Browsing by Author "Campbell, Moray J."

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    Abstract 6346: The chromatin remodeler SMARCA5 selectively shapes nuclear receptor signaling in African American prostate cancer
    (Cancer Res (2025) 85 (8_Supplement_1):, 2025-04-15) Hussain, Shahid; Nayak, Debasis; Wani, Sajad A.; Elhussin, Isra; Freeman, Michael R.; Coss, Christopher C.; Rotimi, Solomon O; Murphy, Adam R.; Yates. Clayton; Campbell, Moray J.
    Motif enrichment in H3K27ac revealed significant differences with Helix-Loop-Helix motifs enriched in RC43N compared to HPr1AR; and STAT motifs enriched in RC43T compared to LNCaP. Similarly, nuclear receptor (NR) motifs were distinct with vitamin D receptor (VDR) and orphan receptors (e.g., RORG) enriched in RC43T compared to LNCaP. Next we up-regulated SMARCA5’s using dCas9-VP64-activator in the same cells and tested the impact on gene expression with RNA-Seq following treatment with the VDR ligand (1, 25(OH)2D3, 100nM). SMARCA5 regulated ∼1200 genes in both RC43T and RC77T, and only ∼200 genes in LNCaP. The SMARCA5-dependent genes in AA PCa cells models were significantly enriched for luminal-differentiation genes. Likewise, in the AA compared to EA PCa models, GSEA analyses revealed enrichment for inflammation responses, and distinct NR signaling, such as progesterone signaling. Likewise LISA analyses revealed enrichment in the SMARCA5-dependent genes in AA PCa for progesterone signaling. Finally, we also identified a subset of miRNA related to differentiation that were uniquely regulated in AA PCa models by 1, 25(OH)2D3 and a significant number were also SMARCA5-dependent. Ongoing studies are addressing the effect of SMARCA5 on chromatin accessibility using ATAC-Seq. Overall, these studies support the concept the epigenome is shaped by genomic ancestry. The epigenomic-regulator SMARCA5 is significantly downregulated in AA PCa and impacts NRs, including VDR signaling. These findings suggest that African ancestry shapes SMARCA5 functions, NR signaling, and tumor outcomes.
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    Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways
    (The Prostate April 2024 Vol 84 No. 5, 2024-01-04) Kaninjing, Ernest T.; Adeniji, Kayode A.; Jibrin, Paul; Obafunwa, John O.; Path, FMC; Path, FRC; Ogo, Chidiebere N.; Mohammed, Faruk; Popoola, Ademola; Fatiregun, Omolara A.; Oluwole, Olabode P.; Thorpe, Roland J.; Karanam, Balasubramanyam; Elhussin, Isra; Ambs, Stefan; Tang, Wei; Davis, Melissa; Polak, Paz; Campbell, Moray J.; Brignole, Kathryn R.; Rotimi, Solomon O.; Dean-Colomb, Windy; Odedina, Folake T.; Yates, Clayton
    Background Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. Methods In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. Results Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventynine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. Conclusions NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies