| 1. |
- Wang, Zhaoming, et al.
(författare)
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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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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 6. |
- Sampson, Joshua N., et al.
(författare)
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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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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)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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| 7. |
- 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. |
- Cho, E, et al.
(författare)
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Dairy foods, calcium, and colorectal cancer : A pooled analysis of 10 cohort studies
- 2004
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Ingår i: Journal of the National Cancer Institute. - Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Loma Linda Univ, Ctr Hlth Res, Sch Med, Loma Linda, CA USA. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. Harvard Ctr Canc Prevent, Boston, MA USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. TNO, Nutr & Food Res Inst, Dept Epidemiol, Zeist, Netherlands. Univ Toronto, Fac Med, Dept Publ Hlth Sci, Toronto, ON, Canada. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. NYU, Dept Obstet Gynecol, Sch Med, New York, NY USA. Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. NYU, Sch Med, Nelson Inst Environm Med & Kaplan Canc Ctr, New York, NY USA. : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 96:13, s. 1015-1022
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Tidskriftsartikel (refereegranskat)abstract
- Background. Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive. Methods: We pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. For most studies, follow-up was extended beyond that in the original publication. The studies included 534 536 individuals, among whom 4992 incident cases of colorectal cancer were diagnosed between 6 and 16 years of follow-up. Pooled multivariable relative risks for categories of milk intake and quintiles of calcium intake and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. Results: Milk intake was related to a reduced risk of colorectal cancer. Compared with the lowest category of intake (<70 g/day), relative risks of colorectal cancer for increasing categories (70-174, 175-249, and greater than or equal to250 g/day) of milk intake were 0.94 (95% CI = 0.86 to 1.02), 0.88 (95% CI = 0.81 to 0.96), and 0.85 (95% CI = 0.78 to 0.94), respectively (P-trend<.001). Calcium intake was also inversely related to the risk of colorectal cancer. The relative risk for the highest versus the lowest quintile of intake was 0.86 (95% CI = 0.78 to 0.95; P-trend = .02) for dietary calcium and 0.78 (95% CI = 0.69 to 0.88; P-trend<.001) for total calcium (combining dietary and supplemental sources). These results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon (P-trend<.001) and rectum (P-trend = .02). Conclusion: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer.
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| 9. |
- Genkinger, J M, et al.
(författare)
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A pooled analysis of 12 cohort studies of dietary fat, cholesterol and egg intake and ovarian cancer
- 2006
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Ingår i: Cancer Causes and Control. - Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Harvard Ctr Canc Prevent, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Loma Linda Univ, Sch Med, Ctr Hlth Res, Loma Linda, CA USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. : SPRINGER. - 0957-5243 .- 1573-7225. ; 17:3, s. 273-285
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Tidskriftsartikel (refereegranskat)abstract
- Fat and cholesterol are theorized to promote ovarian carcinogenesis by increasing circulating estrogen levels. Although case-control studies have reported positive associations between total and saturated fat intake and ovarian cancer risk, two cohort studies have observed null associations. Dietary cholesterol and eggs have been positively associated with ovarian cancer risk. A pooled analysis was conducted on 12 cohort studies. Among 523,217 women, 2,132 incident epithelial ovarian cancer cases were identified. Study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Total fat intake was not associated with ovarian cancer risk (pooled multivariate RR = 1.08, 95% CI 0.86-1.34 comparing >= 45 to 30-< 35% of calories). No association was observed for monounsaturated, polyunsaturated, trans-unsaturated, animal and vegetable fat, cholesterol and egg intakes with ovarian cancer risk. A weakly positive, but non-linear association, was observed for saturated fat intake (pooled multivariate RR = 1.29, 95% CI: 1.01-1.66 comparing highest versus lowest decile). Results for histologic subtypes were similar. Overall, fat, cholesterol and egg intakes were not associated with ovarian cancer risk. The positive association for saturated fat intake at very high intakes merits further investigation.
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| 10. |
- Missmer, S A, et al.
(författare)
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Meat and dairy food consumption and breast cancer : a pooled analysis of cohort studies
- 2002
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Ingår i: International Journal of Epidemiology. - Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Loma Linda Univ, Sch Med, Ctr Hlth Res, Loma Linda, CA USA. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. TNO, Nutr & Food Res Inst, Dept Epidemiol, NL-3700 AJ Zeist, Netherlands. Columbia Univ, Teachers Coll, Dept Hlth & Behav Sci, New York, NY 10027 USA. Deutsch Krebsforschungszentrum, Div Clin Epidemiol, D-6900 Heidelberg, Germany. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, New York, NY USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. NYU, Sch Med, Nelson Inst Environm Med, New York, NY USA. Harvard Ctr Canc Prevent, Boston, MA USA. : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 31:1, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- Background More than 20 studies have investigated the relation between meat and dairy food consumption and breast cancer risk with conflicting results. Our objective was to evaluate the risk of breast cancer associated with meat and dairy food consumption and to assess whether non-dietary risk factors modify the relation. Methods We combined the primary data from eight prospective cohort studies from North America and Western Europe with at least 200 incident breast cancer cases, assessment of usual food and nutrient intakes, and a validation study of the dietary assessment instrument. The pooled database included 351 041 women, 7379 of whom were diagnosed with invasive breast cancer during up to 15 years of follow-up. Results We found no significant association between intakes of total meat, red meat, white meat, total dairy fluids, or total dairy solids and breast cancer risk. Categorical analyses suggested a J-shaped association for egg consumption where, compared to women who did not eat eggs, breast cancer risk was slightly decreased among women who consumed <2 eggs per week but slightly increased among women who consumed greater than or equal to1 egg per day. Conclusions We found no significant associations between intake of meat or dairy products and risk of breast cancer. An inconsistent relation between egg consumption and risk of breast cancer merits further investigation.
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