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Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.
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, 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.
Afiliação
  • White JA; Center for Cancer Research, Tuskegee University, Tuskegee, Alabama, USA.
  • Kaninjing ET; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Adeniji KA; Department of Genetics, Morehouse School of Medicine, Atlanta, Georgia, USA.
  • Jibrin P; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Obafunwa JO; School of Health and Human Performance, Georgia College & State University, Milledgeville, Georgia, USA.
  • Ogo CN; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Mohammed F; College of Health Sciences, University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria.
  • Popoola A; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Fatiregun OA; College of Health Sciences, National Hospital Abuja, Abuja, Federal Capital Territory, Nigeria.
  • Oluwole OP; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Thorpe RJ; Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.
  • Karanam B; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Elhussin I; Department of Surgery, Federal Medical Centre, Abeokuta, Ogun State, Nigeria.
  • Ambs S; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Tang W; Department of Pathology, Ahmadu Bello University, Zaria, Kaduna State, Nigeria.
  • Davis M; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Polak P; College of Health Sciences, University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria.
  • Campbell MJ; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
  • Brignole KR; Department of Clinical Oncology, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.
  • Rotimi SO; College of Health Sciences, University of Abuja, Abuja, Federal Capital Territory, Nigeria.
  • Dean-Colomb W; Center for Health Disparities Solutions, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • Odedina FT; Center for Cancer Research, Tuskegee University, Tuskegee, Alabama, USA.
  • Yates C; Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
Prostate ; 84(5): 460-472, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38192023
ABSTRACT

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 seventy-nine 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 (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperplasia Prostática / Neoplasias da Próstata Limite: Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperplasia Prostática / Neoplasias da Próstata Limite: Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article