Sue Ingles

Background Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. Methods We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). Results In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647 …

BackgroundTumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.MethodsWe meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10−8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage …

BackgroundThe association of fitness with cancer risk is not clear.MethodsWe used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.ResultsAfter a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In …

Background: There is a growing body of evidence supporting the contributions of germline rare variants to the susceptibility of prostate cancer (PCa), especially aggressive PCa. Our previous exome sequencing analysis highlighted 36 aggressive PCa candidate genes in populations of European ancestry. Here we investigated whether rare germline pathogenic, likely pathogenic, or deleterious (P/LD/D) variants in these genes were associated with overall and aggressive PCa risk in men of African ancestry. Methods: This exome sequencing analysis consists of 7,176 prostate cancer cases and 4,873 controls from the Research on Prostate Cancer in Men of African Ancestry (RESPOND) study. Among the PCa cases, 3,283 are aggressive cases (tumor stage T3/T4, regional lymph node involvement, metastatic disease, Gleason score >= 8.0, prostate-specific antigen [PSA] level >= 20 ng/mL or PCa as the underlying …

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African …

Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI …

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with inflammation, which is a risk factor for cancer, including prostate cancer. We previously reported weak evidence of an association between CHIP and prostate cancer risk in men of European ancestry. However, little is known for African ancestry populations. We investigated the association of age-related CHIP with overall and aggressive prostate cancer risk in a large whole-exome sequencing study of 12,049 African ancestry men, including 7,176 prostate cancer cases (of which 3,283 had aggressive disease and 1,074 had metastatic disease) and 4,873 controls. Somatic variant calling was carried out using GATK Mutect2, and only variants with minor allele frequencies (MAF) <0.1% and a variant allelic fraction (VAF) >5% were included. Variants with a MAF ≥0.1% in gnomAD were excluded. CHIP variants were identified from a list …

BackgroundGenetic factors play an important role in prostate cancer (PCa) susceptibility.ObjectiveTo discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participantsWe conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry.Outcome measurements and statistical analysisCommon genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitationsNine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate …

The 24th Workshop on Vitamin D was held September 7-9, 2022 in Austin, Texas and covered a wide diversity of research in the vitamin D field from across the globe. Here, we summarize the meeting, individual sessions, awards and presentations given.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel …

5080Background: Biomarkers are needed to predict clinical outcomes in mHSPC. We previously reported that baseline CTC counts in S1216 were prognostic of PSA response and disease progression (ASCO 2020; CCR 2021). However, the trial’s primary overall survival (OS) endpoint was not yet mature at that time. Here we present the final results of S1216 using all available samples to assess the prognostic value of CTC counts for response, progression, OS, and treatment arm interactions. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline) and at progression to metastatic castrate resistant prostate cancer (mCRPC). CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini). CTC counts were evaluated for associations with 3 pre-specified trial endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. > 4.0 using a generalized logit model; and …

Our primary objective is to verify or refute a 2013 study by Connolly et al. which showed that in early pregnancy, a gestational sac was visualized 99% of the time on transvaginal ultrasound when the HCG level reached 3510 mIU/mL. Our secondary objective was to make clinical correlations by assessing the relationship between human chorionic gonadotropin (HCG) level in early pregnancy when a gestational sac is not seen and pregnancy outcomes of live birth, spontaneous abortion, and ectopic pregnancy. This retrospective study includes 144 pregnancies with an outcome of live birth, 87 pregnancies with an outcome of spontaneous abortion, and 59 ectopic pregnancies. Logistic regression is used to determine the probability of visualizing a gestational sac and/or yolk sac based on the HCG level. A gestational sac is predicted to be visualized 50% of the time at an HCG level of 979 mIU/mL, 90% at 2421 mIU …

