A case-control study on the genetic risks for development of EGFR mutant and wild-type lung adenocarcinoma in never-smoking Chinese population

Abstract

Being the most common malignancy worldwide, killing more than 1.4 million people every year, lung cancer has the highest cancer mortality worldwide. The majority (80%-90%) of lung cancer cases are attributable to smoking. Still, there is around 25% lung cancer cases in overall (10-15% in Europe and North America, 30-40% in Asia) arises in lifelong never smokers. Lung cancer in never smokers (LCINS) ranks as the seventh leading cause of cancer death and is considered as a different disease from those in smokers in terms of epidemiology, pathology and molecular characteristics.

Lung cancer is a heterogeneous disease with different molecular subtypes driven by specific oncogenes: EGFR, ALK, KRAS, etc. The inconsistent evidences from existing genetic association studies might be due to heterogeneity in different molecular subtypes of patients. To understand different mechanisms underlying different molecular subtypes of lung cancer, a two stage case-control study was carried out attempting to evaluate the predisposition SNPs in EGFR mutant and EGFR wild-type lung adenocarcinoma separately among never smokers. Lung cancer cases were recruited from Queen Mary Hospital, Hong Kong and De Sao Januario Hosptial, Macau. Healthy controls were recruited from blood donors in Hong Kong Red Cross. 10mL blood samples were taken for all subjects for SNP MassArray. Questionnaires including demographics, environmental exposures at home/workplace, family histories of lung cancer/other cancer etc. were administered to all subjects. The genetic associations between 51 candidate SNPs and lung cancer development were explored at SNP, gene and pathway level. In the discovery stage, at SNP level, six SNPs (rs238406, rs238416, rs1618536 of ERCC2 gene; rs2854508, rs3213328 of XRCC1 gene in DNA repair pathway; rs2069840 of IL-6 gene in inflammatory pathway) showed significant association with EGFR mutant lung adenocarcinoma among 103 EGFR mutant age- and gender-matched pairs; two SNPs (rs611624 of ATM gene; rs50871 of ERCC2 gene in DNA repair pathway) and seven SNPs (rs189037, rs599558, rs228592, rs609261, rs227062, rs664677, rs609429 of ATM) showed significant/ marginally significant association with EGFR wild-type lung adenocarcinoma among 78 EGFR wild-type age- and gender-matched pairs. The results suggested that predisposition SNPs for EGFR mutant and wild-type lung adenocarcinoma might be different. At gene level, haplotype GGG among three SNPs (rs2069840, rs2069852, rs2066992) of IL-6 in relation to the EGFR mutant lung adenocarcinoma were indicated. At pathway level, gene-gene and gene-environment interactions in DNA repair pathway and inflammatory pathway were revealed for EGFR mutant and wild-type matched pairs. In the validation stage among 84 independent EGFR mutant cases in comparison to 103 Chinese Han, Beijing and 105 Chinese Han, Southern public controls in 1000 genome database, the association for IL-6 rs2069840 was confirmed (P=0.02; OR: 2.76; 95%CI: 1.13-6.72). IL-6 rs2069840 influences IL-6 protein level through binding of transcription factors. IL-6, acting as an EGFR-dependent (paracrine) and independent (autocrine) manner activates STAT3. ERCC2 rs238406 showed a marginally significant association with EGFR mutant lung adenocarcinoma (P=0.096). SNPs associated with EGFR wild-type lung adenocarcinoma need future validation.