Fujita Cancer Center, Fujita Health University, Toyoake, Japan.
Department of Urology School of Medicine, Fujita Health University, Toyoake, Japan.
Cancer Med. 2023 Apr;12(7):8154-8165. doi: 10.1002/cam4.5617. Epub 2023 Jan 16.
The significance of BRCA alterations has been implicated in the development of metastatic castration-resistant prostate cancer (PC). The details of the frequency and significance of BRCA alterations in localized PC remain unknown. In this study, we investigated the frequency and clinical significance of BRCA alterations in localized PCs using an in-house next-generation sequencer (NGS) system.
DNA was extracted from formalin-fixed paraffin-embedded tissues of surgical specimens from 126 patients with clinically localized PC who underwent radical prostatectomy. The mutation information of 164 cancer genes was analyzed using the PleSSision-Rapid test. Both copy number (CN) variation and loss of heterozygosity of various genes, such as BRCA1 and BRCA2, were estimated and reported.
Next-generation sequencer analyses revealed that the BRCA2 CN was decreased in 17 patients (13.5%) and the BRCA1 CN in six (4.8%) patients. NGS-based CN values were shown to be highly correlated with droplet digital PCR-based CN values. Tissue-specific BRCA expression investigated using the Human Protein Atlas showed that the decreased CN of BRCA2, but not BRCA1, is responsible for the decreased BRCA activity in PC. Ten of the 22 patients with decreased BRCA2 CN were presumed to have somatic heterozygous deletion. There were no observed associations between the heterozygous deletion of BRCA2 and various clinicopathological parameters. Furthermore, three of 10 patients developed biochemical recurrence within 3 months after surgery. Multivariate analyses revealed that the initial prostate-specific antigen levels and BRCA2 CN were independent factors for biochemical recurrence.
Our results suggest that a decrease in BRCA2 CN may be used as a biomarker for predicting recurrence after surgery in localized PC. Early screening for somatic alterations in BRCA2 using NGS may help to broadly predict the risk of PC progression.
BRCA 改变的意义已被牵涉到转移性去势抵抗性前列腺癌（PC）的发展中。局限性 PC 中 BRCA 改变的频率和意义的细节尚不清楚。在这项研究中，我们使用内部的下一代测序（NGS）系统研究了局限性 PC 中 BRCA 改变的频率和临床意义。
从 126 名接受根治性前列腺切除术的临床局限性 PC 手术标本的福尔马林固定石蜡包埋组织中提取 DNA。使用 PleSSision-Rapid 测试分析了 164 个癌症基因的突变信息。估计并报告了各种基因（如 BRCA1 和 BRCA2）的拷贝数（CN）变化和杂合性丢失。
下一代测序分析显示，17 名患者（13.5%）的 BRCA2 CN 降低，6 名患者（4.8%）的 BRCA1 CN 降低。基于 NGS 的 CN 值与基于液滴数字 PCR 的 CN 值高度相关。使用人类蛋白质图谱进行的组织特异性 BRCA 表达研究表明，BRCA2 的降低 CN，而不是 BRCA1，导致 PC 中 BRCA 活性降低。22 名 BRCA2 CN 降低的患者中有 10 名被认为存在体细胞杂合性缺失。BRCA2 杂合性缺失与各种临床病理参数之间没有观察到相关性。此外，10 名患者中有 3 名在手术后 3 个月内出现生化复发。多变量分析显示，初始前列腺特异性抗原水平和 BRCA2 CN 是生化复发的独立因素。
我们的结果表明，BRCA2 CN 的降低可用作预测局限性 PC 手术后复发的生物标志物。使用 NGS 对 BRCA2 的体细胞改变进行早期筛查可能有助于广泛预测 PC 进展的风险。
