Corrigendum: Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

[This corrects the article DOI: 10.3389/fmed.2023.1132799.].

Patterns of B-cell lymphocyte expression changes in pre- and post-malignant prostate tissue are associated with prostate cancer progression.

BACKROUND: Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T- and B-cell levels change during carcinogenesis and whether such changes influence disease progression. METHODS: The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre- and post-diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions-benign biopsy glands (BBG), tumor-adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions-were identified using Time-series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region-specific lymphocyte counts and regional trends. RESULTS: The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG-TAG-MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance. CONCLUSIONS: Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course.

A flexible matching strategy for matched nested case-control studies.

PURPOSE: Individual matching in case-control studies improves statistical efficiency over random selection of controls but can lead to selection bias if cases are excluded due to the lack of appropriate controls or residual confounding with less strict matching criteria. We introduce flex matching, an algorithm using multiple rounds of control selection with successively relaxed matching criteria to select controls for cases. METHODS: We simulated exposure-disease relationships in multiple cohort data sets with a range of confounding scenarios and conducted 16,800,000 nested case-control studies, comparing random selection of controls, strict matching, and flex matching. We computed average bias and statistical efficiency in estimates of exposure-disease relationships under each matching strategy. RESULTS: On average, flex matching produced the least biased estimates of exposure-disease associations with the smallest standard errors. Strict matching algorithms that excluded cases for whom matched controls could not be identified produced biased estimates with larger standard errors. Estimates from studies with random assignment of controls were relatively unbiased, but the standard errors were larger than from studies using flex matching. CONCLUSIONS: Flex matching should be considered for case-control designs, especially for biomarker studies where matching on technical artifacts is necessary and maximizing efficiency is a priority.

Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.

Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). Methods: A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. Results: We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. Conclusion: Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

Identification of Environmental Exposures Associated with Risk of Sarcoidosis in African Americans.

Rationale: Sarcoidosis is a racially disparate granulomatous disease likely caused by environmental exposures, genes, and their interactions. Despite increased risk in African Americans, few environmental risk factor studies in this susceptible population exist. Objectives: To identify environmental exposures associated with the risk of sarcoidosis in African Americans and those that differ in effect by self-identified race and genetic ancestry. Methods: The study sample comprised 2,096 African Americans (1,205 with and 891 without sarcoidosis) compiled from three component studies. Unsupervised clustering and multiple correspondence analyses were used to identify underlying clusters of environmental exposures. Mixed-effects logistic regression was used to evaluate the association of these exposure clusters and the 51 single-component exposures with risk of sarcoidosis. A comparison case-control sample of 762 European Americans (388 with and 374 without sarcoidosis) was used to assess heterogeneity in exposure risk by race. Results: Seven exposure clusters were identified, five of which were associated with risk. The exposure cluster with the strongest risk association was composed of metals (P < 0.001), and within this cluster, exposure to aluminum had the highest risk (odds ratio, 3.30; 95% confidence interval [95% CI], 2.23-4.09; P < 0.001). This effect also differed by race (P < 0.001), with European Americans having no significant association with exposure (odds ratio, 0.86; 95% CI, 0.56-1.33). Within African Americans, the increased risk was dependent on genetic African ancestry (P = 0.047). Conclusions: Our findings support African Americans having sarcoidosis environmental exposure risk profiles that differ from those of European Americans. These differences may underlie racially disparate incidence rates that are partially explained by genetic variation differing by African ancestry.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

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.

Convolutional Neural Network Quantification of Gleason Pattern 4 and Association With Biochemical Recurrence in Intermediate-Grade Prostate Tumors.

Differential classification of prostate cancer grade group (GG) 2 and 3 tumors remains challenging, likely because of the subjective quantification of the percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-predicted %GP4 is associated with biochemical recurrence (BCR) risk in intermediate-risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999-2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate 4 tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) tumors for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the 4 tissue types. Furthermore, CNN-predicted %GP4 was significantly higher in GG 3 than in GG 2 tumors (P = 7.2 × 10-11). %GP4 was associated with an increased risk of BCR (adjusted hazard ratio, 1.09 per 10% increase in %GP4; P = .010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted hazard ratio, 1.12; P = .006). Our findings demonstrate the feasibility of CNN-predicted %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathologic assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection.

