Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability

Abstract

Recent evidence suggests that the observed clinical distinctions between lung tumors in smokers and never smokers (NS) extend beyond specific gene mutations, such as EGFR, EML4-ALK, and KRAS, some of which have been translated into targeted therapies. However, the molecular alterations identified thus far cannot explain all of the clinical and biological disparities observed in lung tumors of NS and smokers. To this end, we performed an unbiased genome-wide, comparative study to identify novel genomic aberrations that differ between smokers and NS. High resolution whole genome DNA copy number profiling of 69 lung adenocarcinomas from smokers (n = 39) and NS (n = 30) revealed both global and regional disparities in the tumor genomes of these two groups. We found that NS lung tumors had a greater proportion of their genomes altered than those of smokers. Moreover, copy number gains on chromosomes 5q, 7p, and 16p occurred more frequently in NS. We validated our findings in two independently generated public datasets. Our findings provide a novel line of evidence distinguishing genetic differences between smoker and NS lung tumors, namely, that the extent of segmental genomic alterations is greater in NS tumors. Collectively, our findings provide evidence that these lung tumors are globally and genetically different, which implies they are likely driven by distinct molecular mechanisms.

Figure 1. EGFR and KRAS mutation frequencies and PGA in the BCCA and MSKCC tumors.

In both the BCCA (n = 69) and MSKCC (n = 66) datasets, EGFR and KRAS mutations are more prevalent in NS and smokers, respectively, consistent with the literature (A, B). The PGA in NS was greater than that of smokers in the BCCA and MSKCC tumors (C, D). PGA was also greater in EGFR-mutant versus EGFR-wild type tumors in both datasets (E,F), corroborating the difference we identified in smoker and NS tumors, as NS tumors are enriched for EGFR mutations.

Figure 2. Genomic landscapes of the BCCA NS and smoker lung adenocarcinomas.

The frequency of copy number alterations throughout the genome is depicted for smokers (A) and NS (B) tumors. Frequencies were calculated using a moving average window size of 500 SNP array probes. Each vertical box represents a single chromosome with the hashed line indicating the centromere. The genomic locations of the differentially altered regions (n = 313) identified in the BCCA tumors are indicated in plot C. Red bars indicate NS-specific regions and blue bars indicate smoker-specific regions.

Figure 3. Genes commonly disrupted in smokers and NS.

Frequencies of copy number alteration for 9 genes commonly reported as disrupted in lung adenocarcinoma are shown. The difference in frequencies of alteration in smokers and NS was not statistically different for any of these genes, suggesting they are equally important in lung adenocarcinoma tumorigenesis in both smokers and NS. Fisher's exact test p-values for the comparison of alteration frequencies in NS and smokers are indicated for each gene.