| 1. |
- Teras, Lauren R., et al.
(author)
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Body size and multiple myeloma mortality : a pooled analysis of 20 prospective studies
- 2014
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In: British Journal of Haematology. - : WILEY-BLACKWELL. - 0007-1048 .- 1365-2141. ; 166:5, s. 667-676
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Journal article (peer-reviewed)abstract
- Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1.5 million participants (including 1388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR = 1.22, 95% CI: 1.09-1.35 per 5 kg/m(2)) and for higher cohort-entry BMI (HR 1.09, 95% CI: 1.03-1.16 per 5 kg/m(2)) and waist circumference (HR = 1.06, 95% CI: 1.02-1.10 per 5 cm). In analyses of the joint effect of young adult and baseline BMI, women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18.5 = 25 at both time points (HR = 1.95, 95% CI: 1.33-2.86) but there was no significant association in men. Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
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| 2. |
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| 3. |
- Adams, Charleen, et al.
(author)
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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
- 2019
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216
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Journal article (peer-reviewed)abstract
- BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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| 4. |
- Matejcic, Marco, et al.
(author)
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Germline variation at 8q24 and prostate cancer risk in men of European ancestry
- 2018
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10(-15)), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95% CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for similar to 25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
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| 5. |
- Gaudet, Mia M, et al.
(author)
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Pooled Analysis of Nine Cohorts Reveals Breast Cancer Risk Factors by Tumor Molecular Subtype.
- 2018
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:20, s. 6011-6021
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Journal article (peer-reviewed)abstract
- Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A–like (ER+ or PR+/HER2−), 1,368 luminal B–like (ER+ or PR+/HER2+), 521 HER2-enriched (ER−/PR−/HER2+), and 1,152 triple-negative (ER−/PR−/HER2−) disease. Ever parous compared with never was associated with lower risk of luminal A–like (HR, 0.78; 95% CI, 0.73–0.83) and luminal B–like (HR, 0.74; 95% CI, 0.64–0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02–1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A–like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011–21. ©2018 AACR..
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| 6. |
- Conti, David, V, et al.
(author)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Journal article (peer-reviewed)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 7. |
- Bull, Caroline J., et al.
(author)
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Adiposity, metabolites, and colorectal cancer risk : Mendelian randomization study
- 2020
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In: BMC Medicine. - : BMC. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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| 8. |
- Zhang, Xuehong, et al.
(author)
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Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status : a pooled analysis of 18 prospective cohort studies
- 2012
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In: American Journal of Clinical Nutrition. - : OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 95:3, s. 713-725
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Journal article (peer-reviewed)abstract
- Background: Epidemiologic studies examining associations between carotenoid intakes and risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR) status are limited. Objective: We investigated these associations in a pooled analysis of 18 cohort studies. Design: Of 1,028,438 participants followed for a maximum follow-up of 26 y across studies, 33,380 incident invasive breast cancers were identified. Study-specific RRs and 95% CIs were estimated by using Cox proportional hazards regression and then pooled by using a random-effects model. Results: alpha-Carotene, beta-carotene, and lutein/zeaxanthin intakes were inversely associated with the risk of ER-negative (ER-) breast cancer (pooled multivariable RRs of the comparison between the highest and lowest quintiles): alpha-carotene (0.87; 95% CI: 0.78, 0.97), beta-carotene (0.84; 95% CI: 0.77, 0.93), and lutein/zeaxanthin (0.87; 95% CI: 0.79, 0.95). These variables were not inversely associated with the risk of ER-positive (ER+) breast cancer (pooled multivariable RRs for the same comparison): a-carotene (1.04; 95% CI: 0.99, 1.09), beta-carotene (1.04; 95% CI: 0.98, 1.10), and lutein/zeaxanthin (1.00; 95% CI: 0.93, 1.07). Although the pooled RRs for quintile 5 for beta-cryptoxanthin were not significant, inverse trends were observed for ER- and ER+ breast cancer (P-trend <= 0.05). Nonsignificant associations were observed for lycopene intake. The associations were largely not appreciably modified by several breast cancer risk factors. Nonsignificant associations were observed for PR-positive and PR-negative breast cancer. Conclusions: Intakes of alpha-carotene, beta-carotene, and lutein/zeaxanthin were inversely associated with risk of ER-, but not ER+, breast cancer. However, the results need to be interpreted with caution because it is unclear whether the observed association is real or due to other constituents in the same food sources. Am J Clin Nutr 2012;95:713-25.
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| 9. |
- Fortner, Renée T., et al.
(author)
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Ovarian cancer risk factors by tumor aggressiveness : An analysis from the Ovarian Cancer Cohort Consortium
- 2019
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:1, s. 58-69
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Journal article (peer-reviewed)abstract
- Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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| 10. |
- Gaudet, Mia M., et al.
(author)
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Anthropometry and head and neck cancer : a pooled analysis of cohort data
- 2015
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In: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 44:2, s. 673-681
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Journal article (peer-reviewed)abstract
- Background: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies. Methods: We pooled data from 1 941 300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status. Results: Greater waist circumference (per 5cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers. Conclusions: Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
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