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis.

Race Differences in Telomere Length in Benign Prostate Biopsies and Subsequent Risk of Prostate Cancer.

BACKGROUND: Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin. METHODS: A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk. RESULTS: Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 ± 0.38 vs. 1.45 ± 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 ± 0.38 vs. 1.63 ± 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile [OR = 1.90; 95% confidence interval (CI) = 1.08-3.36]. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25-6.19). CONCLUSIONS: White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease. IMPACT: Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer.

Developing an algorithm across integrated healthcare systems to identify a history of cancer using electronic medical records.

OBJECTIVE: Tumor registries in integrated healthcare systems (IHCS) have high precision for identifying incident cancer but often miss recently diagnosed cancers or those diagnosed outside of the IHCS. We developed an algorithm using the electronic medical record (EMR) to identify people with a history of cancer not captured in the tumor registry to identify adults, aged 40-65 years, with no history of cancer. MATERIALS AND METHODS: The algorithm was developed at Kaiser Permanente Colorado, and then applied to 7 other IHCS. We included tumor registry data, diagnosis and procedure codes, chemotherapy files, oncology encounters, and revenue data to develop the algorithm. Each IHCS adapted the algorithm to their EMR data and calculated sensitivity and specificity to evaluate the algorithm's performance after iterative chart review. RESULTS: We included data from over 1.26 million eligible people across 8 IHCS; 55 601 (4.4%) were in a tumor registry, and 44848 (3.5%) had a reported cancer not captured in a registry. The common attributes of the final algorithm at each site were diagnosis and procedure codes. The sensitivity of the algorithm at each IHCS was 90.65%-100%, and the specificity was 87.91%-100%. DISCUSSION: Relying only on tumor registry data would miss nearly half of the identified cancers. Our algorithm was robust and required only minor modifications to adapt to other EMR systems. CONCLUSION: This algorithm can identify cancer cases regardless of when the diagnosis occurred and may be useful for a variety of research applications or quality improvement projects around cancer care.

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

Racial differences in the systemic inflammatory response to prostate cancer.

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.

Growth and differentiation factor 15 and NF-κB expression in benign prostatic biopsies and risk of subsequent prostate cancer detection.

Growth and differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), may act as both a tumor suppressor and promotor and, by regulating NF-κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation-related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF-15 and NF-κB was done in a study of 503 case-control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF-15 and NF-κB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF-κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77-0.99, while GDF-15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96-1.17. When modeling expression levels by quartiles, the highest quartile of NF-κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29-0.92). In stratified models, NF-κB had the strongest negative association with prostate cancer in non-aggressive cases (p = 0.03), older men (p = 0.03), and in case-control pairs with longer follow-up (p = 0.02). Risk associated with GDF-15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF-15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF-15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case-control pairs with longer follow-up. Therefore, although positively correlated in benign prostatic biopsies, NF-κB and GDF-15 expression appear to exert opposite effects on risk of prostate tumor development.

Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans.

Purpose: Identify genes associated with ocular sarcoidosis (OS).Methods: We genotyped 1.1 million genetic variants to identify significant OS associations, defined as those that achieved p < 5 × 10-8 in a genome-wide comparison of OS cases to healthy controls in our European- or African-American cohorts (EA, AA). Potential functional roles of all associated variants were assessed.Results: Eight significant non-HLA variants were found in AA OS cases compared to healthy controls and confirmed as at least suggestive when comparing OS to non-OS cases. Seven of these were within MAGI1 and include transcription factor binding sites and expression quantitative trait loci. Our EA cohort, while showing similar effect sizes at variants within MAGI1, had no significant variants. Association analysis of HLA-DRB1 alleles confirmed association to OS in EA to *04:01.Conclusion: Our results support organ-specific genetic risk in OS in a compelling candidate, MAGI1, known to be associated with barrier function and autoimmunity.

