Effect of Polymorphisms in XPD on Clinical Outcomes of Platinum-Based Chemotherapy for Chinese Non-Small Cell Lung Cancer Patients

PurposeXeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Experimental Design353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg156Arg, Asp312Asn, Asp711Asp and Lys751Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing. ResultsVariant genotypes of XPD Asp312Asn, Asp711Asp and Lys751Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp312Asn, Asp711Asp and Lys751Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10−4, log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0–1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS. ConclusionsOur study provides evidence for the predictive role of XPD Asp312Asn, Asp711Asp and Lys751Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.研究目的：着色性干皮病D组基因（Xeroderma pigmentosum group D, XPD）编码一种参与核苷酸切除修复的DNA解旋酶，可清除铂类诱导的DNA损伤。XPD的遗传多态性可能影响DNA修复能力，进而导致化疗后患者的预后存在个体差异。本研究旨在探讨XPD多态性是否会影响接受铂类化疗的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的临床疗效。 实验设计：本研究纳入353例接受一线铂类化疗的III~IV期非小细胞肺癌患者。采用基质辅助激光解吸电离飞行时间质谱（matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF MS）或基于PCR的测序技术，对4个具有潜在功能的XPD多态位点（Arg156Arg、Asp312Asn、Asp711Asp及Lys751Gln）进行基因分型。 研究结果：XPD Asp312Asn、Asp711Asp及Lys751Gln的变异基因型与非小细胞肺癌患者较差的生存期显著相关（log-rank检验分别得到P=0.006、0.006、0.014）。以Asp312Asn、Asp711Asp、Lys751Gln顺序命名的最常见单倍型GCA，同样对非小细胞肺癌患者的生存期表现出显著的风险效应（log-rank P=0.001）。该效应在IIIB期患者中更为显著（log-rank检验P=2.21×10⁻⁴）。在体力状态评分为0~1分及腺癌患者中，同样观察到XPD变异单倍型的风险升高。但未发现上述多态性与化疗应答及无进展生存期（progression-free survival, PFS）存在显著关联。 研究结论：本研究证实，XPD Asp312Asn、Asp711Asp及Lys751Gln多态性/单倍型可作为接受铂类化疗的不可手术晚期非小细胞肺癌患者预后的预测标志物。