Advancing genomics to improve health equity.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.

Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Black cancer patients navigating a health-care system of racial discrimination.

BACKGROUND: Exposure to racial discrimination may exacerbate disparities throughout the cancer care continuum. Therefore, we explored how experiences of racial discrimination in the health-care setting manifest for Black cancer patients and how it contributes to racial disparities in cancer care. METHODS: This qualitative analysis used semistructured in-depth interviews with Black cancer survivors not on active treatment from May 2019 to March 2020. All interviews were audio recorded, professionally transcribed, and uploaded into Dedoose software for analysis. We identified major themes and subthemes that highlight exposure to racial discrimination and its consequences for Black cancer patients when receiving cancer care. RESULTS: Participants included 18 Black cancer survivors, aged 29-88 years. Most patients experienced racial discrimination when seeking care. Participants experienced racial discrimination from their interactions with health-care staff, medical assistants, front desk staff, and health insurance administrators. Exposure to overt racial discrimination in the health-care setting was rooted in racial stereotypes and manifested through verbal insults such as physicians using phrases such as "you people." These experiences impacted the ability of the health-care delivery system to demonstrate trustworthiness. Patients noted "walking out" of their visit and not having their health issues addressed. Despite experiences with racial discrimination, patients still sought care out of necessity believing it was an inevitable part of the Black individual experience. CONCLUSION: We identified that exposure to racial discrimination in the health-care setting is pervasive, affects health-seeking behaviors, and degrades the patient-clinician relationship, which may likely contribute to racial disparities in cancer care.

Delays Starting Postoperative Radiotherapy Among Head and Neck Cancer Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: Initiating postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery is the first and only Commission on Cancer (CoC) approved quality metric for head and neck squamous cell carcinoma (HNSCC). No study has systematically reviewed nor synthesized the literature to establish national benchmarks for delays in starting PORT. DATA SOURCES: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed a systematic review of PubMed, Scopus, and CINAHL. REVIEW METHODS: Studies that described time-to-PORT or PORT delays in patients with HNSCC treated in the United States after 2003 were included. Meta-analysis of proportions and continuous measures was performed on nonoverlapping datasets to examine the pooled frequency of PORT delays and time-to-PORT. RESULTS: Thirty-six studies were included in the systematic review and 14 in the meta-analysis. Most studies utilized single-institution (n = 17; 47.2%) or cancer registry (n = 16; 44.4%) data. Twenty-five studies (69.4%) defined PORT delay as >6 weeks after surgery (the definition utilized by the CoC and National Comprehensive Cancer Network Guidelines), whereas 4 (11.1%) defined PORT delay as a time interval other than >6 weeks, and 7 (19.4%) characterized time-to-PORT without defining delay. Meta-analysis revealed that 48.6% (95% confidence interval [CI], 41.4-55.9) of patients started PORT > 6 weeks after surgery. Median and mean time-to-PORT were 45.8 (95% CI, 42.4-51.4 days) and 47.4 days (95% CI, 43.4-51.4 days), respectively. CONCLUSION: Delays in initiating guideline-adherent PORT occur in approximately half of patients with HNSCC. These meta-analytic data can be used to set national benchmarks and assess progress in reducing delays.

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

BACKGROUND: Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. MATERIALS AND METHODS: From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. RESULTS: Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. CONCLUSIONS: In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.

Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes.

INTRODUCTION: The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. METHODS: CaRE2 serves diverse populations in Florida and California using a "molecule to the community and back" model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. RESULTS: Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. CONCLUSION: The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

Ethical, legal, and social implications (ELSI) and challenges in the design of a randomized controlled trial to test the online return of cancer genetic research results to U.S. Black women.

