非小细胞肺癌同源重组修复通路基因与临床特征的相关性分析

Correlation of homologous recombination repair genes with clinical features in non-small cell lung cancer

摘要

目的 采用基因组不稳定评分（genomic instability score，GIS）描述非小细胞肺癌患者的同源重组修复缺陷（homologous recombination deficiency，HRD）状态，探讨HRD状态及同源重组通路基因（homologous recombination repair，HRR）与临床特征的相关性。 方法 本研究纳入2020年1月至2022年1月在重庆医科大学附属第一医院接受治疗的335例非小细胞肺癌患者，采用二代测序法检测GIS评分及35个HRR基因，根据杂合性缺失（loss of heterozygosity，LOH）、端粒等位基因失衡（telomeric allelic imbalance，TAI）、大片段迁移（large-scale state transition，LST）综合评估GIS评分。GIS评分及HRR基因与临床特征之间的关系通过Mann-Whitney U检验，Kruskal-Wallis检验和Dunn-Bonferroni检验分析。GIS评分和肿瘤突变负荷（tumor mutation burden，TMB）值的相关性采用Spearman分析。 结果 在335例患者中，男性患者、年龄大、分期晚、有吸烟史、鳞癌均会导致GIS评分更高，GIS评分M_d （P₂₅，P₇₅ ）分别是13（4，26.75），12（3，22.5），21.5（12，30），16（4，27）和24（18，38.25）（Z=-5.083，P<0.001；Z=2.973，P=0.003；Z=8.225，P<0.001；Z=4.655，P<0.001；Z=-7.082，P<0.001）。HRR体系基因突变组样本GIS评分高于野生组，2组GIS评分分别为18.5（5.25，28.75）和6（1，16）（Z=5.012，P<0.001）。共检测到33个HRR相关基因突变，主要集中在ATM、RECQL4、ATR、FANCM、BRCA1、FANCA、BRIP1、NBN、WRN等基因，其中BRCA2、FANCI、FANCA基因突变均会导致GIS评分升高，GIS评分M_d （P₂₅，P₇₅ ）分别是34（25.25，51），31.5（14.5，50）和22（12，44）（Z=-2.805，P=0.005；Z=-2.216，P=0.027；Z=-2.478，P=0.013）。GIS评分和TMB值之间呈正相关（r_s =0.504，P<0.001）。 结论 揭示中国非小细胞肺癌患者GIS评分及HRR基因突变特征，提示基于二代测序的GIS评分及HRR基因检测可能成为非小细胞肺癌患者靶向治疗及免疫治疗新的生物标志物。

Abstract

Objective To investigae the status of homologous recombination deficiency（HRD）in non-small cell lung cancer（NSCLC）patients by using genomic instability score（GIS）and the correlation of HRD status and homologous recombination repair（HRR）genes with the clinical features of NSCLC. Methods A total of 335 patients with NSCLC who were treated in The First Affiliated Hospital of Chongqing Medical University from January 2020 to January 2022 were enrolled，and next-generation sequencing was used to measure GIS score and 35 HRR genes. GIS score was determined based on loss of heterozygosity，telomeric allelic imbalance，and large-scale state transition. The Mann-Whitney U test，the Kruskal-Wallis test，and the Dunn-Bonferroni test were used to investigate the correlation of GIS score and HRR genes with clinical features. The Spearman analysis was used to investigate the correlation between GIS score and tumor mutation burden（TMB）. Results Among the 335 patients，male sex，older age，advanced stage，smoking history，and squamous cell carcinoma all contributed to a higher GIS score，and the M_d（P₂₅，P₇₅ ）values of GIS scores were 13（4，26.75），12（3，22.5），21.5（12，30），16（4，27），and 24（18，38.25），respectively（Z=-5.083，P<0.001；Z=2.973，P=0.003；Z=8.225，P<0.001；Z=4.655，P<0.001；Z=-7.082，P<0.001）. The GIS score of the samples in the HRR somatic mutation group was significantly higher than that in the wild group，with a M_d（P₂₅，P₇₅ ）value of 18.5（5.25，28.75）and 6（1，16），respectively（Z=5.012，P<0.001）. A total of 33 HRR-related gene mutations were found，which were mainly located in the ATM，RECQL4，ATR，FANCM，BRCA1，FANCA，BRIP1，NBN，and WRN genes，and among these genes，mutations in the BRCA2，FANCI，and FANCA genes could lead to the increase in GIS score，with a M_d（P₂₅，P₇₅ ）value of 34（25.25，51），31.5（14.5，50），and 22（12，44），respectively（Z=-2.805，P=0.005；Z=-2.216，P=0.027；Z=-2.478，P=0.013）. GIS score was positively correlated with TMB（r_s =0.504，P<0.001）. Conclusion This study reveals GIS score and the characteristics of HRR mutations in Chinese NSCLC patients，and these findings suggest that GIS score and HRR gene detection based on next-generation sequencing can become new biomarkers for targeted therapy and immunotherapy in NSCLC patients.

关键词

非小细胞肺癌 / 同源重组修复缺陷 / 基因组不稳定评分 / 同源重组通路

Key words

non-small cell lung cancer / homologous recombination deficiency / genomic instability score / homologous recombination repair

基金资助

重庆英才·创新创业示范团队，新型生物标志物创新转化研究资助项目(CQYC202203091342)