Riaz Farwa, Sultana Sabira, Asad Lareb, Mirjat Dureali, Shazi Muhammad Ilyas, Zia Muhammad Khurram, Aziz Nouman, Abdel-Maksoud Mostafa A, Saleh Ibrahim A, Al-Hawadi Jehad S, Zomot Naser, Almutairi Saeedah Musaed, Ali Akbar
Department of Surgery, Ejaz Memorial Hospital Mandi Shah Jewana, Jhang 35200, Pakistan.
Department of Eastern Medicine, Government College University Faisalabad 38000, Pakistan.
Am J Transl Res. 2024 Sep 15;16(9):4450-4465. doi: 10.62347/QRIF7244. eCollection 2024.
Prostate cancer is characterized by diverse genetic mutations that influence disease progression and treatment response. This study was launched to explore the genetic basis of prostate cancer patients.
We employed Next Generation Sequencing (NGS) to analyze 14 cancer-susceptible genes in prostate cancer patients.
Our study identified genetic mutations in BRCA1, BRCA2, TP53, and PMS2. In BRCA1 gene, we identified two pathogenic mutations, c.181T>G (p.Cys61Gly) and c.2457delC (p.Ala819fs), found in 10 patients, along with three benign mutations, c.5357T>G (p.Leu1786Arg), c.1111T>C (p.Leu371Pro), and c.1201C>G (p.Thr401Arg), present in 13, 11, and 15 patients, respectively. For the BRCA2 gene, one pathogenic mutation, c.6275_6276del (p.Val2092fs), was detected in 10 patients, and four benign mutations, c.5347A>T (p.Met1783Leu), c.5198A>G (p.Asp1733Gly), c.5158A>G (p.Thr1720Ala), and c.5117G>C (p.Gly1706Ala), were found in 17, 21, 34, and 12 patients, respectively. In the TP53 gene, we found two pathogenic mutations, c.1014_1015insT (p.Glu339Ter) and c.916C>T (p.Arg306Ter), in 10 and 11 patients, respectively, and two benign mutations, c.311T>C (p.Ser104Pro) and c.1129C>T (p.Arg377Cys), in 8 and 9 patients, respectively. Lastly, the PMS2 gene exhibited 16 benign mutations. Notably, the detected pathogenic mutations are rare in the broader Asian population according to the gnomAD database. Functional analyses using RT-qPCR and immunohistochemistry showed decreased expression of BRCA1, BRCA2, and TP53 in samples with pathogenic mutations, corroborating their impact on tumor suppressor function. Furthermore, drug sensitivity analysis revealed that BRCA1 and BRCA2 mutations are associated with increased sensitivity to a range of chemotherapeutic agents, supporting the concept of synthetic lethality. However, TP53 did not significantly impact drug sensitivity.
This comprehensive analysis emphasizes the critical roles of BRCA1, BRCA2, TP53, and PMS2 in prostate cancer pathogenesis and highlights the importance of population-specific genetic screening.
前列腺癌具有多种影响疾病进展和治疗反应的基因突变。本研究旨在探索前列腺癌患者的遗传基础。
我们采用下一代测序（NGS）技术分析前列腺癌患者的14个癌症易感基因。
我们的研究在BRCA1、BRCA2、TP53和PMS2基因中发现了基因突变。在BRCA1基因中，我们在10名患者中发现了两个致病突变，即c.181T>G（p.Cys61Gly）和c.2457delC（p.Ala819fs），同时在13名、11名和15名患者中分别发现了三个良性突变，即c.5357T>G（p.Leu1786Arg）、c.1111T>C（p.Leu371Pro）和c.1201C>G（p.Thr401Arg）。对于BRCA2基因，在10名患者中检测到一个致病突变，即c.6275_6276del（p.Val2092fs），在17名、21名、34名和12名患者中分别发现了四个良性突变，即c.5347A>T（p.Met1783Leu）、c.5198A>G（p.Asp1733Gly）、c.5158A>G（p.Thr1720Ala）和c.5117G>C（p.Gly1706Ala）。在TP53基因中，我们分别在10名和11名患者中发现了两个致病突变，即c.1014_1015insT（p.Glu339Ter）和c.916C>T（p.Arg306Ter），在8名和9名患者中分别发现了两个良性突变，即c.311T>C（p.Ser104Pro）和c.1129C>T（p.Arg377Cys）。最后，PMS2基因表现出16个良性突变。值得注意的是，根据gnomAD数据库，检测到的致病突变在更广泛的亚洲人群中很少见。使用RT-qPCR和免疫组织化学进行的功能分析表明，具有致病突变的样本中BRCA1、BRCA2和TP53的表达降低，证实了它们对肿瘤抑制功能的影响。此外，药物敏感性分析表明，BRCA1和BRCA2突变与对一系列化疗药物的敏感性增加有关，支持了合成致死性的概念。然而，TP53对药物敏感性没有显著影响。
这项综合分析强调了BRCA1、BRCA2、TP53和PMS2在前列腺癌发病机制中的关键作用，并突出了特定人群遗传筛查的重要性。
