Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers.

To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at > 60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.

The role of community outreach and engagement in evaluation of NCI Cancer Center Support Grants.

PURPOSE: National Cancer Institute (NCI)-designated cancer centers are required to consider their impact on the catchment area they serve. These activities are facilitated by community outreach and engagement (COE) activities as specified in the Cancer Center Support Grant (CCSG) request for applications. While the critical importance of COE activities to NCI-designated cancer centers is well known, it is less clear what impact the COE component has on the overall CCSG merit descriptor and score. METHODS: We undertook an online survey of all 62 NCI-designated Comprehensive and Clinical centers who reported their COE merit descriptor and overall CCSG priority score as of Fall 2021. RESULTS: Of 48 (77%) of responding centers, we identified a strong correlation between the COE merit descriptor and the overall numerical CCSG score received by the center (Spearman's rank correlation coefficient r = 0.360, p = 0.0053). When stratifying this relationship by center type, we observed a very strong correlation between COE and CCSG ratings for comprehensive cancer centers (n = 40; r = 0.544; p = 0.0003) but not for non-comprehensive cancer centers (n = 8; r = 0.073; p = 0.864). CONCLUSION: COE component merit descriptors for comprehensive cancer center CCSG evaluations are strongly correlated with the overall cancer center review score.

Prostate-specific antigen testing rates in high-risk populations: results from the All of Us Research Program.

BACKGROUND: Early detection of prostate cancer using prostate-specific antigen (PSA) remains controversial and disparities in the receipt of prostate cancer screening persist in the US. We sought to examine disparities in PSA testing rates among groups with higher prostate cancer risk and differential access to healthcare. METHODS: We identified a cohort of 37,706 males within the All of Us Research Program without a history of prostate cancer between the ages of 40 and 85 at time of enrollment (2017-2021). Incidence rate ratios (IRR) for the number of PSA tests received during follow-up through December 2021 were estimated using age- and multivariable-adjusted negative binomial regression models. PSA testing frequencies in the cohort were compared with population-based estimates from the 2020 Behavioral Risk Factor Surveillance System (BRFSS). RESULTS: A total of 6,486 males (17.2%) received at least one PSA test over the course of follow-up. In multivariable-adjusted models, non-Hispanic Black males received PSA tests at a 17% lower rate (IRR = 0.83, 95% CI 0.76, 0.90) than non-Hispanic White males. Higher educational attainment, higher annual income, having self-/employer-purchased insurance, having a spouse or domestic partner, and having a family history of prostate cancer were all associated with higher rates of PSA testing. The proportion of males ages 55 to 69 who received a PSA test within two years was lower in All of Us (12.4%, 95% CI 11.8-13.0%) relative to population-based estimates from the BRFSS (35.2%, 95% CI 34.2-36.3%). CONCLUSION: Absolute PSA testing rates in All of Us were lower than population-based estimates, but associations with PSA testing in the cohort mirrored previously reported disparities in prostate cancer screening. These findings highlight the importance of addressing barriers to care in order to reduce disparities in cancer screening.

Associations Between Neighborhood-Level Income and Triple-Negative Breast Cancer in a Majority-Minority Population.

BACKGROUND: Previous studies on disparities in triple-negative breast cancer (TNBC) focus on race/ethnicity, with few exploring the impact of contextual factors such as neighborhood-level income. This study evaluates the effect of neighborhood-level income on disparities in TNBC among a racially and ethnically diverse cohort, after accounting for granular individual-level risk factors of TNBC. PATIENTS AND METHODS: Patients with stage I-IV breast cancer from 2005 to 2017 were identified from our local tumor registry. The primary outcome was diagnosis of TNBC. Using 5-years estimates from the American Community Survey, we obtained median household income for each census tract which was categorized into quartiles. Mixed effects logistic regression was conducted and stratified by race and ethnicity, controlling for individual-level sociodemographic, comorbidities, and tumor characteristics. RESULTS: Among 5377 breast cancer registry patients, 16.5% were diagnosed with TNBC. The majority were Hispanic (50.1%) followed by non-Hispanic Black (NHB) (28.0%). After controlling for individual-level covariables including race and ethnicity, comorbidities, and tumor characteristics, women from low-income neighborhoods had increased odds of TNBC compared with other breast cancer subtypes, compared with those in high-income neighborhoods [odds ratio (OR) 1.33; 95% confidence interval (CI) 1.04, 1.70, p < 0.001]. In stratified analyses, NHB patients from low-income neighborhoods had two times the odds of TNBC diagnosis compared with those from high-income neighborhoods (OR 2.11; 95% CI 1.02, 4.37). CONCLUSION: We found that living in a low-income neighborhood is associated with an increased odds of TNBC independent of granular individual-level TNBC risk factors, particularly NHB race. More striking, NHB living in low-income neighborhoods had increased odds of TNBC compared with NHB living in high-income neighborhoods. Our results suggest potential unaccounted gene-environment and/or social (api)genomic interactions between neighborhood-level income and TNBC subtype development.

