| 1. |
- Wang, Xiaoliang, et al.
(författare)
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Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 x 10(-8) as genome-wide significant, and p-values < 1 x 10(-5) as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 x 10(5). The strongest evidence was found for rs4674019 (p-value = 2.27 x 10(-7)), which showed genome-wide significant interaction (p-value = 3.8 x 10(-8)) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.
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| 2. |
- Chou, Alisha, et al.
(författare)
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Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population : Stability over Time and Comparison with Polygenic Risk Score
- 2022
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 31:12, s. 2199-2207
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer (PCa) development that may help to risk-stratify men earlier in life.METHODS: We examined PSA levels in men measured up to 10+ years before a PCa diagnosis in association with PCa risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for PCa.RESULTS: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a PCa OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared to men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 vs. 8+ disease. At 10+ years, the association of PCa with PSA was comparable to that with the PRS (OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively).CONCLUSIONS: We found PSA to be an informative marker of PCa risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable to a PRS when measured 10+ years before diagnosis.IMPACT: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in PCa screening practices.
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| 3. |
- Watts, Eleanor L., et al.
(författare)
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Circulating free testosterone and risk of aggressive prostate cancer : Prospective and Mendelian randomisation analyses in international consortia
- 2022
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:7, s. 1033-1046
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
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