title: 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.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. kthu@bccrc.ca
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.forename: Raj
authors.initials: R
authors.lastname: Chari
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: John C
authors.initials: JC
authors.lastname: English
authors.forename: Rong
authors.initials: R
authors.lastname: Fu
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Calum E
authors.initials: CE
authors.lastname: MacAulay
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D011905:Genes, ras; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009367:Neoplasm Staging; D012907:Smoking
chemical_list: D066246:ErbB Receptors