Global viewpoints: updates on prostate cancer in Sub-Saharan Africa.

Prostate cancer (PCa) is a major health concern in Sub-Saharan Africa (SSA), with high incidence and mortality rates. However, the widely used prostate-specific antigen (PSA) screening is not readily available or affordable in SSA. Alternative screening strategies, such as risk stratification approaches and cost-effective PSA tests, are being explored to target high-risk individuals and improve access to screening. Diagnosis of PCa in SSA is challenging due to the lack of access to diagnostic tools and limited healthcare resources. Clinical evaluation and digital rectal examination are commonly used, but PSA testing, magnetic resonance imaging, and biopsy are often limited. As a result, many men in SSA are diagnosed at advanced stages of the disease. Treatment options for PCa in SSA are often limited by a lack of resources and trained healthcare providers. Surgery, radiation therapy, and androgen-deprivation therapy are available but may be inaccessible to many patients. Cultural beliefs and stigma surrounding PCa further impact treatment decisions. Improved patient and community awareness, electronic medical records, and communication between patients and healthcare professionals can enhance evidence-based decision-making and advocate for policy changes. Understanding the genetic determinants and implementing comprehensive strategies can lead to improved outcomes and better control of PCa in SSA.

Influence of Neighborhood Social and Natural Environment on Prostate Tumor Histology in a Cohort of Male Health Professionals.

Adverse neighborhood social and natural (green space) environments may contribute to the etiology of prostate cancer (CaP), but mechanisms are unclear. We examined associations between neighborhood environment and prostate intratumoral inflammation in 967 men diagnosed with CaP with available tissue samples from 1986-2009 in the Health Professionals Follow-up Study. Exposures were linked to work or residential addresses in 1988. We estimated indices of neighborhood socioeconomic status (nSES) and segregation (Index of Concentration at the Extremes (ICE)) using US Census tract-level data. Surrounding greenness was estimated using seasonal averaged Normalized Difference Vegetation Index (NDVI) data. Surgical tissue underwent pathological review for acute and chronic inflammation, corpora amylacea, and focal atrophic lesions. Adjusted odds ratios (aORs) for inflammation (ordinal) and focal atrophy (binary) were estimated using logistic regression. No associations were observed for acute or chronic inflammation. Each interquartile-range increase in NDVI within 1,230 m of the participant's work or home address (aOR = 0.74, 95% confidence interval (CI): 0.59, 0.93), in ICE-income (aOR = 0.79, 95% CI: 0.61, 1.04), and in ICE-race/income (aOR = 0.79, 95% CI: 0.63, 0.99) was associated with lower odds of postatrophic hyperplasia. Interquartile-range increases in nSES (aOR = 0.76, 95% CI: 0.57, 1.02) and ICE-race/income (aOR = 0.73, 95% CI: 0.54, 0.99) were associated with lower odds of tumor corpora amylacea. Histopathological inflammatory features of prostate tumors may be influenced by neighborhood.

Risk factors for endometrial cancer in Black women.

