The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79-0.94, p = 0.0007), 1.31 (1.16-1.47, p = 6.0 × 10-5 ) and 1.27 (1.12-1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (ptrend < 0.0001 for OS and ptrend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.

中文翻译：

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内体相关基因中KIF16B和NEDD4L中的新遗传变异与非小细胞肺癌的生存有关。

内体是大多数真核细胞内部的膜结合器官，通过将内吞抗原传递到MHC I类和II类途径，在适应性免疫中发挥重要作用。在这里，通过分析来自两个已发表的全基因组关联研究（GWAS）的基因分型数据，我们评估了内体相关基因集中的遗传变异与非小细胞肺癌（NSCLC）患者生存之间的关联。该发现在单基因座分析中包括220个基因中的44,112个（3,478个基因型和40,634个估算的）单核苷酸多态性（SNP），这些基因与1185名来自前列腺癌，肺癌，结肠直肠癌和卵巢癌（PLCO）癌症筛查试验的NSCLC患者的生存相关。在通过哈佛肺癌易感性研究对另外984名NSCLC患者中的821个与生存相关的重要SNPs进行验证后，仍有14个SNPs仍然有意义。PLCO数据集的最终多元逐步Cox比例危险回归模型确定了三个潜在功能且独立的SNP（即KIF16B rs1555195 C> T，NEDD4L rs11660748 A> G和rs73440898 A> G），调整后的危险比（HR）为0.86 （95％置信区间[CI] = 0.79-0.94，p = 0.0007），1.31（1.16-1.47，p = 6.0×10-5）和1.27（1.12-1.44，p = 0.0001），分别。对这三个SNP的不利基因型的综合分析显示了基因型与生存的关联性趋势（OS的prend <0.0001，疾病特异性生存的ptrend <0.0001）。此外，存活相关的KIF16B rs1555195T等位基因与肺组织和血细胞中KIF16B的mRNA表达水平降低显着相关。因此，内体相关基因的遗传变异可能是NSCLC生存的生物标记，可能是通过调节相应基因的表达来实现的。