| 1. |
- Sampson, Joshua N., et al.
(author)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Wang, Zhaoming, et al.
(author)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- McKay, James D., et al.
(author)
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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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| 4. |
- Amundadottir, Laufey, et al.
(author)
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Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41, s. 986-990
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Journal article (peer-reviewed)abstract
- We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
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| 5. |
- Petersen, Gloria M, et al.
(author)
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A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 224-228
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Journal article (peer-reviewed)abstract
- We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
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| 6. |
- Fedirko, Veronika, et al.
(author)
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Prediagnostic circulating parathyroid hormone concentration and colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort
- 2011
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 20:5, s. 767-778
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Journal article (peer-reviewed)abstract
- BACKGROUND: Parathyroid hormone (PTH) has been proposed to play a promoting role in carcinogenesis. However, no epidemiologic studies have yet directly investigated its role in colorectal cancer (CRC). METHODS: A case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort was conducted with 1,214 incident, sporadic CRC cases matched to 1,214 controls. Circulating prediagnostic PTH and 25-hydroxy vitamin D [25(OH)D] concentrations were measured by enzyme-linked immunosorbent assays. Detailed dietary and lifestyle questionnaire data were collected at baseline. Multivariable conditional logistic regression was used to estimate the incidence rate ratio (RR) with 95% confidence intervals (95% CI) for the association between circulating PTH and CRC risk. RESULTS: In multivariate analyses [including adjustment for 25(OH)D concentration] with a priori defined cutoff points, high levels of serum PTH (≥65 ng/L) compared with medium PTH levels of 30-65 ng/L were associated with increased CRC risk (RR = 1.41, 95% CI: 1.03-1.93). In analyses by sex, the CRC risk was 1.77 (95% CI: 1.14-2.75) and 1.15 (95% CI: 0.73-1.84) in men and women, respectively (P(heterogeneity) = 0.01). In subgroup analyses by anatomical subsite, the risk for colon cancer was RR = 1.56, 95% CI: 1.03-2.34, and for rectal cancer RR = 1.20, 95% CI: 0.72-2.01 (P(heterogeneity) = 0.21). Effect modification by various risk factors was examined. CONCLUSIONS: The results of this study suggest that high serum PTH levels may be associated with incident, sporadic CRC in Western European populations, and in particular among men. IMPACT: To our knowledge, this is the first study on PTH and CRC. The role of PTH in carcinogenesis needs to be further investigated.
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| 7. |
- Jenab, Mazda, et al.
(author)
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Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations : a nested case-control study
- 2010
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In: BMJ. British Medical Journal. - : BMJ Publishing Group. - 0959-8146 .- 0959-535X. ; 340, s. b5500-
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. DESIGN: Nested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. PARTICIPANTS: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls MAIN OUTCOME MEASURES: Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. RESULTS: 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. CONCLUSIONS: The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.
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| 10. |
- Tjonneland, Anne, et al.
(author)
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Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2007
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In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 18:4, s. 361-373
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Journal article (peer-reviewed)abstract
- Objective Most epidemiologic studies have suggested an increased risk of breast cancer with increasing alcohol intake. Using data from 274,688 women participating in the European Prospective Investigation into Cancer and Nutrition study (EPIC), we investigated the relation between alcohol intake and the risk of breast cancer. Methods Incidence rate ratios (IRRs) based on Cox proportional hazard models were calculated using reported intake of alcohol, recent (at baseline) and lifetime exposure. We adjusted for known risk factors and stratified according to study center as well as potentially modifying host factors. Results During 6.4 years of follow up, 4,285 invasive cases of breast cancer within the age group 35-75 years were identified. For all countries together the IRR per 10 g/day higher recent alcohol intake (continuous) was 1.03 (95% confidence interval (CI): 1.01-1.05). When adjusted, no association was seen between lifetime alcohol intake and risk of breast cancer. No difference in risk was shown between users and non-users of HRT, and there was no significant interaction between alcohol intake and BMI, HRT or dietary folate. Conclusion This large European study supports previous findings that recent alcohol intake increases the risk of breast cancer.
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