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The overall survival rate of prostate cancer (PCa) has improved over the past decades. However, huge socioeconomic and racial disparities in overall and prostate cancer-specific mortality exist. The neighborhood-level factors including socioeconomic disadvantage and lack of access to care may contribute to disparities in cancer mortality. This study examines the impact of neighborhood deprivation on mortality among PCa survivors.North Carolina-Louisiana Prostate Cancer Project (PCaP) data were used. A total of 2113 men, 1046 AA and 1067 EA, with PCa were included in the analysis. Neighborhood deprivation was measured by the Area Deprivation Index (ADI) at the census block group level using data from the US Census Bureau. Quintiles of ADI were created. Cox proportional hazards and competing risk models with mixed effects were performed to estimate the effect of neighborhood deprivation on all-cause and PCa-specific mortality adjusted for age, race, study site, insurance status, and comorbidities.Participants living in the most deprived neighborhoods had an increased risk for all-cause mortality (quintiles 4 + 5: adjusted hazard ratio [aHR] = 1.51, 95% confidence interval [CI] = 1.16-1.96) compared to those in the least deprived (quintile 1) neighborhoods. The risk of prostate cancer-specific mortality was also higher among those living in the deprived neighborhoods (quintiles 4 + 5: aHR = 1.90, 95% CI = 1.10-3.50) than those in the least deprived neighborhood.The findings suggest neighborhood-level resources or health interventions are essential to improve survival among men with PCa. Additional research should focus on the mechanisms of how the neighborhood environment affects mortality.

Patient and clinical characteristics of Caucasian and African American statin users and non-users.

Supplementary Table S1. Associations of Overall Breast Cancer Risk with 74 Breast Cancer Risk Variants in African Americans with Study-specific Results.

Supplemental Figure 2. The association between smoking and ESR1-defined breast cancer subtypes.

Background: Gene expression analyses indicate that breast cancer is a heterogeneous disease with at least five immunohistologic subtypes. Despite growing evidence that these subtypes are etiologically and prognostically distinct, few studies have investigated whether they have divergent genetic risk factors. To help fill in this gap in our understanding, we examined associations between breast cancer subtypes and previously established susceptibility loci among white and African-American women in the Carolina Breast Cancer Study.Methods: We used Bayesian polytomous logistic regression to estimate ORs and 95% posterior intervals for the association between each of 78 single nucleotide polymorphisms (SNP) and five breast cancer subtypes. Subtypes were defined using five immunohistochemical markers: estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptors 1 and 2 (HER1/2), and cytokeratin (CK) 5/6.Results: Several SNPs in TNRC9/TOX3 were associated with luminal A (ER/PR+, HER2−) or basal-like breast cancer (ER−, PR−, HER2−, HER1, or CK 5/6+), and one SNP (rs3104746) was associated with both. SNPs in FGFR2 were associated with luminal A, luminal B (ER/PR+, HER2+), or HER2+/ER− disease, but none were associated with basal-like disease. We also observed subtype differences in the effects of SNPs in 2q35, 4p, TLR1, MAP3K1, ESR1, CDKN2A/B, ANKRD16, and ZM1Z1.Conclusion and Impact: We found evidence that genetic risk factors for breast cancer vary by subtype and further clarified the role of several key susceptibility genes. Cancer Epidemiol Biomarkers Prev; 23(1); 84–97. ©2013 AACR.

Supplementary Figure S1, Supplementary Figure S1. Regional plots of 3p24, 11q13, 12p11, 14q13, 16q12/TOX3, 16q12/FTO, 16q23, and 19p13.

List of Disease and Phenotype Associations used to Generate list of GWAS genes used to prioritize immune pathways

Logistic regression analysis of associations between statin use and prostate cancer aggressiveness, additionally adjusted for education, income and family history of prostate cancer.

