Background:Risk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa. Methods:PRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRSPSA). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis. Results:In the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.061.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation. Conclusions:Among men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.

Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102 . Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

BACKGROUND:Although suspected to alter child development, exposure to glycol ethers (GEs) is widespread in the general population and remains insufficiently characterised, especially given their short half-lives. OBJECTIVE:We investigated the variability of urinary concentrations of GE metabolites in pregnant women using different sampling methods. METHODS:Thirty pregnant women were enroled by medical professional around Rennes, France. They completed questionnaires and underwent a repeated urine sampling protocol to collect all urine voids for one day and then two consecutive days, several weeks apart. We then measured the concentrations of nine GE metabolites in three pooled 24-h samples and three first morning void samples per woman, and all individual samples collected over two days (N = 530). We assessed the temporal variability of urinary GE metabolite concentrations for six sampling methods, calculating intraclass correlation coefficients (ICCs), using mixed-effects models with random effects for each day and participant. RESULTS:The highest ICC ( > 0.75) was observed for sampling methods involving the collection of one or three random urine voids within a day for 2-methoxyproprionic acid (2-MPA), and for the first morning void for both 2-MPA and phenoxyacetic acid (PhAA). For other GE metabolites, none of the sampling methods seemed to offer good enough reproducibility, with ICC < 0.63. SIGNIFICANCE:Among the methods assessed, FMV seemed to provide the best balance between reproducibility for PhAA and 2-MPA. For other metabolites, no sampling method seemed to provide sufficient reproducibility. IMPACT:Perinatal health concerns have been reported in association with exposure to glycol ethers (GEs). Reproducible methods for measuring GE exposure in pregnant women are therefore required. Metabolite-specific sampling strategies may be appropriate to investigate exposure-response associations.

Research question Does maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy affect reproductive hormone levels in adult sons? Design We analyzed data from a cross-sectional study of 2,326 Swiss conscripts collected between 2005 and 2017. At inclusion, the conscripts’ mothers completed a detailed questionnaire about their pregnancy. A job-exposure matrix was used to assess exposure to 10 categories of potential EDCs. Reproductive hormones, such as FSH, LH, total and free testosterone, estradiol and SHBG, were determined in serum samples from all conscripts whose mothers were exposed to EDCs during pregnancy (n=138) and a random sample of non-exposed conscripts (n=276). Multiple linear regression analyses were adjusted for potential confounders. Results Prenatal exposure to phthalates or alkyl phenolic compounds was significantly associated with higher FSH levels (aβ = 0.26; 95% CI = 0.03-0.49, and aβ = 0.22; 95% CI = 0.02-0.42, respectively) and prenatal exposure to pesticides was significantly associated with higher SHBG levels (aβ = 0.22; 95% CI = 0.05-0.38). No statistically significant associations were found between other EDC categories and reproductive hormones. Conclusion Maternal occupational exposure to certain types of EDCs during pregnancy was associated with the levels of reproductive hormones in adult sons. These findings require replication in larger, prospective population studies.

Chlordecone (CLD) is an organochlorine pesticide with various toxicities, widely used from 1972 to 1993 in the French West Indies lands (FWI, Guadeloupe and Martinique). It can remain in environment leading to indoor contamination by pollutants coming from outside. Therefore, investigating indoor pollutants is necessary due to the potential indoor dust ingestion though hand-to-mouth contact, in particular for children. No chemical analytical method measures CLD in indoor dust and we propose to investigate its presence in this specific compartment, in Martinique. CLD was analyzed from dust samples taken from homes and schools (n = 47). We extracted CLD from dust with pressure liquid extraction (PLE) using a suitable mixture solvent of hexane and ethyl acetate (85:15). This was followed with gas chromatography coupled to tandem spectrometry (GC/MS/MS) analysis. A sampled mass of 25 mg was optimal for analysis. Concentrations of CLD in indoor dust varied from < 16-247 ng/g. Exposure to CLD through indoor dust ingestion was also assessed and does not exceed 1.5 % and 0.1 %, of the acceptable daily intake, in children and adults, respectively. However, this exploratory study was conducted on a very limited number of dust samples limiting the generalization to the whole French West Indies population.

