ORCID Profile
0000-0002-9603-0110
Current Organisations
University of California, Irvine
,
University of St Andrews
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 10-10-2022
DOI: 10.1093/JNCI/DJAC160
Abstract: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types. We identified statistically significant risk associations with CNVs at known EOC risk genes BRCA1 (PEOC = 1.60E-21 OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4 odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4 ORHGSOC = 3.31 deletion). Four suggestive associations (P & .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P & .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2020
DOI: 10.1101/2020.11.30.20219220
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to in idual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry 7,669 women of East Asian ancestry 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Publisher: Wiley
Date: 05-11-2017
DOI: 10.1111/PCMR.12653
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 20-01-2019
DOI: 10.1002/IJC.32029
Publisher: Oxford University Press (OUP)
Date: 07-08-2021
DOI: 10.1093/JNCI/DJAA099
Abstract: Parity is associated with decreased risk of invasive ovarian cancer however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large s le sizes, were also evaluated. A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend & .001). An inverse association was observed for all major histotypes it was strongest for clear cell ovarian cancer. Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.
Publisher: Oxford University Press (OUP)
Date: 02-05-2020
DOI: 10.1093/JNCI/DJAA056
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by in idual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Publisher: Oxford University Press (OUP)
Date: 26-07-2023
Abstract: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine three common haplotypes Gc1s, Gc1f, and Gc2. Gc1f may be associated with decreased all-cause death among melanoma patients, based on results of a prior study, but its association with melanoma-specific death is unclear. We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4,490 in iduals with incident, invasive primary melanoma in two population-based studies using multivariable Cox-proportional hazards regression. In the pooled analysis of both datasets, those with the Gc1f haplotype had a 37% lower risk of melanoma-specific death compared to those without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = 0.001) adjusting for age, sex, study center, first or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those with the Gc1f haplotype compared to those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumors ≤2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumors & .0 mm (Pinteraction= 0.003). Our findings suggest that in iduals with the GC haplotype Gc1f may have a lower risk of dying from melanoma—specifically from thicker, higher-risk melanoma—compared to those without Gc1f.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2022
DOI: 10.1200/JCO.21.01900
Abstract: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, in idual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by in idual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity .05), including women with ≥ 2 risk factors (relative risk, 0.81 95% CI, 0.73 to 0.90). This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.
Publisher: Oxford University Press (OUP)
Date: 23-01-2023
DOI: 10.1093/JNCI/DJAD011
Abstract: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). In idual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.
Publisher: Elsevier BV
Date: 04-2020
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Hoda Anton-Culver.