Background: Cigarette smoking is associated with increased head and neck cancer (HNC) risk. Tobacco-related carcinogens are known to cause bulky DNA adducts. Nucleotide excision repair (NER) genes encode enzymes that remove adducts and may be independently associated with HNC, as well as modifiers of the association between smoking and HNC.Methods: Using population-based case–control data from the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study (1,227 cases and 1,325 controls), race-stratified (White, African American), conventional, and hierarchical logistic regression models were used to estimate ORs with 95% intervals (I) for the independent and joint effects of cigarette smoking and 84 single-nucleotide polymorphisms (SNP) from 15 NER genes on HNC risk.Results: The odds of HNC were elevated among ever cigarette smokers and increased with smoking duration and frequency. Among Whites, rs4150403 on ERCC3 was associated with increased HNC odds (AA+AG vs. GG; OR, 1.28; 95% CI, 1.01–1.61). Among African Americans, rs4253132 on ERCC6 was associated with decreased HNC odds (CC+CT vs. TT; OR, 0.62; 95% CI, 0.45–0.86). Interactions between ever cigarette smoking and three SNPs (rs4253132 on ERCC6, rs2291120 on DDB2, and rs744154 on ERCC4) suggested possible departures from additivity among Whites.Conclusions: We did not find associations between some previously studied NER variants and HNC. We did identify new associations between two SNPs and HNC and three suggestive cigarette–SNP interactions to consider in future studies.Impact: We conducted one of the most comprehensive evaluations of NER variants, identifying a few SNPs from biologically plausible candidate genes associated with HNC and possibly interacting with cigarette smoking. Cancer Epidemiol Biomarkers Prev; 22(8); 1428–45. ©2013 AACR.

Supplemental Figure 3. The association between smoking and LS-defined breast cancer subtypes.

Description of Study Populations in AMBER Consortium

PDF file - 147K, Betweeen SNP correlation tables (Tables S1a-S1f), Effect Estimates from race-stratified analysis (Tables S2 and S3), Effect estimates from maximum likelihood analysis (Table S4) and Effect estimates from Bayes sensitivity analysis (Table S5)

Supplementary Fig Leg

Immune-related genes found to be associated with breast cancer in AMBER

Background: Although statin use has been associated with reduced prostate cancer aggressiveness, the impact of race and patient characteristics on this association is not well understood. We examined the association between statin use and prostate cancer aggressiveness in Caucasians (CA) and African Americans (AA) and explored effect modification by health-seeking behaviors associated with statin use.Methods: Of 1,930 cases from The North Carolina-Louisiana Prostate Cancer Project, 344 (18%) were classified as aggressive based on clinical criteria. Utilizing nonaggressive cases as referent, logistic regression was used to examine the association between statin use and prostate cancer aggressiveness, overall and stratified by race. Smoking and prostate cancer screening were examined as effect modifiers of this association.Results: There was an inverse association between statin use and prostate cancer aggressiveness [OR, 0.74; 95% confidence interval (CI), 0.56–0.96], with comparable effect estimates in both races. Although not statistically significant, statin use was associated with reduced ORs for aggressive prostate cancer in never-screened men (OR, 0.79; 95% CI, 0.45–1.39), men screened at low/recommended frequency (≤once/year; OR, 0.66; 95% CI, 0.41–1.06), and men screened at high frequency (>once/year; OR, 0.78; 95% CI, 0.53–1.15). Inverse associations between statins and aggressive prostate cancer were strongest in never smokers (OR, 0.42; 95% CI, 0.25–0.72), attenuated in former smokers (OR, 0.84; 95% CI, 0.59–1.19), and absent in current smokers (OR, 1.36; 95% CI, 0.70–2.64).Conclusions: Statin use was associated with reduced prostate cancer aggressiveness in CA and AAs, with strongest inverse associations in nonsmokers.Impact: Health-seeking behaviors associated with statin use should be considered when examining the impact of statins on prostate cancer aggressiveness. Cancer Epidemiol Biomarkers Prev; 25(4); 670–7. ©2016 AACR.

