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- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Tsilidis, K. K., et al.
(författare)
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Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition
- 2010
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 103:11, s. 1755-1759
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk. METHODS: We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337 802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer. RESULTS: After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83-1.02), although this association was stronger among post-menopausal women (HR, 0.84; 95% CI: 0.74-0.95). Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk. CONCLUSION: Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk. British Journal of Cancer (2010) 103, 1755-1759. doi:10.1038/sj.bjc.6605965 www.bjcancer.com Published online 2 November 2010 (C) 2010 Cancer Research UK
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- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) 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 < 5 × 10-8) 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 < 5 × 10-8, 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.
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- Sund, Malin, et al.
(författare)
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Plasma carotenoids, vitamin C, retinol and tocopherols levels and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition: A nested case-control study Plasma micronutrients and pancreatic cancer risk
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:6, s. E665-E676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (- and -carotene, lycopene, -cryptoxanthin, canthaxanthin, zeaxanthin and lutein), - and -tocopherol and retinol were measured by reverse phase high-performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma -carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31-0.88, p for trend=0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30-0.94, p for trend=0.06) and -tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39-0.99, p for trend=0.08. For - and -carotene, lutein, sum of carotenoids and -tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of -carotene, zeaxanthin and -tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted. What's new? Fruits and vegetables may play a role in the prevention of pancreatic cancer, but associations between the antioxidants those foods contain and disease risk remain unclear. In this study, pancreatic cancer risk was inversely associated with increased prediagnostic plasma concentrations of the antioxidants -carotene, zeaxanthin, and -tocopherol. Geographic variations were also detected. In Northern European countries, inverse associations with risk were found for blood levels of several carotenoids, whereas the association was strongest for -tocopherol in Southern European countries. The role of carotenoids and vitamins should be considered in subsequent investigations of the etiology of pancreatic cancer.
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- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 8. |
- Pischon, T., et al.
(författare)
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General and Abdominal Adiposity and Risk of Death in Europe
- 2008
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 359:20, s. 2105-2120
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-tohip ratio in addition to BMI in assessing the risk of death.
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| 10. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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