PURPOSE: The incidence of endometrial cancer (EC) has been increasing faster among Black women than among other racial/ethnic groups in the United States. Although the mortality rate is nearly twice as high among Black than White women, there is a paucity of literature on risk factors for EC among Black women, particularly regarding menopausal hormone use and severe obesity. METHODS: We pooled questionnaire data on 811 EC cases and 3,124 controls from eight studies with data on self-identified Black women (4 case-control and 4 cohort studies). We analyzed cohort studies as nested case-control studies with up to 4 controls selected per case. We used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We observed a positive association between BMI and EC incidence (Ptrend < 0.0001) The OR comparing BMI ≥ 40 vs. < 25 kg/m2 was 3.92 (95% CI 2.91, 5.27). Abdominal obesity among those with BMI < 30 kg/m2 was not appreciably associated with EC risk (OR 1.21, 95% CI 0.74, 1.99). Associations of reproductive history with EC were similar to those observed in studies of White women. Long-term use of estrogen-only menopausal hormones was associated with an increased risk of EC (≥ 5 years vs. never use: OR 2.08, 95% CI: 1.06, 4.06). CONCLUSIONS: Our results suggest that the associations of established risk factors with EC are similar between Black and White women. Other explanations, such as differences in the prevalence of known risk factors or previously unidentified risk factors likely underlie the recent increases in EC incidence among Black women.

Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry.

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.

Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Current and projected number of years of life lost due to prostate cancer: A global study.

BACKGROUND: Prostate cancer is an important cause of death worldwide. The number of years of life lost (YLL) due to prostate cancer is a metric of the toll of prostate cancer and using projections of demographic changes, can be used to measure future burden. METHODS: Prostate cancer mortality data by country and world region was retrieved from the Global Cancer Observatory and the World Health Organization mortality data set, and life expectancy was from the United Nations Department of Economic and Social Affairs. We estimated YLL as the difference between age at death in people with prostate cancer and remaining life expectancy for people of the same age in the general population. We also estimated the age-standardized YLL rates per 100,000 males over 50 and the average annual percentage change in YLL rates over the period 2000-2019 and the number of YLL for the year 2040 by applying population projections to the 2020 YLL rates. RESULTS: In 2020, 3.5 million person-years of life were lost due to prostate cancer in males over 50, and 40% of YLL were in those aged over 75. Age-standardized rates varied greatly between and within regions. Over the last two decades, rates of YLL have increased in many Asian and African countries while they have decreased in northern American and European countries. Globally, YLL are anticipated to double by 2040 to reach 7.5 million, with the greatest increases in Africa, Asia, and Latin America and the Caribbean. CONCLUSION: There are wide variations in the burden of prostate cancer globally as measured by YLL. The burden of prostate cancer is projected to increase over time and appears to be highest in Sub-Saharan Africa, Eastern Europe, and Latin America and the Caribbean. It will be critical to plan and implement programs to reduce the burden of prostate cancer globally.

Gaps in completion and timeliness of breast surgery and adjuvant therapy: a retrospective cohort of Haitian patients with nonmetastatic breast cancer.

BACKGROUND: There are limited data on breast surgery completion rates and prevalence of care-continuum delays in breast cancer treatment programs in low-income countries. METHODS: This study analyzes treatment data in a retrospective cohort of 312 female patients with non-metastatic breast cancer in Haiti. Descriptive statistics were used to summarize patient characteristics; treatments received; and treatment delays of > 12 weeks. Multivariate logistic regressions were performed to identify factors associated with receiving surgery and with treatment delays. Exploratory multivariate survival analysis examined the association between surgery delays and disease-free survival (DFS). RESULTS: Of 312 patients, 249 (80%) completed breast surgery. The odds ratio (OR) for surgery completion for urban vs. rural dwellers was 2.15 (95% confidence interval [CI]: 1.19-3.88) and for those with locally advanced vs. early-stage disease was 0.34 (95%CI: 0.16-0.73). Among the 223 patients with evaluable surgery completion timelines, 96 (43%) experienced delays. Of the 221 patients eligible for adjuvant chemotherapy, 141 (64%) received adjuvant chemotherapy, 66 of whom (47%) experienced delays in chemotherapy initiation. Presentation in the later years of the cohort (2015-2016) was associated with lower rates of surgery completion (75% vs. 85%) and with delays in adjuvant chemotherapy initiation (OR [95%CI]: 3.25 [1.50-7.06]). Exploratory analysis revealed no association between surgical delays and DFS. CONCLUSION: While majority of patients obtained curative-intent surgery, nearly half experienced delays in surgery and adjuvant chemotherapy initiation. Although our study was not powered to identify an association between surgical delays and DFS, these delays may negatively impact long-term outcomes.

