Genome-wide association study of familial lung cancer

Abstract

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

“…All the samples were genotyped using the Illumina OncoArray-500K BeadChip and 502,933 SNPs remained for analysis after quality control processes. Two independent lung cancer GWAS data were analyzed in the replication study: TRICL Affymetrix GWAS data including 5,397 controls and 4,950 lung cancer cases (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000876.v1.p1), and GELCC (Genetic Epidemiology of Lung Cancer Consortium) familial lung cancer GWAS including 744 controls and 686 lung cancer patients genotyped using Illumina HumanOmniExpressExome-8v1 array [38-39]. The demographic and clinical characteristics of each dataset including age, gender, and smoking status, histology subtypes, etc., were provided in Table 1.…”

Systematic analysis of genetic variants in cancer-testis genes identified two novel lung cancer susceptibility loci in Chinese population

“…In addition, associations between genetic variants in CT genes and the susceptibility of cancers have been described in previous studies. For example, genetic variants in HORMAD2 and GPATCH2 were reported associated with lung cancer risk [9,10], and variants in CTNNA2, CCDC33 and SPAG17 showed significant association with the susceptibility of breast cancer [11,12]. All these studies suggested that genetic variants in CT genes could also contribute to the development of cancers.…”

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

“…The missense SNP rs16969968 of CHRNA5 is significantly associated with both nicotine dependence and increased risk of lung cancer [47,48]. The genome-wide associations of CHRNA3 and CHRNA5 on 15q25.1 were confirmed in familial SCC [49]. The CHRNA3 polymorphism functions as a genetic modifier of lung adenocarcinoma risk in the Chinese population, particularly in nonsmoking women [50].…”