Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

A Linear Relationship between the Number of Cancers among First-degree Relatives and the Risk of Multiple Primary Cancers.

With advances in the early detection and treatment of cancer, the incidence of multiple primary cancers (MPC), or second primary cancers, has risen over time. Characterization of etiologic risk factors, including family history of cancer, within the general population is critical for assessing MPC risk in patients. We examined the association between family history of cancer among first-degree relatives and MPC risk in a prospective study of 139,958 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (95%CI), adjusting for potential confounders. Over a median follow-up of 16 years (interquartile range: 11-19 years), 6,170 participants were diagnosed with MPC. Having a family history of cancer increased the risk of MPC by 18% (HR=1.18, 95%CI: 1.12-1.24). A positive linear trend was observed between the reported number of cancers in the family history and MPC risk with HRs (95%CI) of 1.13 (1.07-1.20), 1.23 (1.14-1.33), 1.29 (1.15-1.45), and 1.42 (1.20-1.70) for 1, 2, 3, and 4+ cancers among first-degree relatives, respectively (Ptrend=2.36x10-13). No significant differences were observed by cancer histology or specific types of cancer reported in the family history. Our study demonstrates that family history of cancer is an important risk factor for the development of multiple primary cancers and that a comprehensive of assessment of the number of cancers reported among first-degree relatives may identify those at higher risk who may benefit from targeted cancer prevention and screening strategies.

A Linear Relationship between the Number of Cancers among First-Degree Relatives and the Risk of Multiple Primary Cancers.

With advances in the early detection and treatment of cancer, the incidence of multiple primary cancers (MPC) or second primary cancers has increased over time. Characterization of etiologic risk factors, including family history of cancer, within the general population is critical for assessing MPC risk in patients. We examined the association between family history of cancer among first-degree relatives and MPC risk in a prospective study of 139,958 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox proportional hazard models were used to calculate HRs and 95% confidence intervals (95% CI), adjusting for potential confounders. Over a median follow-up of 16 years (IQR: 11-19 years), 6,170 participants were diagnosed with MPC. Having a family history of cancer increased the risk of MPC by 18% (HR, 1.18; 95% CI, 1.12-1.24). A positive linear trend was observed between the reported number of cancers in the family history and MPC risk with HRs (95% CI) of 1.13 (1.07-1.20), 1.23 (1.14-1.33), 1.29 (1.15-1.45), and 1.42 (1.20-1.70) for one, two, three, and four or more cancers among first-degree relatives, respectively (Ptrend = 2.36 × 10-13). No significant differences were observed by cancer histology or specific cancer types reported in the family history. Our study demonstrates that the family history of cancer is an important risk factor for the development of MPCs and that a comprehensive assessment of the number of cancers reported among first-degree relatives may identify those at higher risk who may benefit from targeted cancer prevention and screening strategies. Prevention Relevance: Our study makes a substantial contribution to the understanding of risk factors for MPCs in the general population. It demonstrates that individuals with a strong family history of cancer are at higher risk for MPCs and may benefit from more targeted cancer prevention and screening interventions.

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases.

The majority of disease-associated variants identified through genome-wide association studies are located outside of protein-coding regions. Prioritizing candidate regulatory variants and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb ( https://forgedb.cancer.gov/ ; https://forge2.altiusinstitute.org/files/forgedb.html ; and https://doi.org/10.5281/zenodo.10067458 ), a standalone and web-based tool that integrates multiple datasets, delivering information on associated regulatory elements, transcription factor binding sites, and target genes for over 37 million variants. FORGEdb scores provide researchers with a quantitative assessment of the relative importance of each variant for targeted functional experiments.

Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.

BACKGROUND: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION: Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING: The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.

Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.

Background and Aims: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. Methods: SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. Results: In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5x10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1x10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88-positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. Conclusion: SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Glyphosate Use and Mosaic Loss of Chromosome Y among Male Farmers in the Agricultural Health Study.

BACKGROUND: Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce. OBJECTIVES: We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers. METHODS: We analyzed blood-derived DNA from 1,606 farmers ≥50 years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or mLOY affecting ≥10% of cells (expanded mLOY). RESULTS: Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; OR=1.75 (95% CI: 1.00, 3.07), ptrend=0.03] but not with overall mLOY; the associations with expanded mLOY were most apparent among older (≥70 years of age) men [OR=2.30 (95% CI: 1.13, 4.67), ptrend=0.01], never smokers [OR=2.32 (95% CI: 1.04, 5.21), ptrend=0.04], and nonobese men [OR=2.04 (95% CI: 0.99, 4.19), ptrend=0.03]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use. DISCUSSION: High lifetime glyphosate use could be associated with mLOY affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies. https://doi.org/10.1289/EHP12834.

Antinuclear Antibodies Are Associated with an Increased Risk of Diffuse Large B-Cell Lymphoma.

Immune dysregulation is thought to increase the risk of non-Hodgkin lymphoma (NHL), but the evidence varies by subtype. We evaluated whether antinuclear antibodies (ANA), double-stranded DNA antibodies (anti-dsDNA), and extractable nuclear antigen antibodies (anti-ENA) were associated with the risk of common NHL subtypes in a nested case-control study. The autoantibodies were tested in serum collected years prior to NHL diagnosis in 832 cases and 809 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (95% CI) for the association with NHL risk. No association was observed between ANA positivity and NHL risk overall (OR: 1.18, 95% CI: 0.88-1.58); however, ANA positivity was associated with an increased risk of diffuse large B-cell lymphoma (DLBCL) (OR: 1.83, 95% CI: 1.15-2.91), with 19.7% of cases and 12.2% of controls testing positive. The presence of either anti-ENA or anti-dsDNA was associated with an increased risk of NHL (OR: 2.93, 95% CI: 1.18-7.28), particularly DLBCL (OR: 3.51, 95% CI: 1.02-12.0) and marginal zone lymphoma (OR: 8.86, 95% CI: 1.26-62.0). Our study demonstrates that autoantibodies are associated with an elevated risk of DLBCL, providing support for autoimmunity as a risk factor.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Heterogeneous genetic architectures and evolutionary genomics of prostate cancer in Sub-Saharan Africa.

Men of African descent have the highest prostate cancer (CaP) incidence and mortality rates, yet the genetic basis of CaP in African men has been understudied. We used genomic data from 3,963 CaP cases and 3,509 controls recruited in Ghana, Nigeria, Senegal, South Africa, and Uganda, to infer ancestry-specific genetic architectures and fine-mapped disease associations. Fifteen independent associations at 8q24.21, 6q22.1, and 11q13.3 reached genome-wide significance, including four novel associations. Intriguingly, multiple lead SNPs are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of CaP differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African CaP associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer.

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06-1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09-2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer.

Importance: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective: To identify genes associated with aggressive PCa. Design, Setting, and Participants: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.