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Supplemental Figure 1. The association between smoking and ER-defined breast cancer subtypes.

PDF file - 195K, Table 1S. Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes Inclusion and Exclusion Criteria, Carolina Head and Neck Cancer Epidemiology (CHANCE) Study.: Table 2S. Odds Ratios for Environmental Tobacco Smoke and Head and Neck Cancer in the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study.: Table 3S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in ERCC3 and Head and Neck Cancer Tumor Sites Using Hierarchical Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 4S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in ERCC6 Genes and Laryngeal Cancer Using Hierarchical Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, African Americans.: Table 5S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Head and Neck Cancer Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 6S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Head and Neck Cancer Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, African Americans.: Table 7S. Odds Ratios and Relative Excess Risk Due to Interaction Estimates for Joint Effects of Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Former/Current Cigarette Smoking on Head and Neck Cancer Risk Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 8S. Odds Ratios and Relative Excess Risk Due to Interaction Estimates for Joint Effects of Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Ever Environmental Tobacco Smoke on Head and Neck Cancer Risk Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.

Background: Smoking is a possible risk factor for breast cancer and has been linked to increased risk of estrogen receptor–positive (ER+) disease in some epidemiologic studies. It is unknown whether smoking has quantitative effects on ER expression.Methods: We examined relationships between smoking and ER expression from tumors of 1,888 women diagnosed with invasive breast cancer from a population-based study in North Carolina. ER expression was characterized using binary (±) and continuous measures for ER protein, ESR1 mRNA, and a multigene luminal score (LS) that serves as a measure of estrogen signaling in breast tumors. We used logistic and linear regression models to estimate temporal and dose-dependent associations between smoking and ER measures.Results: The odds of ER+, ESR1+, and LS+ tumors among current smokers (at the time of diagnosis), those who smoked 20 or more years, and those who smoked within 5 years of diagnosis were nearly double those of nonsmokers. Quantitative levels of ESR1 were highest among current smokers compared with never smokers overall [mean (log2) = 9.2 vs. 8.7, P < 0.05] and among ER+ cases; however, we did not observe associations between smoking measures and continuous ER protein expression.Conclusions: In relationship to breast cancer diagnosis, recent smoking was associated with higher odds of the ER+, ESR1+, and LS+ subtype. Current smoking was associated with elevated ESR1 mRNA levels and an elevated LS, but not with altered ER protein.Impact: A multigene LS and single-gene ESR1 mRNA may capture tumor changes associated with smoking. Cancer Epidemiol Biomarkers Prev; 27(1); 67–74. ©2017 AACR.

Supplemental Figure Legends

Logistic regression analysis of associations between statin use and prostate cancer aggressiveness, excluding men using non-statin cholesterol-lowering drugs.

Supplemental Table 1. Estimated biomarker expression values for the effect of categorical smoking measures among all cases; Supplemental Table 2. Estimated biomarker expression values for the effect of categorical smoking measures among ER+ cases.

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016–26. ©2017 AACR.

Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women.Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants.Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER− cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79–0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER− disease. The only genes showing heterogeneity between ER− and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders.Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER− breast cancers.Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321–30. ©2018 AACR.

Background: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study’s objective is to evaluate SNP–SNP interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. Methods: We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). Both individual SNP effects and pairwise SNP–SNP interactions were analyzed. Results: None of the 11 individual polymorphisms were significant for EAs and AAs. Three SNP–SNP interaction pairs can predict PCa aggressiveness with a medium to large effect size. For the EA PCa patients, the interaction between rs1801133 (MTHFR) and rs2236225 (MTHFD1), and rs1801131 (MTHFR) and rs7587117 (SLC4A5) were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. Conclusions: These SNP–SNP interactions in the folate metabolism-related genes have a larger impact than SNP individual effects on tumor aggressiveness for EA and AA PCa patients. These findings can provide valuable information for potential biological mechanisms of PCa aggressiveness.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common 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 limitations: Nine 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-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Patients with advanced cancer and minor children experience high rates of depression and anxiety. However, associations between parental status and other aspects of the patient experience are not well understood. This study compared patient-reported outcomes of patients with and without minor children.This was a retrospective analysis of 448 adults with stage III or IV solid tumors from a public research registry.Multiple linear regression models or modified Poisson regression models were fitted to evaluate differences in health-related quality of life, global health, and patient satisfaction scores between patients living with and without minors.One in five patients lived with minor children. They reported significantly worse health-related quality of life, global physical health, and global mental health. They also expressed lower satisfaction with time spent with their provider, communication, and financial aspects.Patients with minor children may benefit from earlier identification and support for their psychosocial needs and concerns.