Chlordecone is a persistent organochlorine insecticide that was widely used to control banana root borer in the French West Indies until 1993. Animal studies have reported an impact of chlordecone exposure on female fertility, but no data are available for humans. Here, we investigated the association between chlordecone exposure in women and time to pregnancy (TTP). We included 668 pregnant women from the Timoun mother-child cohort study performed in Guadeloupe between 2004 and 2007. TTP was measured with a questionnaire at the inclusion visit. Chlordecone concentrations in maternal blood samples were determined at the time of delivery. A discrete-time Cox model was used to estimate fecundability odds ratios (fOR) and their 95

RESEARCH QUESTION:Does maternal occupational exposure to endocrine-disrupting chemicals (EDC) during pregnancy affect reproductive hormone concentrations in adult sons? DESIGN:Data from a cross-sectional study of 2326 Swiss conscripts collected between 2005 and 2017 were analysed. On inclusion, the conscripts' mothers completed a detailed questionnaire about their pregnancy. A job-exposure matrix was used to assess exposure to 10 categories of potential EDC. Reproductive hormones - FSH, LH, total and free testosterone, oestradiol and sex hormone-binding globulin (SHBG) - were determined in serum samples from all conscripts whose mothers were exposed to EDC during pregnancy (n = 138) and a random sample of non-exposed conscripts (n = 276). Multiple linear regression analyses were adjusted for potential confounders. RESULTS:Prenatal exposure to phthalates or alkyl phenolic compounds was significantly associated with higher FSH concentrations (aβ = 0.26, 95% CI 0.03-0.49, and aβ = 0.22, 95% CI 0.02-0.42, respectively) and prenatal exposure to pesticides was significantly associated with higher SHBG concentrations (aβ = 0.22, 95% CI 0.05-0.38). No statistically significant associations were found between other EDC categories and reproductive hormones. CONCLUSIONS:Maternal occupational exposure to certain types of EDC during pregnancy was associated with the concentrations of reproductive hormones in adult sons. These findings require replication in larger, prospective population studies.

OBJECTIVE:To describe cause-specific mortality patterns of banana plantation workers in the French West Indies. METHODS:The study included 11 221 farmers and farm workers who had work in banana cultivation in the French West Indies (Guadeloupe or Martinique) between 1973 and 1993, followed up from January 1981 to December 2017. We calculated standardised mortality ratios (SMRs), causal mortality ratios (CMRs) and relative standardised mortality ratios (rSMRs) using regional reference rates. RESULTS:SMR analyses showed mortality deficits in the overall mortality and for almost all causes of deaths. In contrast, analyses using CMRs revealed a significant excess in the overall mortality. The CMRs were significantly elevated for all cancers combined and for stomach cancer, colorectal cancer, prostate cancer and haematopoietic malignancies, as well as for several non-cancer causes of death, including diabetes mellitus, Parkinson's disease, Alzheimer's disease, non-ischaemic heart diseases, pneumonia and diseases of the skin and subcutaneous tissue. rSMRs were in general consistent with CMRs with regards to the direction of the association, although rSMRs were lower and in some instances not statistically significant. CONCLUSION:The CMR approach showed an elevated mortality for several causes of death, for which work in banana farming and/or exposure to pesticides are plausible explanations.

BACKGROUND AND OBJECTIVE:The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry. METHODS:We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based on family history, polygenic risk score (PRS), and PV carrier status. KEY FINDINGS AND LIMITATIONS:PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were presented in 4% of aggressive/metastatic PCa cases and were significantly associated with an increased risk of aggressive PCa (odds ratio 2.18-5.96, p < 0.05). Lifetime absolute risk varied widely depending on PV carrier status, PRS, and family history, ranging from 3.0% to 74% for overall PCa, 0.6% to 41% for aggressive PCa, and 0.2% to 37% for metastatic PCa. PV carriers with a positive family history and a PRS in the 90th percentile had seven, 18, and 34 times the risks of overall, aggressive, and metastatic PCa, respectively, compared with average-risk individuals. Oversampling of aggressive cases may limit the generalizability of these findings to screening populations. CONCLUSIONS AND CLINICAL IMPLICATIONS:Integration of PV status, PRS, and family history enables more refined PCa risk estimates. The wide range of PCa risk observed among men of African ancestry in our study supports future prospective studies in the development of risk-stratified cancer screening programs to identify high-risk individuals who may benefit from screening at an earlier age.

