Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA. GSEA, Connectivity Map, CIBERSORT, cancer immunotherapy antigen profiling, and hypergeometric testing for overlapping miRNA targets were performed.

Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA.

Project description:Abstract: Background and aims: Portal hypertension (PH) is the most frequent and severe clinical syndrome associated to chronic liver disease (CLD), defined by a pathological increase in the hepatic venous pressure gradient (HVPG). Considering the known mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesized that PH could not only be a consequence of, but significantly influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of pathological hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH. Methods: Primary LSECs were cultured under normal or increased hydrodynamic pressure within a pathophysiological range (1 vs 12 mmHg) using a microfluidic liver-on-a-chip device. RNAseq was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of CLD patients with PH (n=73) vs subjects without PH (n=23). Biomarker discovery was performed in plasma from a third independent cohort of 64 patients (46 with PH vs 18 w/o). Results: Transcriptomic analysis revealed a marked deleterious effect of pathological pressure in LSECs and identified chromobox 7 (CBX7) as a key transcription factor diminished by pressure. Hepatic CBX7 downregulation was validated in patients with PH and significantly correlated with HVPG. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Analysis of two downstream targets of CBX7, ECAD and SPINK1, were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH, with a sensitivity of 91.3% and 91.4% respectively. Conclusions: We describe the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose that the combination of two of its reported products could be used as plasma biomarkers of PH.

Project description:Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity. Methods: From self-identified, healthy, 20-29 year old AA (n=21) and CA (n=17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology. Results: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower in AA. “PSPH” exhibited the greatest fold-change (AA>CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA>CA, SOS1, AMFR, FGFR3; and for AA<CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system. Conclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden amongst AA.

Project description:Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity. Methods: From self-identified, healthy, 20-29 year old AA (n=21) and CA (n=17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology. Results: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower in AA. “PSPH” exhibited the greatest fold-change (AA>CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA>CA, SOS1, AMFR, FGFR3; and for AA<CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system. Conclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden amongst AA. From self-identified, healthy, 20-29 year old AA (n=21) and CA (n=17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology.

Dataset Information

Genetics of Hypertension Associated Treatment Study (GenHAT) Genomic Background of Blood Pressure Response to Thiazide Diuretic in African Americans

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