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Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history.

Karlsson, Anna K LU ; Ringnér, Markus LU ; Lauss, Martin LU ; Botling, Johan; Micke, Patrick; Planck, Maria LU and Staaf, Johan LU (2014) In Clinical Cancer Research 20(18). p.4912-4924
Abstract
Purpose Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis, and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. Experimental Design 1398 (277 never-smokers, 1121 smokers) genomic and 1449 (370 never-smokers, 1079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n=423). Unsupervised and supervised methods were used to identify smoking-related copy number alterations (CNAs), predictors of smoking status, and molecular subgroups. Results Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of... (More)
Purpose Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis, and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. Experimental Design 1398 (277 never-smokers, 1121 smokers) genomic and 1449 (370 never-smokers, 1079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n=423). Unsupervised and supervised methods were used to identify smoking-related copy number alterations (CNAs), predictors of smoking status, and molecular subgroups. Results Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although, specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20-30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies ~60-80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included ~55-90% of never-smokers and ~20-40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intra-group heterogeneity in smoking-defined subgroups, especially among former-smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma. Conclusions The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
20
issue
18
pages
4912 - 4924
publisher
American Association for Cancer Research
external identifiers
  • pmid:25037737
  • wos:000342358500020
  • scopus:84907445431
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-14-0246
language
English
LU publication?
yes
id
ca9b17d0-303b-45af-b1e3-cdac766f4214 (old id 4581946)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25037737?dopt=Abstract
date added to LUP
2014-08-08 17:39:30
date last changed
2017-10-22 03:06:50
@article{ca9b17d0-303b-45af-b1e3-cdac766f4214,
  abstract     = {Purpose Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis, and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. Experimental Design 1398 (277 never-smokers, 1121 smokers) genomic and 1449 (370 never-smokers, 1079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n=423). Unsupervised and supervised methods were used to identify smoking-related copy number alterations (CNAs), predictors of smoking status, and molecular subgroups. Results Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although, specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20-30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies ~60-80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included ~55-90% of never-smokers and ~20-40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intra-group heterogeneity in smoking-defined subgroups, especially among former-smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma. Conclusions The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers.},
  author       = {Karlsson, Anna K and Ringnér, Markus and Lauss, Martin and Botling, Johan and Micke, Patrick and Planck, Maria and Staaf, Johan},
  issn         = {1078-0432},
  language     = {eng},
  number       = {18},
  pages        = {4912--4924},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-14-0246},
  volume       = {20},
  year         = {2014},
}