Clinical research studies have navigated many changes throughout the COVID-19 pandemic. We sought to describe the pandemic's impact on research operations in the context of a clinical genomics research consortium that aimed to enroll a majority of participants from underrepresented populations. We interviewed (July to November 2020) and surveyed (May to August 2021) representatives of six projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, which studies the implementation of genome sequencing in the clinical care of patients from populations that are underrepresented in genomics research or are medically underserved. Questions focused on COVID's impact on participant recruitment, enrollment, and engagement, and the transition to teleresearch. Responses were combined and thematically analyzed. Projects described factors at the project, institutional, and community levels that affected their experiences. Project factors included the project's progress at the pandemic's onset, the urgency of in-person clinical care for the disease being studied, and the degree to which teleresearch procedures were already incorporated. Institutional and community factors included institutional guidance for research and clinical care and the burden of COVID on the local community. Overall, being responsive to community experiences and values was essential to how CSER navigated evolving challenges during the COVID-19 pandemic.

Long-term population-based cohort studies of men diagnosed with prostate cancer are limited. However, adverse outcomes can occur many years after treatment. Herein, we aim to assess the utility of using claims data to identify prostate cancer progression 10-15 years after diagnosis.The study population was derived from the North Carolina-Louisiana Prostate Cancer Project (PCaP). PCaP-North Carolina (NC) included 1031 men diagnosed with prostate cancer from 2004 to 2009. An initial follow-up with a survey and manual medical record abstraction occurred from 2008 to 2011 (Follow-up 1). Herein, we extended this follow-up with linkage to healthcare claims data from North Carolina (2011-2017) and a second, supplementary 10-year follow-up survey (2018-2020) (Follow-up 2). Vital statistics data also were utilized. Long-term oncological progression was determined using these data sources in combination with expert clinical input.Among the 1031 baseline PCaP-NC participants, 652 were linked to medical claims. Forty-two percent of the men had insurance coverage for the entire 72 months of follow-up. In addition, 275 baseline participants completed the supplementary 10-year follow-up survey. Using all sources of follow-up data, we identified a progression event in 259 of 1031 (25%) men with more than 10 years of follow-up data after diagnosis.Understanding long-term clinical outcomes is essential for improving the lives of prostate cancer survivors. However, access and utility of long-term clinical outcomes with claims alone remain a challenge due to individualized agreements required with each insurer for data access, lack of detailed clinical information, and gaps in insurance coverage. We were able to utilize claims data to determine long-term progression due to several unique advantages that included the availability of detailed baseline clinical characteristics and treatments, detailed manually abstracted clinical data at 5 years of follow-up, vital statistics data, and a supplementary 10-year follow-up survey.