Proceedings of the fifth international Molecular Pathological Epidemiology (MPE) meeting.

Cancer heterogeneities hold the key to a deeper understanding of cancer etiology and progression and the discovery of more precise cancer therapy. Modern pathological and molecular technologies offer a powerful set of tools to profile tumor heterogeneities at multiple levels in large patient populations, from DNA to RNA, protein and epigenetics, and from tumor tissues to tumor microenvironment and liquid biopsy. When coupled with well-validated epidemiologic methodology and well-characterized epidemiologic resources, the rich tumor pathological and molecular tumor information provide new research opportunities at an unprecedented breadth and depth. This is the research space where Molecular Pathological Epidemiology (MPE) emerged over a decade ago and has been thriving since then. As a truly multidisciplinary field, MPE embraces collaborations from diverse fields including epidemiology, pathology, immunology, genetics, biostatistics, bioinformatics, and data science. Since first convened in 2013, the International MPE Meeting series has grown into a dynamic and dedicated platform for experts from these disciplines to communicate novel findings, discuss new research opportunities and challenges, build professional networks, and educate the next-generation scientists. Herein, we share the proceedings of the Fifth International MPE meeting, held virtually online, on May 24 and 25, 2021. The meeting consisted of 21 presentations organized into the three main themes, which were recent integrative MPE studies, novel cancer profiling technologies, and new statistical and data science approaches. Looking forward to the near future, the meeting attendees anticipated continuous expansion and fruition of MPE research in many research fronts, particularly immune-epidemiology, mutational signatures, liquid biopsy, and health disparities.

Overall and central obesity and prostate cancer risk in African men.

PURPOSE: African men are disproportionately affected by prostate cancer (PCa). Given the increasing prevalence of obesity in Africa, and its association with aggressive PCa in other populations, we examined the relationship of overall and central obesity with risks of total and aggressive PCa among African men. METHODS: Between 2016 and 2020, we recruited 2,200 PCa cases and 1,985 age-matched controls into a multi-center, hospital-based case-control study in Senegal, Ghana, Nigeria, and South Africa. Participants completed an epidemiologic questionnaire, and anthropometric factors were measured at clinic visit. Multivariable logistic regression was used to examine associations of overall and central obesity with PCa risk, measured by body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), respectively. RESULTS: Among controls 16.4% were obese (BMI ≥ 30 kg/m2), 26% and 90% had WC > 97 cm and WHR > 0.9, respectively. Cases with aggressive PCa had lower BMI/obesity in comparison to both controls and cases with less aggressive PCa, suggesting weight loss related to cancer. Overall obesity (odds ratio: OR = 1.38, 95% CI 0.99-1.93), and central obesity (WC > 97 cm: OR = 1.60, 95% CI 1.10-2.33; and WHtR > 0.59: OR = 1.68, 95% CI 1.24-2.29) were positively associated with D'Amico intermediate-risk PCa, but not with risks of total or high-risk PCa. Associations were more pronounced in West versus South Africa, but these differences were not statistically significant. DISCUSSION: The high prevalence of overall and central obesity in African men and their association with intermediate-risk PCa represent an emerging public health concern in Africa. Large cohort studies are needed to better clarify the role of obesity and PCa in various African populations.

Prostate Cancer Screening, Diagnostic, Treatment Procedures and Costs in Sub-Saharan Africa: A Situational Analysis.

