[Background] Lung cancer in never-smoker (NS) is known as a seventh cause of cancer-related death. Activating mutation of epidermal growth factor receptor (EGFR) gene is frequently observed in non-small-cell lung cancers (NSCLCs) with never smoking history and it is significantly associated with the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI). Recently, NFKBIA gene, a tumor suppressor gene, has been reported to be silenced by deletion in glioblastomas, and in NSCLCs, its expression level is associated with clinical outcome of EGFR-TKI therapy. In this study, we examined NFKBIA expression and the genetic alterations of EGFR, K-ras, EML4-ALK to investigate the inter-relationship between these genetic alterations and clinicopathological factors among lung adenocarcinomas in NS. [Material and Method] We obtained ninety seven lung adenocarcinomas samples in NS which were resected at our institution. Four NSCLC cell lines (NCI-H1299, NCI-H1650, HCC827, NCI-H1819) were also investigated. We examined NFKBIA expression using immunohistochemistory (IHC) in tumor samples and real time reverse transcriptional PCR (RT-PCR) in cell lines, respectively. Mutational statuses of EGFR and K-ras genes were determined using mutant-enriched PCR assay and direct sequencing, respectively. EML4-ALK fusion was screened by ALK IHC and confirmed using RT-PCR assay. The methylation status of NFKBIA gene is investigated by methylation specific PCR assay and bisulfite sequencing. [Result] NFKBIA expression was silenced in 36 out of 97 samples (37.1%). EGFR mutation, K-ras mutation, and EML4-ALK fusion were detected in 61.8%, 2.1%, and 1.0% of 97 samples, respectively. Of note, the silencing of NFKBIA expression was significantly frequent in EGFR wild-type patients than in EGFR mutant patients (p=0.0024), while there was no correlation between NFKBIA expression level and K-ras mutation or EML4-ALK fusion. Although NFKBIA expression was silenced in NCI-H1299 and NCI-H1650, NFKBIA expression was not restored after 5-Aza treatment in these cell lines. In addition, NFKBIA methylation was found in these two cell lines. [Conclusion] Our findings suggest that the degradation of NFKBIA expression is a frequent event in lung adenocarcinomas of NS and may mediate an important non-tobacco carcinogenic pathway especially among lung adenocarcinoma with wild-type EGFR.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3988. doi:1538-7445.AM2012-3988