Qian Danwen, Liu Hongliang, Zhao Lingling, Wang Xiaomeng, Luo Sheng, Moorman Patricia G, Patz Edward F, Su Li, Shen Sipeng, Christiani David C, Wei Qingyi
Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
Transl Lung Cancer Res. 2020 Jun;9(3):575-586. doi: 10.21037/tlcr-19-318.
Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC).
We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients.
In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs ( rs9673682 T>G and rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10] and 1.18 (95% CI: 1.08-1.29 and 1.32×10, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of in 373 transformed lymphoblastoid cell-lines (P=7.20×10). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues.
Genetic variants in of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of rs115613985 is warranted.
抗体依赖的细胞毒性作用和吞噬作用均可激活固有免疫，而Fcγ受体（FCGR）介导的吞噬作用是这一过程的重要组成部分。我们评估了FCGR相关基因中的单核苷酸多态性（SNP）与非小细胞肺癌（NSCLC）患者生存之间的关联。
我们使用来自前列腺、肺、结肠和卵巢（PLCO）癌症筛查试验的已发表全基因组关联研究（GWAS）数据集，评估了97个FCGR相关基因中的24734个SNP与1185例NSCLC患者生存之间的关联，并在另一个包含894例NSCLC患者的独立数据集中验证了结果。
在采用贝叶斯错误发现概率（BFDP）进行多重检验校正的单基因座分析中，我们发现1084个SNP与总生存期（OS）显著相关（P<0.050且BFDP≤0.80），其中两个独立的SNP（rs9673682 T>G和rs115613985 T>A）在来自哈佛肺癌易感性（HLCS）研究的另一个包含894例患者的GWAS数据集中得到进一步验证，OS的合并等位基因风险比分别为0.87 [95%置信区间（CI）：0.81 - 0.94，P = 5.90×10]和1.18（95% CI：1.08 - 1.29，P = 1.32×10）。表达数量性状位点分析表明，rs9673682 G等位基因与373个转化淋巴母细胞系中的mRNA表达水平升高显著相关（P = 7.20×10）。差异表达分析的其他证据进一步支持了其对肺癌患者OS的肿瘤抑制作用，肺鳞癌和腺癌中的mRNA表达水平均低于相邻正常组织。
FCGR介导的吞噬作用途径中的基因变异可能是NSCLC生存的有前景的预测指标，可能是通过调节基因表达，但rs115613985的分子机制还需要进一步研究。
