引言: 铂类化学药物是卵巢癌患者的一线治疗策略。卵巢癌的低预后与肿瘤细胞对该治疗的异质性密切相关，因此了解卵巢癌的铂敏感性对改善患者的生活质量和临床结果很有帮助。利用HRDetect对患者的同源重组修复缺陷进行表征可用于预测患者对铂类化学药物的反应。然而，每个单个特征对HRD评分的贡献是否与铂敏感性相关仍然不明确。方法: 我们分析了TCGA数据库中196名接受铂类化学药物治疗的患者的全外显子组测序数据。确定了各个遗传特征是否能指示患者对铂类化学药物的反应和预后，并将其集成到使用LASSO回归模型评估其预测性能的Pt分数中。结果与讨论: 多个遗传特征，包括BRCA1/2基因的双等位基因不活化和参与HR通路的基因，参与DNA损伤修复(DDR)的基因的多个体突变，以及先前报道的与HRD相关的特征，被发现与铂敏感性和改善预后密切相关。更高的SBS39或ID6突变标记预示着更好的总生存率。此外，chr4p或chr5q的一等位基因丧失异质性(LOH)预测明显更好的无病生存率。值得注意的是，其中一些特征发现与HRD无关。而HRD相关特征SBS3与铂敏感性无关。使用LASSO模型综合所有候选标记生成Pt分数，与HRDetect相比，在确定铂敏感性和预测患者预后方面显示了更好的预测能力，并在一个独立队列中进行了验证。我们研究的结果对于制定有效的卵巢癌铂类化学药物治疗策略至关重要。版权所有©2023 Yang, Wei, Li, Lan, Liu, Gao, Zhang, Fan and Li.

Introduction: Platinum-based chemotherapy is the first-line treatment strategy for ovarian cancer patients. The dismal prognosis of ovarian cancer was shown to be stringently associated with the heterogeneity of tumor cells in response to this therapy, therefore understanding platinum sensitivity in ovarian cancer would be helpful for improving patients' quality of life and clinical outcomes. HRDetect, utilized to characterize patients' homologous recombination repair deficiency, was used to predict patients' response to platinum-based chemotherapy. However, whether each of the single features contributing to HRD score is associated with platinum sensitivity remains elusive. Methods: We analyzed the whole-exome sequencing data of 196 patients who received platinum-based chemotherapy from the TCGA database. Genetic features were determined individually to see if they could indicate patients' response to platinum-based chemotherapy and prognosis, then integrated into a Pt-score employing LASSO regression model to assess its predictive performance. Results and discussion: Multiple genetic features, including bi-allelic inactivation of BRCA1/2 genes and genes involved in HR pathway, multiple somatic mutations in genes involved in DNA damage repair (DDR), and previously reported HRD-related features, were found to be stringently associated with platinum sensitivity and improved prognosis. Higher contributions of mutational signature SBS39 or ID6 predicted improved overall survival. Besides, arm-level loss of heterozygosity (LOH) of either chr4p or chr5q predicted significantly better disease-free survival. Notably, some of these features were found independent of HRD. And SBS3, an HRD-related feature, was found irrelevant to platinum sensitivity. Integrated all candidate markers using the LASSO model to yield a Pt-score, which showed better predictive ability compared to HRDetect in determining platinum sensitivity and predicting patients' prognosis, and this performance was validated in an independent cohort. The outcomes of our study will be instrumental in devising effective strategies for treating ovarian cancer with platinum-based chemotherapy.Copyright © 2023 Yang, Wei, Li, Lan, Liu, Gao, Zhang, Fan and Li.