Background Breast cancer incidence rates in women of Asian descent have been increasing in the United States and Asia. Methods In a case–control study of Asian American women from the San Francisco Bay Area, we assessed associations with birthplace and migration-related characteristics and compared risk factors between Asian American and non-Hispanic White women by birthplace and birth cohort. Results Birthplace and migration-related characteristics were associated with breast cancer risk only among women in the younger birth cohort (1951–1984) that comprised 355 cases diagnosed at age ≤55 years and 276 sister and population controls. Breast cancer risk was marginally increased among foreign-born women [OR = 1.40; 95% confidence interval (CI), 0.97–2.03] and two-fold among foreign-born Chinese women (OR = 2.16; 95% CI, 1 …

Background: Orofacial clefts (OFCs) are common congenital disabilities that can occur as isolated non-syndromic events or as part of Mendelian syndromes. OFC risk factors vary due to differences in regional environmental exposures, genetic variants, and ethnicities. In recent years, significant progress has been made in understanding OFCs, due to advances in sequencing and genotyping technologies. Despite these advances, very little is known about the genetic interplay in the Malagasy population. Methods: Here, we performed high-resolution whole-exome sequencing (WES) on non-syndromic cleft lip with or without palate (nCL/P) trios in the Malagasy population (78 individuals from 26 families (trios)). To integrate the impact of genetic ancestry admixture, we computed both global and local ancestries. Results: Participants demonstrated a high percentage of both African and Asian admixture. We identified damaging variants in primary cilium-mediated pathway genes WNT5B (one family), GPC4 (one family), co-occurrence in MSX1 (five families), WDR11 (one family), and tubulin stabilizer SEPTIN9 (one family). Furthermore, we identified an autosomal homozygous damaging variant in PHGDH (one family) gene that may impact metabiotic activity. Lastly, all variants were predicted to reside on local Asian genetic ancestry admixed alleles. Conclusion: Our results from examining the Malagasy genome provide limited support for the hypothesis that germline variants in primary cilia may be risk factors for nCL/P, and outline the importance of integrating local ancestry components better to understand the multi-ethnic impact on nCL/P.

Our primary objective is to verify or refute a 2013 study by Connolly et al. which showed that in early pregnancy a gestational sac was visualized 99% of the time on transvaginal ultrasound when the HCG level reached 3,510 mIU/mL. Our secondary objective was to make clinical correlations by assessing the relationship between human chorionic gonadotropin (HCG) level in early pregnancy when a gestational sac is not seen with pregnancy outcomes of live birth, spontaneous abortion, and ectopic pregnancy. This retrospective study includes 144 pregnancies with an outcome of live birth, 87 pregnancies with an outcome of spontaneous abortion, and 59 ectopic pregnancies. Logistic regression is used to determine the probability of visualizing a gestational sac and/or yolk sac based on HCG level. A gestational sac is predicted to be visualized 50% of the time at an HCG level of 979 mIU/mL, 90% at 2,421 mIU/mL, and 99% of the time at 3,994 mIU/mL. A yolk sac was predicted to be visualized 50% of the time at an HCG level of 4,626 mIU/mL, 90% at 12,892 mIU/mL, and 99% at 39,454 mIU/mL. 90% of ectopic pregnancies presented with an HCG level below 3,994 mIU/mL. These results are in agreement with the study by Connolly et al. Since most early ectopic pregnancies had an HCG value below the discriminatory level for gestational sac visualization, other methods for evaluation of pregnancy of unknown location such as repeat HCG values are clinically important.

Aims/hypothesisEpidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.MethodsWe developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10−8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary …

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population‐based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity‐specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non‐Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends = .0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association …

Background:Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers.Methods:We examined associations of urinary PAH metabolites with pubertal development in 358 girls 6–16 years of age from the San Francisco Bay Area enrolled in a prospective cohort from 2011 to 2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N= 176) or pubic hair (N= 179) development or menstruation (N= 267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with the onset of breast and pubic hair development, menstruation, and pubertal tempo …

Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study …

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 …