Genetic predisposition to lung cancer: comprehensive literature integration, meta-analysis, and multiple evidence assessment of candidate-gene association studies

Junjun Wang,Na Wu,Shuai Yuan,Qingyun Liu,Ying Xiang,Zhifu Sun,Yafei Li,Tongjian Cai,Xiangyu Ma,Weijia Xie,Yuan Liu,Yao Zhang,Long Wu

doi:10.1038/s41598-017-07737-0

Junjun Wang, Na Wu + Show 11 more

Open Access

https://doi.org/10.1038/s41598-017-07737-0

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Journal: Scientific Reports	Publication Date: Aug 21, 2017
Citations: 88	License type: open-access

Affiliation: Army Medical University, Mayo Clinic

Abstract

More than 1000 candidate-gene association studies on genetic susceptibility to lung cancer have been published over the last two decades but with few consensuses for the likely culprits. We conducted a comprehensive review, meta-analysis and evidence strength evaluation of published candidate-gene association studies in lung cancer up to November 1, 2015. The epidemiological credibility of cumulative evidence was assessed using the Venice criteria. A total of 1018 publications with 2910 genetic variants in 754 different genes or chromosomal loci were eligible for inclusion. Main meta-analyses were performed on 246 variants in 138 different genes. Twenty-two variants from 21 genes (APEX1 rs1130409 and rs1760944, ATM rs664677, AXIN2 rs2240308, CHRNA3 rs6495309, CHRNA5 rs16969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1 rs4646903, CYP2E1 rs6413432, ERCC1 rs11615, ERCC2 rs13181, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164, MIR196A2 rs11614913, OGG1 rs1052133, PON1 rs662, REV3L rs462779, SOD2 rs4880, TERT rs2736098, and TP53 rs1042522) showed significant associations with lung cancer susceptibility with strong cumulative epidemiological evidence. No significant associations with lung cancer risk were found for other 150 variants in 98 genes; however, seven variants demonstrated strong cumulative evidence. Our findings provided the most updated summary of genetic risk effects on lung cancer and would help inform future research direction.

Highlights

IntroductionGenetic variants influencing lung-cancer risk fall into three categories: rare high-risk variants (prevalence of 1% or less), moderate-risk variants (prevalence of not more than 5%), and common low-risk variants (prevalence of more than 5%)
Genetic variants influencing lung-cancer risk fall into three categories: rare high-risk variants, moderate-risk variants, and common low-risk variants
A total of 2,910 genetic variants from 754 unique candidate genes or loci were eligible for further analyses

Summary

Introduction

Genetic variants influencing lung-cancer risk fall into three categories: rare high-risk variants (prevalence of 1% or less), moderate-risk variants (prevalence of not more than 5%), and common low-risk variants (prevalence of more than 5%). Over the past ten years, common genetic variations at 5p15.33 (TERT/CLPTM1L), 6p21.33 (BAT3/MSH5) and 15q25.1 (CHRNA5/ CHRNA3/CHRNB4) are identified to modify the lung cancer susceptibility in GWAS8–13 and GWAS-based www.nature.com/scientificreports/. Meta-analyses[14, 15] (eg, TERT rs2736100, CHRNA3 rs8042374, APOM rs3117582, MSH5 rs3131379, and GTF2H4 rs114596632) These only explain less than 10% of the risk contribution to lung cancer[16]. Candidate-gene approaches were the mainstay of genetic association studies before the GWAS era. They are relatively cost-effective and easy to perform. The main objective of our study was to identify, consolidate, and interpret genetic associations of common variants with lung cancer using a comprehensive research synopsis and systematic meta-analysis. To get a better insight of the differences in genetic variations among populations with different characters, associations stratified by ethnicity, histological types, and smoking status were examined

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