Abstract A15: Lung cancer genomes of smokers and never smokers harbor differential regions of copy number alteration
Authors: Thu Kelsie L. , Chari Raj , Zhang Wei , MacAulay Calum , Gazdar Adi F. , Lam Stephen , Lam Wan L. 
Published: January 2011

Background: Recent studies have revealed that never smoker (NS) lung cancer patients are characterized by specific clinical and genetic features. NS lung tumors occur more frequently in women (especially those of Asian ethnicity), have greater EGFR mutation frequencies than those of smokers, and are typically adenocarcinomas. These findings suggest lung cancer in NS is a different disease than lung cancer in smokers, and that NS lung cancer patients may benefit from management strategies tailored to their specific genetic alterations. We hypothesized that differential regions of copy number alteration exist in lung tumors of smokers and NS. Identification of alterations specific to NS provides evidence that tumors in NS are driven by distinct genetic mechanisms which could have potential diagnostic or therapeutic implications.

Methods: Lung adenocarcinomas and matched non-malignant tissues were collected from 30 NS, 39 current smokers (CS), and 14 former smokers (FS) (CS and FS collectively referred to as ever smokers, ES). DNA was extracted from all samples and copy number profiles were generated using Affymetrix SNP 6.0 arrays. Data were processed with Partek Genomics Suite software using each matched non-malignant sample as a reference to identify somatic copy number alterations. For 81 of the 83 tumors, mutation status for EGFR and KRAS were also determined.

Results: As expected, mutation patterns of EGFR and KRAS were consistent with previous literature; NS had more EGFR mutations than ES (p=0.001), while ES (p=0.008) had more KRAS mutations than NS. Analyses of copy number alterations in lung tumors of ES versus NS revealed several common regions of alteration including gains of 17q and losses of 9p. Several differentially altered regions were also evident, such as more frequent gains of 1p in NS and 1q in ES. Moreover, a trend towards higher frequency of chromosome X gain was evident in NS. In addition to regional differences in copy number, we noted global distinctions. When comparing the proportion of genome altered between ES and NS lung tumors, it was found that NS genomes had a higher proportion altered than ES (p=0.130). Similarly, comparing the number of distinct genetic events, a higher number of alterations was observed in NS compared to ES (p=0.049). Interestingly, when examining only the CS subset of ES and comparing the proportion of genome altered and the number of distinct genetic alterations with NS, the same trend was observed but with higher statistical significance (p=0.062 and p=0.017, respectively). In addition, when total copy number events and proportion of genome altered were considered, FS more closely resembled NS than CS, having more alterations per genome and a larger proportion of genome altered.

Conclusion: We found that lung tumors of NS harbor alterations distinct from those of CS and ES, and that they harbor more alterations overall. This suggests some genes may be preferentially altered in NS and that NS may require more DNA alterations to drive cellular transformation, perhaps due to the absence of tobacco carcinogens. Our copy number and mutation data support the hypothesis that lung tumors in NS arise via distinct genetic mechanisms, providing a rationale for the development of novel strategies for diagnosis and treatment of lung cancer specific for NS.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A15.