Cigarette smoking increases copy number alterations in nonsmall-cell lung cancer

Cigarette smoking has been a well-established risk factor of lung cancer for decades. How smoking contributes to tumorigenesis in the lung remains not fully understood. Here we report the results of a genome-wide study of DNA copy number and smoking pack-years in a large collection of nonsmall-cell lung cancer (NSCLC) tumors. Genome-wide analyses of DNA copy number and pack-years of cigarette smoking were performed on 264 NSCLC tumors, which were divided into discovery and validation sets. The copy number-smoking associations were investigated in three scales: whole-genome, chromosome/arm, and focal regions. We found that heavy cigarette smokers (>60 pack-years) have significantly more copy number gains than non- or light smokers (≤60 pack-years) (P = 2.46 × 10−4), especially in 8q and 12q. 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). Focal copy number analyses showed that there are strong associations of copy number and cigarette smoking pack-years in 12q23 (P = 9.69 × 10−10) where IGF1 (insulin-like growth factor 1) is located. All of the above analyses were tested in the discovery set and confirmed in the validation set. DNA double-strand break assays using...