PDF(Pubmed)
Abstract：
Homologous recombination deficiency (HRD) score is a reliable indicator of genomic instability. The significance of HRD in nasopharyngeal carcinoma (NPC), particularly its influence on prognosis and the immune microenvironment, has yet to be adequately explored. Understanding HRD status comprehensively can offer valuable insights for guiding precision treatment. We utilised three cohorts to investigate HRD status in NPC: the Zhujiang cohort from local collection and the Hong Kong (SRA288429) and Singapore (SRP035573) cohorts from public datasets. The GATK (genome analysis toolkit) best practice process was employed to investigate germline and somatic BRCA1/2 mutations and various bioinformatics tools and algorithms to examine the association between HRD status and clinical molecular characteristics. We found that individuals with a negative HRD status (no-HRD) exhibited a higher risk of recurrence [hazard ratio (HR), 1.43; 95% confidence interval (CI), 2.03-333.76; p = 0.012] in the Zhujiang cohort, whereas, in the Singapore cohort, they experienced a higher risk of mortality (HR, 26.04; 95% CI, 1.43-34.21; p = 0.016) compared with those in the HRD group. In vitro experiments demonstrated that NPC cells with BRCA1 knockdown exhibit heightened sensitivity to chemoradiotherapy. Furthermore, the HRD group showed significantly higher tumour mutational burden and tumour neoantigen burden levels than the no-HRD group. Immune infiltration analysis indicated that HRD tissues tend to have a non-inflamed tumour microenvironment. In conclusion, patients with HRD exhibit a comparatively favourable prognosis in NPC, possibly associated with a non-inflammatory immune microenvironment. These findings have positive implications for treatment stratification, enabling the selection of more precise and effective therapeutic approaches and aiding in the prediction of treatment response and prognosis to a certain extent.
摘要：
同源重组缺陷(HRD)评分是基因组不稳定性的可靠指标。HRD在鼻咽癌中的意义特别是它对预后和免疫微环境的影响，还有待充分探索。全面了解HRD状况可以为指导精准治疗提供有价值的见解。我们利用三个队列来调查NPC中的HRD状况：来自本地收集的珠江队列以及来自公共数据集的香港（SRA288429）和新加坡（SRP035573）队列。GATK（基因组分析工具包）最佳实践过程用于研究种系和体细胞BRCA1/2突变以及各种生物信息学工具和算法，以检查HRD状态与临床分子特征之间的关联。我们发现，HRD状态阴性（无HRD）的个体表现出更高的复发风险[风险比（HR），1.43；95%置信区间(CI)，2.03-333.76；p=0.012]在珠江队列中，然而,在新加坡队列中，他们经历了更高的死亡风险(HR，26.04；95%CI，1.43-34.21；p=0.016）与HRD组相比。体外实验表明，BRCA1敲低的NPC细胞对放化疗的敏感性提高。此外，HRD组的肿瘤突变负荷和肿瘤新抗原负荷水平显著高于非HRD组.免疫浸润分析表明HRD组织倾向于具有非发炎的肿瘤微环境。总之,HRD患者在NPC中表现出相对良好的预后，可能与非炎性免疫微环境有关。这些发现对治疗分层有积极的意义，能够选择更精确和有效的治疗方法，并在一定程度上帮助预测治疗反应和预后。