BACKGROUND: A central challenge to precision medicine research efforts is the return of genetic research results in a manner that is effective, ethical, and efficient. Formal tests of alternate modalities are needed, particularly for racially marginalized populations that have historically been underserved in this context. METHODS: We are conducting a randomized controlled trial (RCT) to test scalable modalities for results return and to examine the clinical utility of returning genetic research results to a research cohort of Black women. The primary aim is to compare the efficacy of two communication modalities for results return: 1) a conventional modality that entails telephone disclosure by a Board-certified genetic counselor, and 2) an online self-guided modality that entails results return directly to participants, with optional genetic counselor follow-up via telephone. The trial is being conducted among participants in the Black Women's Health Study (BWHS), where targeted sequencing of 4000 participants was previously completed. RESULTS: Several ethical, legal, and social implications (ELSI) and challenges presented, which necessitated substantial revision of the original study protocol. Challenges included chain of custody, re-testing of research results in a CLIA lab, exclusion of VUS results, and digital literacy. Bioethical principles of autonomy, justice, non-maleficence, and beneficence were considered in the design of the study protocol. CONCLUSION: This study is uniquely situated to provide critical evidence on the effectiveness of alternative models for genetic results return and provide further insight into the factors influencing access and uptake of genetic information among U.S. Black women. CLINICALTRIALS: gov: NCT04407611.

Supporting the Capture of Social Needs Through Natural Language Processing.

Social factors impact morbidity and mortality among patients. Documenting social needs in the clinical notes is currently widely done by family physicians. The unstructured format of information on social factors in electronic health records limits the ability of providers to address these issues. A proposed solution is using natural language processing to identify social needs from the electronic health record. This could support physicians in capturing structured social needs information that is consistent and reproducible without increasing documentation burden.

African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A.

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function. Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Differences in intention to use flavored oral nicotine products among young adult e-cigarette users and non-users.

New oral nicotine products (ONPs; nicotine pouches, gums, lozenges, and gummies), which are regulated as nonmedicinal tobacco products in the U.S., have flavors and other characteristics that previously attracted young adults to e-cigarettes. Whether young adults' interest in ONPs differs by e-cigarette use status and quit-vaping motivation is unknown but important for understanding the possible health impact of ONPs. It is particularly important to study if nonmedicinal ONPs attract e-cigarette users interested in quitting vaping, given that nicotine replacement (NRT) therapy uptake in young adults is low. In this study, ONP non-users (ages: 20-24) from California viewed digital images of 5 flavored ONPs (4 nonmedicinal and one NRT gum product) and reported intention to use each ONP (0-100 score). Main and interactive effects of Group (past-6-month e-cigarette non-users [n = 1,1388], e-cigarette users unmotivated to quit vaping [n = 168], and e-cigarette users motivated to quit vaping [n = 99]) and ONP type (nonmedicinal gum, nonmedicinal lozenge, gummy, pouch, and NRT gum) on use intention were tested. For each nonmedicinal ONP, use intention was higher in both e-cigarette user groups than non-users (ds = 0.47-0.59; Ps < 0.001), but did not differ between e-cigarette users with and without quit-vaping motivation (Ps ≥ 0.31). A Group × ONP type interaction was found, whereby higher use intention for e-cigarette users with vs without quit motivation was present for only gum NRT (Cohens d = 0.17; P =.01). Among young adults, e-cigarette users might be more inclined than e-cigarette non-users to try nonmedicinal ONPs regardless of quit-vaping motivation.

Racial Distribution of Neighborhood-Level Social Deprivation in a Retrospective Cohort of Prostate Cancer Survivors.