Financial toxicity (FT) is a growing concern among cancer survivors that adversely affects the quality of life and survival. Individuals diagnosed with aggressive cancers are often at a greater risk of experiencing FT. The objectives of this study were to estimate FT among prostate cancer (PCa) survivors after 10-15 years of diagnosis, assess the relationship between PCa aggressiveness at diagnosis and FT, and examine whether current cancer treatment status mediates the relationship between PCa aggressiveness and FT.PCa patients enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP) were recontacted for long-term follow-up. The prevalence of FT in the PCaP cohort was estimated. FT was estimated using the COmprehensive Score for Financial Toxicity, a validated measure of FT. The direct effect of PCa aggressiveness and an indirect effect through current cancer treatment on FT was examined using causal mediation analysis.More than one-third of PCa patients reported experiencing FT. PCa aggressiveness was significantly independently associated with high FT; high aggressive PCa at diagnosis had more than twice the risk of experiencing FT than those with low or intermediate aggressive PCa (adjusted odds ratio [aOR] = 2.13, 95% CI = 1.14-3.96). The proportion of the effect of PCa aggressiveness on FT, mediated by treatment status, was 10%, however, the adjusted odds ratio did not indicate significant evidence of mediation by treatment status (aOR = 1.05, 95% CI = 0.95-1.20).Aggressive PCa was associated with high FT. Future studies should collect more information about the characteristics of men with high FT and identify additional risk factors of FT.

To assess the prevalence and predictors of mental health disorders (MDHs) among head and neck squamous cell carcinoma (HNSCC) survivors, and the association with health-related quality of life (HRQOL), pain, and survival outcomes.This was a retrospective, cross-sectional study of HNSCC survivors surveyed at an outpatient oncology clinic from May 2012 through July 2016.Among 198 HNSCC survivors, 21% reported a MHD. Female sex (OR 6.60, 95% CI 2.08 to 20.98; p = 0.001) and Medicare insurance status (OR 4.95, 95% CI 1.52 to 16.11; p = 0.008) were significant predictors of reporting a MHD in the fully adjusted model. Patients reporting a MHD reported significantly worse pain (p 0001) and worse HRQOL on the PROMIS Physical (p 0.001), PROMIS Mental (p 0.001), and FACT-GP (p 0.026) questionnaires. Diagnosis of a MHD was not correlated with 5-year OS (74% vs. 84%; p = 0.087).Initiatives for early identification and intervention of MHDs as part of survivorship initiatives may engender clinically meaningful outcomes in head and neck cancer.

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) 5% were included. Variants with a MAF ≥0.1% in gnomAD were excluded. CHIP variants were identified from a list of pre-specified mutations in 74 genes. Associations were tested using regression models adjusting for age, sub-study, and top 10 principal components, with statistical significance tested by the likelihood ratio test and applying a Bonferroni correction to account for multiple testing. In total, 998 variants in 57 CHIP genes were identified. Consistent with previous results, we observed a strong association between CHIP and age at blood draw. CHIP genes in aggregate were not statistically significantly associated with risks of total (OR=1.12, 95% CI=0.97-1.28), aggressive (OR=1.14, 95% CI=0.92-1.43) or metastatic (OR=1.17, 95% CI=0.91-1.49) prostate cancer. We observed that carriers of variants in DNMT3A, which is the gene that harbors the most CHIP driver mutations, had a nominally elevated risk of prostate cancer compared to non-carriers (OR=1.35, 95% CI=1.08-1.68, p=0.007). Additionally, carriers of variants in EZH2, which is implicated in cancer progression, showed a suggestive association with aggressive prostate cancer (OR=7.33, 95% CI=1.01-53.21, p=0.029). After adjusting for age at blood draw, CHIP genes in aggregate were not associated with age at prostate cancer diagnosis. However, we found that EZH2 variants carriers were diagnosed 12.9 years earlier on average than non-carriers (95% CI=6.1-19.7, adjusted p=0.01). A prostate cancer polygenic risk score (PRS) constructed using 269 risk variants was not associated with CHIP carrier status in aggregate (OR=0.99, 95% CI=0.92-1.06, p=0.70) or with any individual gene (all adjusted p>0.05). In summary, overall CHIP is not likely to be a risk factor of prostate cancer or aggressive disease in men of African ancestry. However, our results do confirm the association of CHIP in DNMT3A with prostate cancer risk as reported in previous studies in men of European ancestry. Future work will be needed to evaluate the biological causality of DNMT3A- and EZH2- related CHIP on prostate cancer. Citation Format: Anqi Wang, Yili Xu, Xin Sheng, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W. Fernandez, Akin Olupelumi Adebiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, 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, Adam de Smith, Fei Chen, Burcu F. Darst, David V. Conti, Christopher A. Haiman. Association between clonal hematopoiesis and risk of prostate cancer in a large sample of African ancestry men [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 3508.

