Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival.

Yang, Sen

Tang, Dongfang

Zhao, Yu C

Liu, Hongliang

Luo, Sheng

Stinchcombe, Thomas E

Glass, Carolyn

Su, Li

Shen, Sipeng

Christiani, David C

Wang, Qiming

Wei, Qingyi

2020-01-01T15:45:17Z

2020-01-01T15:45:17Z

2019-10-16

2020-01-01T15:45:16Z

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 two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small 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 single locus 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 model in the PLCO datasets identified three potentially functional and independent SNPs (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. This article is protected by copyright. All rights reserved.

0020-7136

1097-0215

https://hdl.handle.net/10161/19676

eng

Wiley

International journal of cancer

10.1002/ijc.32739

Non-small cell lung cancer

endosome pathway

genome-wide association study

single-nucleotide polymorphism

survival

Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival.

Journal article

Luo, Sheng|0000-0003-4214-5809

Glass, Carolyn|0000-0002-8850-9906

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

School of Medicine

Duke

Duke Cancer Institute

Institutes and Centers

Population Health Sciences

Basic Science Departments

Medicine, Medical Oncology

Medicine

Clinical Science Departments

Duke Clinical Research Institute

Biostatistics & Bioinformatics

Pathology

Published