Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, 10675, Taiwan.
Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, 10675, Taiwan.
BMC Cancer. 2024 Oct 25;24(1):1319. doi: 10.1186/s12885-024-13045-4.
Interpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.
We collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.
We identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.
PTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.
解读遗传变异仍然是前列腺癌（PCa）的一个挑战。尽管有许多注释工具可用于优先考虑因果变异，但这些变异的临床相关性很少被研究。
我们收集了一项队列研究，该研究纳入了 2017 年 6 月至 2020 年 12 月的 274 例 PCa 患者，并对这些患者的 19 个 DNA 损伤修复（DDR）基因进行了测序，探讨了这些不同方法的临床后果。我们还比较了携带 DDR 基因突变与未携带基因突变的患者在接受雄激素受体（AR）靶向治疗后的全因和 PCa 特异性生存情况。
我们使用不同的注释方法在总共 14 例（5.1%）患者中鉴定出 19 个 DDR 基因中的 13 个变异，其中 4 个变异被注释为致病性，11 个变异被预测为蛋白截断变异（PTV），4 个变异的综合注释依赖性耗竭评分（Combined Annotation-Dependent Depletion scores）>30，只有 1 个变异被所有三种方法鉴定为致病性变异或具有功能效应。携带 PTV 的 PCa 患者与发病年龄早、癌症分期高以及对 AR 靶向治疗反应差显著相关。然而，携带代理有害变异的患者仅与较高的 T（肿瘤）分期和 N（节点）分期相关，而与其他临床特征无关。在接受 AR 靶向治疗的患者中，携带 PTV 的患者全因死亡风险增加（调整后的危险比[aHR]=3.51，95%置信区间[CI]：1.0611.56）和 PCa 特异性死亡风险增加（aHR=4.49，95% CI：1.8710.77），调整后与未携带 PTV 的患者相比。由于患者数量较少，我们无法检查特定基因的风险。
PTV 可能有助于指导 PCa 的治疗和早期筛查，而针对致病性变异的人群特异性数据仍在积累中。
