Center for Cancer Research, Tuskegee University, Tuskegee, Alabama, USA.
Prostate Cancer Transatlantic Consortium (CaPTC), Abuja, Wuse Zone 1, Nigeria.
Prostate. 2024 Apr;84(5):460-472. doi: 10.1002/pros.24662. Epub 2024 Jan 8.
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 < 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.
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.
通过对 60 份尼日利亚（NGRn）良性前列腺增生（BPH）福尔马林固定石蜡包埋样本的全外显子组测序，我们确定了影响 BPH 发展和进展的凋亡途径中的种系和体细胞改变。前列腺增大是男性衰老的常见现象；然而，这种增大可能导致下尿路症状，从而对生活质量产生负面影响。这种影响在非洲裔男性中不成比例地存在。BPH 的病理生理学尚未得到很好的理解，缺乏研究非欧洲人群的研究。
在这项研究中，对 NGRn BPH、正常前列腺和前列腺癌（PCa）肿瘤样本进行测序，以描述 NGRn BPH 中的遗传改变。
在 NGRn BPH 样本中存在 202 种非良性、ClinVar 注释的种系变异。有 6 个基因 [BRCA1（92%）、HSD3B1（85%）、TP53（37%）、PMS2（23%）、BARD1（20%）和 BRCA2（17%）] 在至少 10%的样本中发生改变；然而，与 NGRn 正常和肿瘤相比，BPH 样本中基因或变异水平的改变频率没有显著差异。BRCA2_rs11571831 和 TP53_rs1042522 种系改变在 BPH 样本中具有统计学显著的共同发生相互作用。在至少两个 BPH 样本中，173 个基因携带有临床可操作的已知体细胞变异。有三个基因（COL18A1、KIF16B 和 LRP1）在 BPH 中表现出统计学上显著（p<0.05）更高的频率。NGRn BPH 还具有五个基因对（PKD1/KIAA0100、PKHD1/PKD1、DNAH9/LRP1B、NWD1/DCHS2 和 TCERG1/LMTK2）具有统计学显著（p<0.05）的共同发生相互作用。在 NGRn BPH 中有 279 个基因含有新的体细胞变异。有三个基因（CABP1、FKBP1C 和 RP11-595B24.2）在 NGRn BPH 中的改变频率具有统计学显著（p<0.05）升高，有三个基因在 NGRn 肿瘤中显著升高（CACNA1A、DMKN 和 CACNA2D2）。成对 Fisher 精确检验显示有 14 个基因对具有统计学显著（p<0.05）的相互作用，有四个相互作用接近显著（p<0.10）。NGRn BPH 的突变模式与与衰老和功能失调的 DNA 损伤修复相关的 COSMIC（癌症体细胞突变目录）特征相似。
NGRn BPH 存在显著的种系改变相互作用（BRCA2_rs11571831 和 TP53_rs1042522）和增加的体细胞改变频率（LMTK2、LRP1、COL18A1、CABP1 和 FKBP1C），这些改变影响凋亡。正常前列腺的发育是通过平衡凋亡和增殖活动来维持的。这两个机制中的任何一个功能障碍都可能导致前列腺异常生长。这项工作是首次对 NGRn BPH 进行基因组测序，并提供了数据，填补了我们对 BPH 的理解以及它如何影响非洲裔男性的已知空白。