PURPOSE: Prostate cancer mortality is predicted to nearly double by 2040 in Sub-Saharan Africa (SSA). The lack of prostate cancer screening in SSA contributes to late-stage diagnosis, treatment delays, and poor survival among patients. We analyzed the availability and use of prostate cancer screening, diagnostic and treatment guidelines, procedures, and costs in few SSA countries to determine factors for consideration in the development of prostate cancer screening guidelines for SSA. METHODS: We applied mixed methods approaches to collect data through an electronic survey administered to clinicians (oncologists, urologists, pathologists, nurses, and radiation oncologists) providing prostate cancer screening, diagnosis, and treatment services in multiple sub-Saharan countries. RESULTS: Inconsistencies in respondents' understanding of the availability and use of prostate cancer screening guidelines in their countries were noted. Prostate Specific Antigen (PSA) and Digital Rectal Examination (DRE) were the most commonly available screening modalities. Available diagnostic procedures included a combination of prostate biopsies, transrectal ultrasonography, and DRE. Our study's data suggest that PSA and DRE exams are available for early diagnosis and screening procedures. Availability of treatment modalities with curative intent and costs for prostate cancer related procedures varied between and within countries. CONCLUSIONS: PSA and DRE are available for detecting prostate cancer and may detect aggressive cancers early, leading to improved outcomes. However, PSA screening is also associated with overdiagnosis and over-treatment. National prostate cancer policies should consider health systems, evidence-based guidelines, population characteristics and healthcare financing to ensure access to clinically relevant and safe prostate cancer related care.

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

BACKGROUND: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERGnegative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied. METHODS: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections. RESULTS: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERGnegative 81.4% vs. ERGpositive 18.6%; p = .005) and EAM (ERGnegative 60.4% vs. ERGpositive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERGnegative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERGnegative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC). CONCLUSIONS: ERGnegative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.

Prostate tumors of native men from West Africa show biologically distinct pathways-A comparative genomic study.

BACKGROUND: Native African men (NAM) experience a disproportionate burden of prostate cancer (PCa) and have higher mortality rates compared to European American men (EAM). While socioeconomic status has been implicated as a driver of this disparity, little is known about the genomic mechanisms and distinct biological pathways that are associated with PCa of native men of African origin. METHODS: To understand biological factors that contribute to this disparity we utilized a total of 406 multi-institutional localized PCa samples, collected by Men of African Descent and Carcinoma of the Prostate biospecimen network and Moffitt Cancer Center/University of Pennsylvania Health science system. We performed comparative genomics and immunohistochemistry to identify the biomarkers that are highly enriched in NAM from west Africa and compared them with African American Men (AAM) and EAM. Quantified messenger RNA expression and Median H scores based on immune reactivity of staining cells, were compared using Mann Whitney test. For gene expression analysis, p values were further adjusted for multiple comparisons using false discovery rates. RESULTS: Immunohistochemical analysis on selected biomarkers showed a consistent association between ETS related gene (ERG) status and race with 83% of NAM exhibiting tumors that lacked TMPRSS2-ERG translocation (ERGnegative ) as compared to AAM (71%) and EAM (52%). A higher proportion of NAM (29%) were also found to be double negative (ERGnegative and PTENLoss ) as compared to AAM (6%) and EAM (7%). NAM tumors had significantly higher immunoreactivity (H-score) for PSMA, and EZH2, whereas they have lower H-score for PTEN, MYC, AR, RB and Racemase, (all p < .05). Comparative genomics revealed that NAM had significant transcriptomic variability in AR-activity score. In pathways enrichment analysis NAM tumors exhibited the enrichment of proinflammatory pathways including cytokine, interleukins, inflammatory response, and nuclear factor kappa B signaling. CONCLUSIONS: Prostate tumors in NAM are genomically distinct and are characterized by the dysregulation of several biomarkers. Furthermore, these tumors are also highly enriched for the major proinflammatory pathways. These distinct biological features may have implications for diagnosis and response to targeted therapy among Black men, globally.

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

Trends in mortality among Black and White men with prostate cancer in Massachusetts and Pennsylvania: Race and neighborhood socioeconomic position.

