Abstract 2132: Cigarette smoking increases copy number alterations in non-small cell lung cancer

Abstract

Abstract BACKGROUND: Cigarette smoking is a well-established risk factor of lung cancer. How smoking induces oncogenesis in lung remains not fully understood. We conducted a genome-wide study of copy number and smoking pack-years in a large collection of non-small cell lung cancer (NSCLC) tumors on three different scales: whole genome, chromosome and focal region. METHODS: Genome-wide analyses of copy number and pack-years of cigarette smoking were performed on NSCLC tumors (n=264), which was randomly divided into a discovery set (n=134) and a validation set (n=130). Copy numbers were inferred from the dense single nucleotide polymorphisms array by dChip. On the scales of whole genome and chromosome, four indices were proposed to test large-scale copy number alterations (CNAs) patterns between heavy and light smokers: total CNAs events, continuous CNAs pattern, discrete CNAs pattern, and selecting effect with respect to gene locations. On the scale of focal region, genome-wide association (GWA) analyses of focal copy number and smoking pack-years were performed on 256,554 loci. RESULTS: On the whole genome scale, heavy cigarette smokers (>60 pack-years) have significantly more copy number gains than non-/light smokers (≤60 pack-years) (p=2.46×10−4). Copy number losses tend to occur away from genes in non-/light smokers (p=5.15×10−5) but not in heavy smokers (p=0.52). Smoking-associated copy number gains are most significant on chromosomes 8 (p=1.19×10−5), 10 (p=4.81×10−4) and 12 (p=3.31×10−3). For the focal region, GWA analyses show six loci with strong association of copy number and cigarette smoking pack-years, including four neighboring loci at 12q23.2 (p=1.79×10−8 to 6.17×10−7) where IGF1 (insulin-like growth factor 1) is located. All above analyses were tested in the discovery set and confirmed in the validation set. CONCLUSIONS: Heavy smokers have more copy number gains and less selection of gene locations in copy number losses. Copy number increases in 12q23.2 where IGF1 is located are positively associated with cigarette smoking pack-years. Supported by US National Institutes of Health Grants No. CA092824, CA074386, CA090578; and the Norwegian Cancer Society Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2132.