Liu Lihua, Liu Hongliang, Luo Sheng, Patz Edward F, Glass Carolyn, Su Li, Lin Lijuan, Christiani David C, Wei Qingyi
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University Nanning, Guangxi 530021, China.
Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.
Am J Cancer Res. 2020 Aug 1;10(8):2603-2616. eCollection 2020.
Although lymphangiogenesis is a vital step in lung cancer metastasis, the association between lymphangiogenesis and non-small cell lung cancer (NSCLC) survival remains unclear. Since single-nucleotide polymorphisms (SNPs) have been reported to predict NSCLC survival, we investigated associations between SNPs in lymphangiogenesis-related pathway genes and NSCLC survival in a discovery genotyping dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility Study. We evaluated associations between 34,509 genetic variants (3252 genotyped and 31,257 imputed) in 247 genes involved in lymphangiogenesis-related pathway and NSCLC survival. After validation, we finally identified two independent SNPs ( rs11787670 A>G and rs67715745 T>C) to be significantly associated with NSCLC overall survival (OS), with adjusted hazards ratios of 0.77 and 0.83 (95% confidence interval =0.66-0.90, =7.20×10) and 0.84 (95% confidence interval =0.75-0.92, =3.50×10), respectively. Moreover, an increasing number of combined protective alleles of these two SNPs was significantly associated with an improved NSCLC OS and disease-specific survival (DSS) in the PLCO dataset ( =0.011 and 0.006, respectively). Furthermore, the addition of these protective alleles to the prediction model for the 5-year survival increased the time-dependent area under the curve both from 87% to 87.67% for OS (=0.029) and from 88.54% to 89.06% for DSS (=0.022). Subsequent expression quantitative trait loci (eQTL) functional analysis revealed that the rs11787670 G allele was significantly associated with an elevated mRNA expression in normal tissues. Additional analyses suggested a suppressor role for both and in NSCLC survival. Collectively, these findings indicated that rs11787670 A>G and rs67715745 T>C may be independent prognostic factors for NSCLC survival once further validated.
尽管淋巴管生成是肺癌转移的关键步骤，但淋巴管生成与非小细胞肺癌（NSCLC）生存之间的关联仍不明确。由于单核苷酸多态性（SNP）已被报道可预测NSCLC的生存情况，我们在前列腺、肺、结肠和卵巢（PLCO）癌症筛查试验的1185例患者的发现基因分型数据集中，研究了淋巴管生成相关通路基因中的SNP与NSCLC生存之间的关联，并在哈佛肺癌易感性研究的984例患者的另一个基因分型数据集中验证了这些发现。我们评估了参与淋巴管生成相关通路的247个基因中的34509个遗传变异（3252个基因分型和31257个推算）与NSCLC生存之间的关联。经过验证，我们最终确定了两个独立的SNP（rs11787670 A>G和rs67715745 T>C）与NSCLC总生存（OS）显著相关，调整后的风险比分别为0.77和0.83（95%置信区间=0.66 - 0.90，=7.20×10）以及0.84（95%置信区间=0.75 - 0.92，=3.50×10）。此外，在PLCO数据集中，这两个SNP的联合保护性等位基因数量增加与NSCLC OS和疾病特异性生存（DSS）改善显著相关（分别为=0.011和0.006）。此外，将这些保护性等位基因添加到5年生存预测模型中，OS的曲线下时间依赖性面积从87%增加到87.67%（=0.029），DSS从88.54%增加到89.06%（=0.022）。随后的表达定量性状位点（eQTL）功能分析表明，rs11787670 G等位基因与正常组织中mRNA表达升高显著相关。进一步分析表明，和在NSCLC生存中均起抑制作用。总体而言，这些发现表明，一旦进一步验证，rs11787670 A>G和rs67715745 T>C可能是NSCLC生存的独立预后因素。