BACKGROUND: Reducing disparities in men with prostate cancer (PCa) that may be caused by racial and socioeconomic differences is a major public health priority. Few reports have studied whether these disparities have changed over time. METHODS: Men diagnosed with PCa from January 1, 2000 to December 31, 2015 were identified from the Massachusetts and Pennsylvania cancer registries. All-cause mortality and PCa and cardiovascular cause-specific mortality were assessed. To estimate neighborhood socioeconomic position (nSEP), a summary score was generated using census tract-level measures of income, wealth, educational attainment, and racial and income segregation. Participants were grouped by diagnosis year (2000-2003, 2004-2007, 2008-2011, or 2012-2015), and changing trends in the mortality rate ratio by race and nSEP were estimated using covariate-adjusted Cox models with follow-up for up to 10 years, until death, or until censoring on January 1, 2018. RESULTS: There were 193,883 patients with PCa and 43,661 deaths over 1,404,131 person-years of follow-up. The Black-White adjusted hazard ratio (aHR) from 2000 to 2003 through 2012 to 2015 was stable for all-cause mortality (aHR, 1.14 to 0.97; P for heterogeneity = .42), decreased for PCa-specific mortality (aHR, 1.38 to 0.93; P for heterogeneity = .005), and increased for cardiovascular mortality (aHR, 1.09 to 1.28; P for heterogeneity = .034). The aHR comparing those in the lowest versus the highest nSEP quintile increased significantly for all-cause mortality (aHR, 1.54 to 1.79; P for heterogeneity = .008), but not for PCa-specific mortality (aHR, 1.60 to 1.72; P for heterogeneity = .40) or cardiovascular mortality (aHR, 1.72 to 1.89; P for heterogeneity = .085). CONCLUSIONS: Although Black-White disparities in prostate mortality declined in Massachusetts and Pennsylvania over the study period, nSEP mortality disparity trends were stagnant or increased, warranting further attention. LAY SUMMARY: Few reports have examined whether racial and socioeconomic disparities in prostate cancer mortality have widened or narrowed in recent years. Using data from 2 state registries (Massachusetts and Pennsylvania) with differing intensities of government-mandated health insurance, trends in racial and neighborhood socioeconomic disparities were studied among Black and White men diagnosed from 2000 to 2015. Overall, trends in racial disparities were stagnant for all-cause mortality, shrank for prostate mortality, and widened for cardiovascular mortality. Disparities associated with neighborhood socioeconomic status either were stagnant or widened across all mortality end points. In general, disparities were more pronounced in Pennsylvania than in Massachusetts.

Racial differences in the treatment and outcomes for prostate cancer in Massachusetts.

BACKGROUND: Massachusetts is a northeastern state with universally mandated health insurance since 2006. Although Black men have generally worse prostate cancer outcomes, emerging data suggest that they may experience equivalent outcomes within a fully insured system. In this setting, the authors analyzed treatments and outcomes of non-Hispanic White and Black men in Massachusetts. METHODS: White and Black men who were 20 years old or older and had been diagnosed with localized intermediate- or high-risk nonmetastatic prostate cancer in 2004-2015 were identified in the Massachusetts Cancer Registry. Adjusted logistic regression models were used to assess predictors of definitive therapy. Adjusted and unadjusted survival models compared cancer-specific mortality. Interaction terms were then used to assess whether the effect of race varied between counties. RESULTS: A total of 20,856 men were identified. Of these, 19,287 (92.5%) were White. There were significant county-level differences in the odds of receiving definitive therapy and survival. Survival was worse for those with high-risk cancer (adjusted hazard ratio [HR], 1.50; 95% CI, 1.4-1.60) and those with public insurance (adjusted HR for Medicaid, 1.69; 95% CI, 1.38-2.07; adjusted HR for Medicare, 1.2; 95% CI, 1.14-1.35). Black men were less likely to receive definitive therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.83) but had a 17% lower cancer-specific mortality (adjusted HR, 0.83; 95% CI, 0.7-0.99). CONCLUSIONS: Despite lower odds of definitive treatment, Black men experience decreased cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population. LAY SUMMARY: There is a growing body of evidence showing that the excess risk of death among Black men with prostate cancer may be caused by disparities in access to care, with few or no disparities seen in universally insured health systems such as the Veterans Affairs and US Military Health System. Therefore, the authors sought to assess racial disparities in prostate cancer in Massachusetts, which was the earliest US state to mandate universal insurance coverage (in 2006). Despite lower odds of definitive treatment, Black men with prostate cancer experience reduced cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.