Comprehensive expression analysis using microarrays has identified a number of differentially expressed genes in
smoke-exposed bronchial epithelium and non-small cell
lung cancers (NSCLCs). To evaluate the prognostic relevance of these
proteins in NSCLCs, we used immunohistochemistry to investigate the expression of
beta-catenin (CTNNB1), dickkopf, Xenopus, homolog of 3 (DKK3 gene),
fibroblast growth factor receptor 3 (FGFR3), fragile
histidine triad (FHIT),
tumor protein p53 (TP53), mucin1 (MUC1),
topoisomerase II alpha (TOP2A), and
glutathione S-transferase-Pi (GST) in a cohort of patients (n = 125). We correlated the expression data with clinicopathologic features and clinical outcome. In addition, SNaPshot multiplex assays (Applied Biosystems, Darmstadt, Germany) and restriction fragment length polymorphism analysis were used to screen for activating point mutations at the hot spots of FGFR3 in a cohort of 30 samples of NSCLC. Using Kaplan-Meier analysis, we observed significantly better overall survival in
adenocarcinomas compared with
squamous cell cancers (P = .049). Loss of FHIT expression showed a strong association with shorter overall survival in both histologic types of NSCLC (
squamous cell cancers, P < .001;
adenocarcinomas, P = .001). In
adenocarcinomas, the cytoplasmic expression of
beta-catenin was associated with shorter survival (P = .012); MUC1 expression was associated with worse prognosis in patients with
squamous cell cancers (P = .002). The nuclear staining of TP53 (P = .008) and TOP2A (P = .059) was associated with
cancers without lymphonodal
metastases. A correlation with positive staining of TOP2A (P = .03) and FGFR3 positivity (P = .057) was found in
adenocarcinomas of male patients. Positive MUC1 stainings were associated with
squamous cell cancers of male patients (P = .03). DKK3 expression did not show any significant association with clinical outcome or pathologic features. The screening of the FGFR3 sequence in
lung cancers showed only wild-type sequences and did not detect mutations in the known hot spots for FGFR3 mutations. We conclude that the immunohistochemical loss of FHIT expression and the positivity for
beta-catenin and MUC1 in NSCLC are useful prognostic markers, whereas the variable expression of TP53, TOP2A, and FGFR3 in relation to the different histologic types of NSCLC and sex of the patients is suggestive for different underlying molecular pathways.