Background: A better understanding of neighborhood-level factors' contribution is needed in order to increase the precision of cancer control interventions that target geographic determinants of cancer health disparities. This study characterized the distribution of neighborhood deprivation in a racially diverse cohort of prostate cancer survivors. Methods: A retrospective cohort of 253 prostate cancer patients who were treated with radical prostatectomy from 2011 to 2019 was established at the Medical University of South Carolina. Individual-level data on clinical variables (e.g., stage, grade) and race were abstracted. Social Deprivation Index (SDI) and Healthcare Professional Shortage (HPS) status was obtained from the Robert Graham Center and assigned to participants based on their residential census tract. Data were analyzed with descriptive statistics and multivariable logistic regression. Results: The cohort of 253 men consisted of 168 white, 81 African American, 1 Hispanic and 3 multiracial men. Approximately 49% of 249 men lived in areas with high SDI (e.g., SDI score of 48 to 98). The mean for SDI was 44.5 (+27.4), and the range was 97 (1−98) for all study participants. African American men had a significantly greater likelihood of living in a socially deprived neighborhood compared to white men (OR = 3.7, 95% C.I. 2.1−6.7, p < 0.01), while men who lived in areas with higher HPS shortage status were significantly more likely to live in a neighborhood that had high SDI compared to men who lived in areas with lower HPS shortages (OR = 4.7, 95% C.I. = 2.1−10.7, p < 0.01). African Americans had a higher likelihood of developing biochemical reoccurrence (OR = 3.7, 95% C.I. = 1.7−8.0) compared with white men. There were no significant association between SDI and clinical characteristics of prostate cancer. Conclusions: This study demonstrates that SDI varies considerably by race among men with prostate cancer treated with radical prostatectomy. Using SDI to understand the social environment could be -particularly useful as part of precision medicine and precision public health approaches and could be used by cancer centers, public health providers, and other health care specialists to inform operational decisions about how to target health promotion and disease prevention efforts in catchment areas and patient populations.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

Change in distress about police brutality and substance use among young people, 2017-2020.

BACKGROUND: It is unknown whether increasing attention to police brutality is a source of stress associated with substance use risk among young people. METHODS: A longitudinal racially/ethnically diverse cohort from Los Angeles, California (n = 1797) completed baseline (2017; mean age: 17.9) and follow-up (2020; mean age: 21.2) surveys assessing level of concern, worry, and stress about police brutality (range: 0 'not at all' - 4 'extremely') and past 30-day nicotine, cannabis, alcohol, other drug, and number of substances used (0-19). Regression models, adjusted for demographic characteristics and baseline substance use, evaluated whether changes in distress about police brutality from 2017 to 2020 were associated with substance use in 2020 overall and stratified by race/ethnicity. RESULTS: Distress about police brutality increased between 2017 (mean: 1.59) and 2020 (mean: 2.43) overall. Black/African American and Hispanic/Latino respondents consistently had the highest mean distress levels at both timepoints. In the full sample, each one-unit greater increase in distress about police brutality from 2017 to 2020 was associated with 11% higher odds of cannabis use, 13% higher odds of alcohol use, and 8% higher risk of using an additional substance for the number of substances used outcome. Race/ethnicity-stratified models indicated that greater increases in distress from 2017 to 2020 was associated with substance use among Black/African American, Hispanic, and multiracial respondents in 2020, but not Asian American/Pacific Islander and White respondents. CONCLUSIONS: Distress about police brutality may be associated with substance use, particularly among certain racial/ethnic minority young people. Further investigation of whether police brutality affects health in disparity populations is needed.

Fusion Genes in Prostate Cancer: A Comparison in Men of African and European Descent.

Prostate cancer is one of the most prevalent cancers worldwide, particularly affecting men living a western lifestyle and of African descent, suggesting risk factors that are genetic, environmental, and socioeconomic in nature. In the USA, African American (AA) men are disproportionately affected, on average suffering from a higher grade of the disease and at a younger age compared to men of European descent (EA). Fusion genes are chimeric products formed by the merging of two separate genes occurring as a result of chromosomal structural changes, for example, inversion or trans/cis-splicing of neighboring genes. They are known drivers of cancer and have been identified in 20% of cancers. Improvements in genomics technologies such as RNA-sequencing coupled with better algorithms for prediction of fusion genes has added to our knowledge of specific gene fusions in cancers. At present AA are underrepresented in genomic studies of prostate cancer. The primary goal of this study was to examine molecular differences in predicted fusion genes in a cohort of AA and EA men in the context of prostate cancer using computational approaches. RNA was purified from prostate tissue specimens obtained at surgery from subjects enrolled in the study. Fusion gene predictions were performed using four different fusion gene detection programs. This identified novel putative gene fusions unique to AA and suggested that the fusion gene burden was higher in AA compared to EA men.

