基于DNA修复基因多态性的肺癌患者生命质量自我评价影响因素追踪研究

Lung cancer is the first leading cause of cancer-related death in China. It is particularly important to improve quality of life (QOL) among patients with lung cancer due to the low rate of early diagnosis and the short survival time of lung cancer. QOL in lung cancer patients is assessed mainly by self-reported scales. Patient-reported QOL has dynamic change characteristics. There is emerging evidence for a genetic basis of patient-reported QOL outcomes, which are also affected by a variety of non-genetic (environmental) factors. However, there are few QOL-related studies involving dynamic change characteristics of QOL and genetic factors. Our previous study has revealed that single nucleotide polymorphisms (SNP) of DNA repair genes (ERCC1, XPD, BRCA1) are significantly associated with treatment response and prognosis in lung cancer patients. We speculated that SNPs of DNA repair genes may affect QOL of lung cancer. This prospective follow-up study involves 300 patients with lung cancer. The following work will be carried out: assess QOL for five times using self-reported scales (EORTC QLQ-C30, QLQ-LC13, SCL90, SAS and SDS); detect 12 tagSNPs of ERCC1, XPD and BRCA1 by Taqman probe assay; survey non-genetic factors affected QOL by questionnaire such as demographic factors, sociological factors and therapeutic factors. By analysis, the influence of SNPs and haplotypes and gene-environment interaction on self-reported QOL will be revealed. This study aims to investigate the dynamic change characteristics of QOL and investigate the influence of DNA repair gene polymorphisms on self-reported QOL. This prospective follow-up study may provide the theoretical basis to develop individualized physical/mental intervention programs and improve prognosis and long-term survival of patients with lung cancer.

肺癌居我国癌症死因首位，早期诊断率低，生存时间短，提高患者生命质量（QOL）尤为重要。肺癌QOL自我评价有动态变化特点并受到遗传和环境多种因素的影响。既往研究较少探讨遗传因素在QOL动态变化中的作用。我们前期研究表明DNA修复基因多态性（SNPs）与肺癌生存期显著相关，推测其可能影响肺癌QOL。本研究拟通过追踪调查按时间顺序5次采集300例肺癌患者的QOL自评结果，以Taqman探针法检测患者DNA修复途径中功能相关的3个基因的12个tagSNPs，并设计问卷调查患者QOL非遗传影响因素，综合分析明确肺癌患者QOL自我评价的动态变化规律，明确DNA修复相关基因SNPs和单倍型对肺癌QOL自评变化的影响及其与非遗传因素的交互作用。本研究旨在明确肺癌QOL自我评价的动态变化和影响因素，为根据个体特点及时对患者进行心理/生理干预，改善预后和远期生存状态提供理论依据。

肺癌是我国发病率和死亡率最高的肿瘤，患者生命质量和预后均较差。既往研究较少探讨遗传因素对肺癌生命质量的影响。本研究调查了300例肺癌患者的生命质量，采用iMLDR多重SNP分型技术检测ERCC1、XPD、BRCA1、RAPGEF6及CSE1L基因的14个SNP位点，并对患者进行了生存时间随访，综合分析明确了SNPs和单倍型对肺癌生命质量和生存时间的影响。此外，还通过分析29825名肺癌登记患者的随访数据，明确了癌症知情情况对患者生存的影响。主要结果为：1. ERCC1、BRCA1、ERCC2的SNP和单倍型均与肺癌生命质量的多个领域相关。ERCC1 rs11615 G与情绪功能较差有关（P=0.041）；ERCC1 rs762562-rs3212986 AA单倍型、ERCC1 rs3212986-rs11615 AG单倍型、BRCA1 rs1799966-rs3737559-rs8067269 TCG和CTA单倍型、ERCC2 rs13181-rs3916874-rs238416 TCT和TCC单倍型分别与情绪功能、认知功能、躯体功能、食欲丧失、咽下困难、气促、外周神经病变、其他部位痛、胸痛等症状相关，患者生命质量较差（P<0.05）。2.教育背景、临床分期、化疗次数、子女数目和吸烟分别与总健康状况、恶心呕吐症状、经济困难和咽下困难、外周神经病变、胸痛等生命质量领域有关（P<0.05）。3. ERCC1 rs3212986-rs11615 CA单倍型和ERCC2 rs13181-rs3916874-rs238416 GCC单倍型是肺癌患者焦虑的保护因素。4. BRCA1 rs1799966 CC型、rs8067269 AA型、CCA单倍型与肺癌患者生存时间较长相关（P<0.05）。BRCA1 CCA/CCA单倍型是肺癌生存的保护因素（HR=0.107，95%CI=0.015-0.770，P=0.026）。5.知晓癌症病情的肺癌患者生存时间显著长于不知病情的患者（P<0.001），癌症病情知晓情况是肺癌患者生存时间的独立影响因素（HR=0.826, P<0.001）。研究结果明确了ERCC1、XPD、BRCA1基因多态性/单倍型、人口学特点和临床特点对肺癌患者生命质量和生存时间的影响，有助于临床实践中及时对患者进行针对性的心理生理干预，改善生命质量和预后。