Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways

• Published in: The Prostate 2024-04, Vol.84 (5), p.460-472
• Main Authors: White, Jason A, Kaninjing, Ernest T, Adeniji, Kayode A, Jibrin, Paul, Obafunwa, John O, Ogo, Chidiebere N, Mohammed, Faruk, Popoola, Ademola, Fatiregun, Omolara A, Oluwole, Olabode P, Thorpe, Jr, 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
• Format: Article
• Language: English
• Subjects: Aging; Apoptosis; Axonemal Dyneins - genetics; BRCA1 protein; BRCA2 protein; DNA damage; DNA repair; Enlargement; Exome Sequencing; Genes; Genital diseases; Humans; Hyperplasia; Kinesins - genetics; Male; p53 Protein; Population studies; Prostate; Prostate - pathology; Prostate cancer; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - pathology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Quality of Life; Statistical analysis; Transcriptional Elongation Factors - genetics; Tumors; Urinary tract
• ISSN: 0270-4137; 1097-0045; 1097-0045
• DOI: 10.1002/pros.24662

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. In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. 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