Differences in Young Adults' Perceptions of and Willingness to Use Nicotine Pouches by Tobacco Use Status.

Oral nicotine pouches may appeal to young adult current nicotine/tobacco users interested in alternative forms of nicotine that lack pulmonary exposure, but may also appeal to young adult non-users of nicotine/tobacco products. We used data from a 2020 remote digital survey of an ongoing cohort study of young adults from Southern California (aged 19-23) to examine differences in pouch perceptions and use willingness across nicotine/tobacco use statuses. Participants who had never used nicotine pouches (N = 1167) viewed text/imagery from mass-marketed pouch packaging and advertising, then completed measures of willingness to use nicotine pouches, pouch harm perceptions, and hypothetical choice of cigarettes or e-cigarettes over pouches. Willingness to use pouches was significantly higher among non-combustible only (33.8%), combustible only (29.3%), and dual (43.9%) users than non-users (14.7%). Overall, 49.1% of participants were uncertain whether pouches were less harmful than cigarettes and 52.4% were uncertain whether pouches were less harmful than e-cigarettes. Relative harm perceptions did not significantly differ by tobacco use status. Those using non-combustible products (either alone or as part of dual use with combustible tobacco) had greater odds than non-users of reporting that they would use e-cigarettes over nicotine pouches. By contrast, all tobacco product user groups reported greater odds than non-users that they would use cigarettes over pouches. In sum, a sizable minority of young adults might be willing to try using nicotine pouches, but most are uncertain about the relative harm of pouches.

Racial Disparities and Diagnosis-to-Treatment Time Among Patients Diagnosed with Breast Cancer in South Carolina.

OBJECTIVES: Diagnosis-to-treatment interval is an important quality measure that is recognized by the National Accreditation Program for Breast Centers, and the American Society of Breast Surgeons and the National Quality Measures for Breast Care. The aim of this study was to assess factors related to delays in receiving breast cancer treatment. METHODS: This retrospective cohort study (2002 to 2010) used data from the South Carolina Central Cancer Registry (SCCCR) and Office of Revenue and Fiscal Affairs (RFA) to examine racial differences in diagnosis-to-treatment time (in days), with adjuvant hormone receipt, surgery, chemotherapy, and radiotherapy assessed separately. Chi-square tests, and logistic regression and generalized linear models were used to compare diagnosis-to-treatment days. RESULTS: Black women on average received adjuvant hormone therapy, surgery, chemotherapy, and radiotherapy 25, 8, 7, and 3 days later than their White counterparts, respectively. Black women with local stage cancer had later time to surgery (OR: 1.6; CI: 1.2-2.2) compared with White women with local stage cancer. Black women living in rural areas had higher odds (OR: 2.0; CI: 1.1-3.7) of receiving late chemotherapy compared with White women living in rural areas. Unmarried Black women also had greater risk (OR: 2.0; CI: 1.0-4.0) of receiving late radiotherapy compared to married White women. CONCLUSIONS: To improve timely receipt of effective BrCA treatments, programs aimed at reducing racial disparities may need to target subgroups of Black breast cancer patients based on their social determinants of health and geographic residence.

Comparison of a Cancer Family History Collection and Risk Assessment Tool - ItRunsInMyFamily - with Risk Assessment by Health-Care Professionals.

INTRODUCTION: Primary care providers (PCPs) and oncologists lack time and training to appropriately identify patients at increased risk for hereditary cancer using family health history (FHx) and clinical practice guideline (CPG) criteria. We built a tool, "ItRunsInMyFamily" (ItRuns) that automates FHx collection and risk assessment using CPGs. The purpose of this study was to evaluate ItRuns by measuring the level of concordance in referral patterns for genetic counseling/testing (GC/GT) between the CPGs as applied by the tool and genetic counselors (GCs), in comparison to oncologists and PCPs. The extent to which non-GCs are discordant with CPGs is a gap that health information technology, such as ItRuns, can help close to facilitate the identification of individuals at risk for hereditary cancer. METHODS: We curated 18 FHx cases and surveyed GCs and non-GCs (oncologists and PCPs) to assess concordance with ItRuns CPG criteria for referring patients for GC/GT. Percent agreement was used to describe concordance, and logistic regression to compare providers and the tool's concordance with CPG criteria. RESULTS: GCs had the best overall concordance with the CPGs used in ItRuns at 82.2%, followed by oncologists with 66.0% and PCPs with 60.6%. GCs were significantly more likely to concur with CPGs (OR = 4.04, 95% CI = 3.35-4.89) than non-GCs. All providers had higher concordance with CPGs for FHx cases that met the criteria for genetic counseling/testing than for cases that did not. DISCUSSION/CONCLUSION: The risk assessment provided by ItRuns was highly concordant with that of GC's, particularly for at-risk individuals. The use of such technology-based tools improves efficiency and can lead to greater numbers of at-risk individuals accessing genetic counseling, testing, and mutation-based interventions to improve health.

A Systems Approach to Interrogate Gene Expression Patterns in African American Men Presenting with Clinically Localized Prostate Cancer.

An emerging theory about racial differences in cancer risk and outcomes is that psychological and social stressors influence cellular stress responses; however, limited empirical data are available on racial differences in cellular stress responses among men who are at risk for adverse prostate cancer outcomes. In this study, we undertook a systems approach to examine molecular profiles and cellular stress responses in an important segment of African American (AA) and European American (EA) men: men undergoing prostate biopsy. We assessed the prostate transcriptome with a single biopsy core via high throughput RNA sequencing (RNA-Seq). Transcriptomic analyses uncovered impacted biological pathways including PI3K-Akt signaling pathway, Neuroactive ligand-receptor interaction pathway, and ECM-receptor interaction. Additionally, 187 genes mapping to the Gene Ontology (GO) terms RNA binding, structural constituent of ribosome, SRP-dependent co-translational protein targeting to membrane and the biological pathways, translation, L13a-mediated translational silencing of Ceruloplasmin expression were differentially expressed (DE) between EA and AA. This signature allowed separation of AA and EA patients, and AA patients with the most severe clinical characteristics. AA patients with elevated expression levels of this genomic signature presented with higher Gleason scores, a greater number of positive core biopsies, elevated dehydroepiandrosterone sulfate levels and serum vitamin D deficiency. Protein-protein interaction (PPI) network analysis revealed a high degree of connectivity between these 187 proteins.

Direct N-Glycosylation Profiling of Urine and Prostatic Fluid Glycoproteins and Extracellular Vesicles.

Expressed prostatic secretions (EPS), also called post digital rectal exam urines, are proximal fluids of the prostate that are widely used for diagnostic and prognostic assays for prostate cancer. These fluids contain an abundant number of glycoproteins and extracellular vesicles secreted by the prostate gland, and the ability to detect changes in their N-glycans composition as a reflection of disease state represents potential new biomarker candidates. Methods to characterize these N-glycan constituents directly from clinical samples in a timely manner and with minimal sample processing requirements are not currently available. In this report, an approach is described to directly profile the N-glycan constituents of EPS urine samples, prostatic fluids and urine using imaging mass spectrometry for detection. An amine reactive slide is used to immobilize glycoproteins from a few microliters of spotted samples, followed by peptide N-glycosidase digestion. Over 100 N-glycan compositions can be detected with this method, and it works with urine, urine EPS, prostatic fluids, and urine EPS-derived extracellular vesicles. A comparison of the N-glycans detected from the fluids with tissue N-glycans from prostate cancer tissues was done, indicating a subset of N-glycans present in fluids derived from the gland lumens. The developed N-glycan profiling is amenable to analysis of larger clinical cohorts and adaptable to other biofluids.