Gene expression signatures in non-small cell lung cancer (NSCLC) according to cigarette smoking history

Abstract

22082 Background: Epidemiological and experimental studies confirm that cigarette smoking is the principal causal agent of lung cancer. It is estimated that about 2–5% of all lung cancer patients (pts) have never smoked. A knowledge on molecular features of lung cancers not related to smoking might lead to better understanding of their carcinogenesis and allow development of new therapeutic targets. In this study we compared gene expression signatures in non-smoking vs smoking NSCLC pts. Methods: Study group included 70 NSCLC pts, of those 25 never-smokers (WHO criteria) and 45 current or past smokers (mean 49.7 pack-years, range 6–130). All pts underwent curative pulmonary resection. There were more women among non-smokers (p=0.003), whereas other major characteristics did not significantly differ between both groups. Qualitative RT-PCR analysis was performed on mRNA derived from snap frozen tumor specimens. Expression of 27 genes: potentially related to smoking, including kinase receptors, sex hormone receptors, transcription factors and genes involved in HPV infection pathways was investigated. 18S rRNA subunit, POLR2A, ESD and YAP1 were used as normalization genes. Gene expressions were compared by parametric permutation test with Benjamini-Hochberg correction for multiple comparisons (False Discovery Rate assessment). Results: In univariate analysis 3 genes were particularly overexpressed in tumors of non-smokers: RRAD (p=0.0002), TGF-beta receptor-2 (TGFBR2; p=0.002) and progesterone receptor (PgR; p=0.007). TGF-beta receptor-3 (TGFBR3; p=0.02), SOX9 (p=0.02) and androgen receptor (AR; p=0.03) were also significantly overexpressed in these tumors. After correction for the impact of sex, histopathology, stage of disease, and multiple comparisons, RRAD and TGFBR2 were independently correlated with smoking history. Conclusions: NSCLC in non-smokers is characterized by a specific gene expression signature. Overexpression of TGFBR2 provides the basis for developing new targeted therapies. No significant financial relationships to disclose.