Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival.
BACKGROUND
Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.


RESULTS
We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.


CONCLUSIONS
Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.
Landi
Maria Teresa
MT
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland, USA.
Dracheva
Tatiana
T
Rotunno
Melissa
M
Figueroa
Jonine D
JD
Liu
Huaitian
H
Dasgupta
Abhijit
A
Mann
Felecia E
FE
Fukuoka
Junya
J
Hames
Megan
M
Bergen
Andrew W
AW
Murphy
Sharon E
SE
Yang
Ping
P
Pesatori
Angela C
AC
Consonni
Dario
D
Bertazzi
Pier Alberto
PA
Wacholder
Sholom
S
Shih
Joanna H
JH
Caporaso
Neil E
NE
Jen
Jin
J
D000230:Adenocarcinoma / Q000209:etiology*; D001706:Biopsy; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018816:Genes, cdc; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics*