cancer SocietySwedish Research CouncilRegion SkåneVästerbotten County Council
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-07-10Bibliographically approved
Huyghe, J. R., Bien, S. A., Harrison, T. A., Kang, H. M., Chen, S., Schmit, S. L., . . . Peters, U. (2019). Discovery of common and rare genetic risk variants for colorectal cancer. Nature Genetics, 51(1), 76-+
Open this publication in new window or tab >>Discovery of common and rare genetic risk variants for colorectal cancer
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 76-+Article in journal (Refereed) Published
Abstract [en]

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155208 (URN)10.1038/s41588-018-0286-6 (DOI)000454108800015 ()30510241 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Harlid, S., Xu, Z., Kirk, E., Wilson, L. E., Troester, M. A. & Taylor, J. A. (2019). Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study. Epigenetics, 14(2), 146-157
Open this publication in new window or tab >>Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study
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2019 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 2, p. 146-157Article in journal (Refereed) Published
Abstract [en]

Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10-7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
DNA methylation, Hormone therapy, epigenetics, epigenome wide association, normal breast tissue
National Category
Cancer and Oncology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-157445 (URN)10.1080/15592294.2019.1580111 (DOI)000463795900004 ()30821641 (PubMedID)2-s2.0-85062450476 (Scopus ID)
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-04-26Bibliographically approved
Schmit, S. L., Edlund, C. K., Schumacher, F. R., Gong, J., Harrison, T. A., Huyghe, J. R., . . . Gruber, S. B. (2019). Novel Common Genetic Susceptibility Loci for Colorectal Cancer. Journal of the National Cancer Institute, 111(2), 146-157
Open this publication in new window or tab >>Novel Common Genetic Susceptibility Loci for Colorectal Cancer
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2019 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 2, p. 146-157Article in journal (Refereed) Published
Abstract [en]

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5x10(-8)) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results: The discovery GWAS identified 11 variants associated with CRC at P < 5x10(-8), of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-159635 (URN)10.1093/jnci/djy099 (DOI)000467900500008 ()29917119 (PubMedID)
Available from: 2019-06-05 Created: 2019-06-05 Last updated: 2019-06-05Bibliographically approved
Sundkvist, A., Myte, R., Palmqvist, R., Harlid, S. & van Guelpen, B. (2019). Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer [Letter to the editor]. Gut, 68(2), 373-374
Open this publication in new window or tab >>Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer
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2019 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 2, p. 373-374Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
cancer, colorectal cancer, epidemiology, gastrointestinal hormones
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-146376 (URN)10.1136/gutjnl-2018-316110 (DOI)000459027800022 ()29491131 (PubMedID)
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-04-16Bibliographically approved
Costas, L., Lujan-Barroso, L., Benavente, Y., Allen, N. E., Amiano, P., Ardanaz, E., . . . Casabonne, D. (2019). Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition. American Journal of Epidemiology, 188(2), 274-281
Open this publication in new window or tab >>Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition
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2019 (English)In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 2, p. 274-281Article in journal (Refereed) Published
Abstract [en]

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2019
Keywords
cohort studies, hormone therapy, hysterectomy, lymphoma, menopause, menstrual factors, phorectomy, parity
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157536 (URN)10.1093/aje/kwy259 (DOI)000460620100002 ()30481275 (PubMedID)
Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2019-04-01Bibliographically approved
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