基于全外显子组测序的上皮性卵巢癌同源重组缺陷检测

Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.

作者信息

Chiang Ying-Cheng, Huang Hsien-Neng, Kuo Kuan-Ting, Hwu Wuh-Liang, Lin Po-Han

机构信息

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei City, Taiwan.

Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei City, Taiwan.

出版信息

J Ovarian Res. 2025 Jan 30;18(1):19. doi: 10.1186/s13048-024-01565-3.

DOI:10.1186/s13048-024-01565-3

PMID:39885596

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11780812/

Abstract

BACKGROUND

The homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC.

METHODS

We enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC.

RESULTS

The HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice CDx test (r = 0.82, p < 0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p = 0.002) as well as the superior progression-free survival (both log-rank p = 0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, p = 0.013) or WES-based test Myriad MyChoice CDx test (HR 0.34, 95% CI 0.14-0.80, p = 0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients.

CONCLUSION

The WES-based test is a potential option for determining the HRD status in EOC patients, and desires for further validation in large-scale cohorts.

摘要

背景

同源重组缺陷（HRD）检测是识别上皮性卵巢癌（EOC）患者是否能从聚（二磷酸腺苷 - 核糖）聚合酶抑制剂（PARPi）治疗中获益的重要工具。使用基于全外显子组测序（WES）的平台可以提供基因突变和HRD评分信息；然而，基于WES的HRD检测在EOC中的临床价值尚未得到充分验证。

方法

我们纳入了40例EOC患者作为训练队列，23例作为验证队列。使用scarHRD软件计算基于WES的HRD评分。我们首先评估了由Myriad MyChoice CDx定义的HRD状态的一致性，然后评估了HRD对EOC患者临床预后的价值。

结果

在训练队列中，基于WES检测定义的HRD评分与Myriad MyChoice CDx检测的评分呈正相关（r = 0.82，p < 0.01）。与Myriad检测的HRD状态相比，基于WES的HRD检测的敏感性、特异性、阳性预测值和阴性预测值分别为93.5%（29/31）、77.8%（7/9）、93.5%（29/31）和77.8%（7/9）。基于WES的scarHRD检测和Myriad MyChoice CDx检测定义为HRD阳性的患者均与铂敏感反应高度相关（Fisher精确检验，p均 = 0.002）以及无进展生存期更长（对数秩检验，p均 = 0.002）。纳入最佳减瘤手术的多变量Cox回归模型显示，无论是由Myriad MyChoice CDx检测（风险比（HR）0.33，95%置信区间（CI）0.14 - 0.79，p = 0.013）还是基于WES的检测定义为HRD阳性的患者，复发风险均降低。9例患者在参与HR DNA修复的基因中存在突变，且所有这些患者的HRD均为阳性。在验证组中，23例患者通过基于WES的检测被定义为HRD阳性。6例HRD阳性患者和5例HRD阴性患者接受了PARPi维持治疗。PARPi在HRD阳性患者中的中位反应间期为17个月，在HRD阴性患者中为3个月。