Background and Aims Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. Methods This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. Results With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. Conclusion According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. Trial registration ClinicalTrials.gov Identifier: NCT03373396.

Background: Hypospadias is a male genital tract defect for which an increase in prevalence has been documented over the last few decades. A role for environmental risk factors is suspected, including prenatal exposure to pesticides. Objectives: To study the risk of hypospadias in association with multiple pesticide measurements in meconium samples. Methods: The Brittany Registry of Congenital Anomalies (France) conducted a case–control study between 2012 and 2018. Cases were hypospadias, ascertained by a pediatrician and a pediatric surgeon, excluding genetic conditions, following European Surveillance of Congenital Anomalies guidelines (N = 69). Controls (N = 135) were two male infants without congenital anomaly born after each case in the same maternity unit. Mothers in the maternity units completed a self-administered questionnaire, we collected medical data from hospital records, and medical staff collected meconium samples. We performed chemical analysis of 38 pesticides (parent compound and/or metabolite) by UHPLC/MS/MS following strict quality assurance/quality control criteria and blind to case–control status. We carried out logistic regression accounting for frequency-matching variables and major risk factors. Results: Among the 38 pesticides measured, 16 (42%) were never detected in the meconium samples, 18 (47%) were in <5% of samples, and 4 (11%) in ≥5% of the samples. We observed an association between the detection of fenitrothion in meconium and the risk of hypospadias (OR = 2.6 [1.0–6.3] with n cases = 13, n controls = 21), but not the other pesticides. Conclusions: Our small study provides a robust assessment of fetal exposure. Fenitrothion’s established antiandrogenic activities provide biologic plausibility for our observations. Further studies are needed to confirm this hypothesis.

Background: As healthcare moves from a one-size-fits-all approach towards precision care, individual risk prediction is an important step in disease prevention and early detection. Biobank-linked healthcare systems can generate knowledge about genomic risk and test the impact of implementing that knowledge in care. Risk-stratified prostate cancer screening is one clinical application that might benefit from such an approach. Methods: We developed a clinical translation pipeline for genomics-informed prostate cancer screening in a national healthcare system. We used data from 585,418 male participants of the Veterans Affairs (VA) Million Veteran Program (MVP), among whom 101,920 self-identify as Black/African-American, to develop and validate the Prostate CAncer integrated Risk Evaluation (P-CARE) model, a prostate cancer risk prediction model based on a polygenic score, family history, and genetic principal components. The model was externally validated in data from 18,457 PRACTICAL Consortium participants. A novel blended genome-exome (BGE) platform was used to develop a clinical laboratory assay for both the P-CARE model and rare variants in prostate cancer-associated genes, including additional validation in 74,331 samples from the All of Us Research Program. Results: In overall and ancestry-stratified analyses, the polygenic score of 601 variants was associated with any, metastatic, and fatal prostate cancer in MVP and PRACTICAL. Values of the P-CARE model at ≥80th percentile in the multiancestry cohort overall were associated with hazard ratios (HR) of 2.75 (95% CI 2.66-2.84), 2.78 (95% CI 2.54-2.99), and 2.59 (95% CI 2.22-2.97) for any, metastatic, and fatal prostate cancer in MVP, respectively, compared to the median. When high- and low-risk groups were defined as P-CARE HR>1.5 and HR<0.75 for metastatic prostate cancer, the 220,062 (37.6%) high-risk vs.146,826 (25.1%) low-risk participants in MVP had a 47.9% vs. 14.1%, 9.3% vs. 2.0%, and 3.6% vs. 0.8% cumulative cause-specific incidence of any, metastatic, and fatal prostate cancer by age 90, respectively. The clinical assay and reports are now being implemented in a clinical trial of precision prostate cancer screening in the VA healthcare system (Clinicaltrials.gov [NCT05926102][1]). Conclusions: A model consisting of a polygenic score, family history, and genetic principal components describes a clinically important gradient of prostate cancer risk in a diverse patient population and demonstrates the potential of learning health systems to implement and evaluate precision health care approaches. ### Competing Interest Statement N.L. has received speaking honoraria from Illumina Inc and is an advisory board member for FYR Diagnostics and Everygene. N.L has received research collaborative funding (for work unrelated to this publication) from Illumina Inc and PacBio Inc. JAL, KML, and CTC report grants from Alnylam Pharmaceuticals, Inc., Astellas Pharma, Inc., AstraZeneca Pharmaceuticals LP, Biodesix, Inc, Celgene Corporation, Cerner Enviza, GSK PLC, IQVIA Inc., Janssen Pharmaceuticals, Inc., Novartis International AG, Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. ASK reports fundings (for work unrelated to this publication) from Janssen, Pfizer, Profound, Bristol Myers Squibb, and Merck. SLD reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma, and Alnylam Pharmaceuticals. RAE reports speaking honoraria from GU-ASCO, Janssen, University of Chicago, and Dana Farber Cancer Institute, educational honorarium from Bayer and Ipsen, being a member of external expert committee to Astra Zeneca UK and Member of Active Surveillance Movember Committee and is a member of the SAB of Our Future Health; additionally undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. LAM reports research funding from Astra Zeneca to Harvard University; she holds equity in Convergent Therapeutics. TMS reports honoraria from Varian Medical Systems, WebMD, GE Healthcare, and Janssen; he has an equity interest in CorTechs Labs, Inc. and serves on its Scientific Advisory Board; he receives research funding from GE Healthcare through the University of California San Diego. These companies might potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. The other authors have no disclosures. ### Funding Statement This work was funded by the Million Veteran Program MVP022 award #I01CX001727 (PI: RLH) and MVP084 award #I01CX002635 (PI: JLV). See Supplement for additional funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Veterans Affairs Central Institutional Review Board approved this study (IRBNet 1735869 and 1735136). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes It is not possible for the authors to directly share the individual-level data that were obtained from the Million Veteran Program (MVP) due to constraints stipulated in the informed consent. Anyone wishing to gain access to this data should inquire directly to MVP at MVPLOI@va.gov. The data generated from our analyses are included in the manuscript. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05926102&atom=%2Fmedrxiv%2Fearly%2F2024%2F11%2F04%2F2024.11.03.24316516.atom

Periodically, the French West Indies receive dust originating from North Africa (NA). Microorganisms associated with desert dust can be transported over long distances through the atmosphere and could represent a means for the remote colonization of new habitats by putatively pathogenic microorganisms. The aim of this study was to determine the diversity and frequency of microbial agents (bacteria, eukaryotes) in NA dusts and the potential threat toward human and/or animal health by comparing microbial air composition during dust events and in control samples. In 2017 and 2018, 16 samples were collected during seven NA dust episodes and there were 9 controls. The microbial composition of the samples was characterized using a cultivable approach and by metabarcoding analyses (16S and 18S). A greater bacterial load and greater diversity were observed during the dust events, and some genera were significantly associated with the events. Some, such as Geodermatophilus, can be considered signature species of NA dust. No pathogenic species were found with the cultivable approach, whereas the metabarcoding analyses highlighted the presence of several potentially pathogenic species or known human pathogens such as Naegleria fowleri.