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.

To better understand health care utilization and develop decision support tools, methods for identifying patients with suspected genetic diseases (GDs) are needed. Previous studies had identified inpatient-relevant International Classification of Diseases (ICD) codes that were possibly, probably, or definitely indicative of GDs. We assessed whether these codes identified GD-related inpatient, outpatient, and emergency department encounters among pediatric patients with suspected GDs from a previous study (the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing [NCGENES] study).Using the electronic medical records of 140 pediatric patients from the NCGENES study, we characterized the presence of ICD codes representing possible, probable, or definite GD-related diagnoses across encounter types. In addition, we examined codes from encounters for which initially no GD-related codes had been found and determined whether these codes were indicative of a GD.Among NCGENES patients with visits between 2014 and 2017, 92% of inpatient, 75% of emergency department, and 63% of outpatient encounters included ≥1 GD-related code. Encounters with highly specific (ie, definite) GD codes had fewer low-specificity GD codes than encounters with only low-specificity GD codes. We identified an additional 32 ICD-9 and 56 ICD-10 codes possibly indicative of a GD.Code-based strategies can be refined to assess health care utilization among pediatric patients and may contribute to a systematic approach to identify patients with suspected GDs.

Objective: Results of studies examining the association between intake of meat or fish and prostate cancer have been mixed. However, few of the previous studies have included a racially diverse population or focused on aggressive prostate cancer. We aimed to examine the association between intake of meat and fish and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project, a case-only study of Black and White men in the United States. Methods: Meat and fish intakes in the year prior to diagnosis were estimated using an interviewer-administered modified version of the National Cancer Institute Diet History Questionnaire in 909 Black and 991 White men with a recent histologically confirmed diagnosis of prostate cancer. High aggressive prostate cancer (n=332) was defined as Gleason sum ≥8, or PSA> 20ng/ml, or Gleason sum ≥7 AND clinical stage T3-T4, and the comparison group was all other prostate cancer cases (n=1,568). Logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (95% CI) for high aggressive prostate cancer by tertile of meat and fish intake variables, with adjustment for age, energy intake, race, study site, education, family history of prostate cancer, prostate cancer screening history, Charlson comorbidity index, NSAIDs use, smoking status, alcohol intake, and intake of vegetables, fruits, and milk. Results: We observed increased odds of aggressive prostate cancer among men in the second tertile compared to the first tertile for total red meat (OR:1.23. 95% CI: 0.91 – 1.68) and unprocessed red meat (OR:1.30. 95% CI: 0.96 – 1.76), though confidence intervals were imprecise and associations in the top tertile were weaker. For processed meat, a non-statistically significant increased odds of aggressive prostate cancer was observed among men in the third tertile compared to the first tertile (OR:1.27. 95% CI: 0.91 – 1.78). ORs for higher intake of fish and poultry were in the inverse direction but were weak and not statistically significant. Conclusions: In this racially diverse case-only study, we observed weak positive associations between red and processed meat and aggressive prostate cancer, and little evidence of an association with fish or poultry intake. While high temperature cooking and charring of meat is known to increase carcinogen formation, one limitation of our study was the lack of information on cooking methods or doneness of the meat consumed. Additional research is warranted among racially diverse populations that considers cooking methods and doneness preferences. Citation Format: Jessica Sainyo, Susan E. Steck, L. Joseph Su, Lenore Arab, Jeannette T. Bensen, Elizabeth T.H. Fontham, James L. Mohler. Associations between meat and fish intake and aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP). [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P035.