Levels of plasma glycan-binding auto-IgG biomarkers improve the accuracy of prostate cancer diagnosis.

Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment.

Breast and prostate cancers harbor common somatic copy number alterations that consistently differ by race and are associated with survival.

BACKGROUND: Pan-cancer studies of somatic copy number alterations (SCNAs) have demonstrated common SCNA patterns across cancer types, but despite demonstrable differences in aggressiveness of some cancers by race, pan-cancer SCNA variation by race has not been explored. This study investigated a) racial differences in SCNAs in both breast and prostate cancer, b) the degree to which they are shared across cancers, and c) the impact of these shared, race-differentiated SCNAs on cancer survival. METHODS: Utilizing data from The Cancer Genome Atlas (TCGA), SCNAs were identified using GISTIC 2.0, and in each tumor type, differences in SCNA magnitude between African Americans (AA) and European Americans (EA) were tested using linear regression. Unsupervised hierarchical clustering of the copy number of genes residing in race-differentiated SCNAs shared between tumor types was used to identify SCNA-defined patient groups, and Cox proportional hazards regression was used to test for association between those groups and overall/progression-free survival (PFS). RESULTS: We identified SCNAs that differed by race in breast (n = 58 SCNAs; permutation p < 10- 4) and prostate tumors (n = 78 SCNAs; permutation p = 0.006). Six race-differentiated SCNAs common to breast and prostate found at chromosomes 5q11.2-q14.1, 5q15-q21.1, 8q21.11-q21.13, 8q21.3-q24.3, 11q22.3, and 13q12.3-q21.3 had consistent differences by race across both tumor types, and all six were of higher magnitude in AAs, with the chromosome 8q regions being the only amplifications. Higher magnitude copy number differences in AAs were also identified at two of these race-differentiated SCNAs in two additional hormonally-driven tumor types: endometrial (8q21.3-q24.3 and 13q12.3-q21.3) and ovarian (13q12.3-q21.3) cancers. Race differentiated SCNA-defined patient groups were significantly associated with survival differences in both cancer types, and these groups also differentiated within triple negative breast cancers based on PFS. While the frequency of the SCNA-defined patient groups differed by race, their effects on survival did not. CONCLUSIONS: This study identified race-differentiated SCNAs shared by two related cancers. The association of SCNA-defined patient groups with survival demonstrates the clinical significance of combinations of these race-differentiated genomic aberrations, and the higher frequency of these alterations in AA relative to EA patients may explain racial disparities in risk of aggressive breast and prostate cancer.

The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis.

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P < 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease.

Prostate-specific antigen testing after the US Preventive Services Task Force recommendation: a population-based analysis of electronic health data.

PURPOSE: This study describes longitudinal trends in the use of prostate-specific antigen (PSA)-based testing in two geographically distinct healthcare systems following the 2011 US Preventive Services Task Force (USPSTF) recommendations against routine PSA screening. METHODS: We analyzed population-based health claims data from 253,139 men aged 40-80 who were enrolled at two US healthcare systems. We assessed trends in the percentage of eligible men receiving ≥ 1 PSA test per year by time period (2000-2008, 2009-2011, 2012-2014), age (40-54, 55-69, 70-80), and race (white, black, other, unknown), and conducted a joinpoint regression analysis. RESULTS: Men aged 55-69 and 70-80 years of all races had similar use of PSA testing between 2000 and 2011, ranging between 47 and 56% of eligible men by year, while only 22-26% of men aged 40-54 had a PSA test per year during this period. Overall, the percentage of men receiving at least one PSA test per year decreased by 26% between 2009-2011 and 2012-2014, with similar trends across race and age groups. PSA testing declined significantly after 2011 (annual percent change = - 11.28). CONCLUSIONS: Following the 2011 USPSTF recommendations against routine PSA screening, declines in PSA testing were observed among men of all races and across all age groups in two large US healthcare systems.