BACKGROUND:The cardiotoxicity of prenatal exposure to mercury has been suggested in populations having regular contaminated seafood intake, though replications in the literature are inconsistent. METHODS:The Timoun Mother-Child Cohort Study was set up in Guadeloupe, an island in the Caribbean Sea where seafood consumption is regular. At seven years of age, 592 children underwent a medical examination, including cardiac function assessment. Blood pressure (BP) was taken using an automated blood pressure monitor, heart rate variability (HRV, 9 parameters) and electrocardiogram (ECG) characteristics (QT, T-wave parameters) were measured using Holter cardiac monitoring during the examination. Total mercury concentrations were measured in cord blood at birth (median = 6.6 μg/L, N = 399) and in the children's blood at age 7 (median = 1.7 μg/L, N = 310). Adjusted linear and non-linear modelling was used to study the association of each cardiac parameter with prenatal and childhood exposures. Sensitivity analyses included co-exposures to lead and cadmium, adjustment for maternal seafood consumption, selenium and polyunsaturated fatty acids (n3-PUFAs), and for sporting activity. RESULTS:Higher prenatal mercury was associated with higher systolic BP at 7 years of age (βlog2 = 1.02; 95% Confidence Interval (CI) = 0.10, 1.19). In boys, intermediate prenatal exposure was associated with reduced overall HRV and parasympathetic activity, and longer QT was observed with increasing prenatal mercury (βlog2 = 4.02; CI = 0.48, 7.56). In girls, HRV tended to increase linearly with prenatal exposure, and no association was observed with QT-wave related parameters. Mercury exposure at 7 years was associated with decreased BP in girls (βlog2 = -1.13; CI = -2.22, -0.004 for diastolic BP). In boys, the low/high-frequency (LF/HF) ratio increased for intermediate levels of exposure. CONCLUSION:Our study suggests sex-specific and non-monotonic modifications in some cardiac health parameters following prenatal exposure to mercury in pre-pubertal children from an insular fish-consuming population.

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 cause of death) including 1,074 metastatic cases, and 1,752 are non-aggressive cases (Gleason score ⇐ 7.0, PSA < 20 ng/mL, and tumor stage T1/T2). P/LP/D variants analyzed were rare (minor allele frequency < 1% in controls) and had either a Variant Effect Predictor impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. The association between P/LP/D carrier status with risk of overall PCa, aggressive PCa, and metastatic PCa was evaluated in logistic regression models, adjusting for age and the top ten principal components. All statistical tests are two-sided. Results: Of the 36 PCa candidate genes, BRCA2 was the most frequently affected gene, with 1.7% of cases and 1.1% of controls harboring a germline P/LP/D variant, followed by MUTYH (1.5%/1.3%) ATM (0.93%/0.49%), MSH5 (0.70%/0.51%) and HOXB13 (0.70%/0.35%). Nominally significant associations with overall PCa were observed for ATM (OR=1.83, 95% CI=1.14-2.92, P=0.012), BRCA2 (OR=1.52, 95% CI=1.10-2.10, P=0.011), HOXB13 (OR=2.10, 95% CI=1.12-3.66, P=0.008), and PALB2 (OR=3.46, 95% CI=1.18-10.1, P=0.02). In case-case analyses (aggressive vs. non-aggressive cases), the association with aggressive PCa was nominally significant for ATM (OR=5.10, 95% CI=1.96-13.3, P=8.7 × 10−4) and BRCA2 (OR=2.00, 95% CI=1.19-3.38, P=0.009) and was suggestive for PALB2 (OR=2.99, 95% CI=0.83-10.7, P=0.09). Similar associations with metastatic PCa were also observed for these three genes. Conclusion: The associations of BRCA2, ATM, and PALB2 with overall PCa and aggressive PCa observed in men of African ancestry are consistent with findings from our previous study in men of European ancestry. These findings further support the importance of these genes in the consideration of screening and active surveillance for high-risk and advanced disease. Citation Format: Fei Chen, Burcu F. Darst, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A. Adjei, James Mensah, Pedro W. Fernandez, Akindele O. Adebiyi, Oseremen Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, David V. Conti, Christopher A. Haiman. Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1182.

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 prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Background Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys. Objective To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe. Methods We examined 576 children from the TIMOUN mother–child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children’s blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child’s mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex. Results Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children’s blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls. Conclusions These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.