基因组不稳定性 (GI)/同源重组缺陷 (HRD) 评分，计算为杂合性丢失 (LOH)、大规模状态转换 (LST) 和端粒等位基因失衡 (TAI) 事件的总和，用于指导多种癌症的治疗选择，但其与肺癌基因组特征、临床病理特征和预后的关系知之甚少，这可能导致前瞻性研究中的群体偏差。我们回顾性分析了 1011 名肺癌患者，他们的肿瘤样本成功地通过高通量测序面板进行了分析，包括 GI/HRD 评分。许多抑癌基因的改变与较高的 GI/HRD 评分相关，TP53 的双等位基因失活与较高的 GI/HRD 评分相关。两个基因改变的组合表现出比单个基因改变更高的 GI/HRD 分数。 GI/HRD 评分与肺腺癌晚期相关，但与肺鳞状细胞癌无关。此外，GI/HRD 评分较高的患者的总生存期和无进展生存期显着短于 GI/HRD 评分较低的患者。最后，与具有较低 GI/HRD 评分和野生型 TP53 的患者相比，具有较高 GI/HRD 评分和 TP53 改变组合的患者表现出极差的预后（总生存期、训练队列、风险比 (HR) = 8.56 ，P < 0.001；验证队列，HR = 6.47，P < 0.001；无进展生存期，HR = 4.76，P < 0.001）。我们的研究揭示了 GI/HRD 评分对肺腺癌的预后价值，但不适用于所有肺癌。此外，GI/HRD 评分和 TP53 状态的结合可能是预测肺腺癌患者预后的一种有前景的策略。© 2023。作者。

The genomic instability (GI) /homologous recombination deficiency (HRD) score, calculated as the sum of the events of loss of heterozygosity (LOH), large-scale state transition (LST) and telomere allele imbalance (TAI), is used to guide the choice of treatment in several cancers, but its relationship with genomic features, clinicopathological characteristics and prognosis in lung cancer is poorly understood, which could lead to population bias in prospective studies. We retrospectively analyzed 1011 lung cancer patients whose tumor samples were successfully profiled by high-throughput sequencing panel including GI/HRD score. Alterations of many cancer suppressor genes were associated with higher GI/HRD scores, biallelic inactivation of TP53 was correlated with a high GI/HRD score. A combination of two gene alterations exhibited a higher GI/HRD scores than single gene alterations. The GI/HRD score was associated with advanced stages in lung adenocarcinoma but not in lung squamous cell carcinoma. Furthermore, patients with higher GI/HRD scores had significantly shorter overall survival and progression-free survival than patients with lower GI/HRD scores. Finally, patients with a combination of a higher GI/HRD scores and TP53 alteration exhibited an extremely poor prognosis compared with patients with a lower GI/HRD scores and wild-type TP53 (overall survival, training cohort, hazard ratio (HR) = 8.56, P < 0.001; validation cohort, HR = 6.47, P < 0.001; progression-free survival, HR = 4.76, P < 0.001). Our study revealed the prognostic value of the GI/HRD score in lung adenocarcinoma, but not for all lung cancer. Moreover, the combination of the GI/HRD score and TP53 status could be a promising strategy to predict the prognosis of patients with lung adenocarcinoma.© 2023. The Author(s).