Bax, bcl-2 and c-kit expression in non-small-cell lung cancer and their effects on prognosis

Abstract

In non-small-cell lung cancer (NSCLC), stage of the disease is still the most important prognostic factor. Other than stage, many biological markers and many other prognostic factors are studied to define their effects on prognosis of lung cancer. In this study, we aimed to evaluate the expressions of Bax and bcl-2 genes which are important in apoptosis and c-kit, which is a tyrosine kinase transmembrane receptor, as well as searched their response to treatment modalities and effects on survival. Sixty-nine NSCLC cases' pathological samples were stained with specific Bax, bcl-2 and c-kit dyes by immunohistochemical (IHC) methods. IHC evaluation was done by the semichantitative method according to the distribution and intensity of the staining. Twelve of 69 cases (17.4%) were stage I, 28 (40.5%) were stage II, 17 were (24.6%) stage IIIA, nine cases were (13.1%) stage IIIB and three cases (4.4%) were stage IV patients. Their histological subtypes were as follows: of 69 cases, 36 (52.2%) were squamous cell carcinoma, 28 (40.6%) were adenocarcinoma, five (7.2%) were adenosquamous cell carcinoma (two patients) and large-cell carcinoma (three patients). The positive immunostaining rates for Bax and bcl-2 in whole group, squamous cell carcinoma and adenocarcinoma groups were 40.6%/36.2%, 55.6/69.4% and 25.0/0.0%, respectively. The positive immune staining rates for c-kit in whole group, squamous cell carcinoma and adenocarcinoma groups were 7.2, 5.6 and 7.1%, respectively. We didn't find any correlation with Bax, bcl-2 and c-kit expressions and clinicopathological parameters such as age, tumour size, lymph node involvement, smoking, stage of the disease, response to radiotherapy and chemotherapy. Results are interpreted according to survival; bax and bcl-2 expressions were not so effective both in whole group and histologically subgrouped patients. C-kit expression was also found not related with survival in whole group whereas found as a bad prognostic factor in patients with squamous cell carcinoma. These findings could indicate that the expression of apoptotic pathway markers and c-kit may have a role in the prognosis of early stage NSCLC, especially with squamous cell carcinoma subtype.

High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology

“…Bcl-2 expression has been confirmed in 20% to 58% of NSCLC and 32% to 69.4% of squamous cell carcinomas of the lung [19,22,28] and this is consistent with our findings of 50% and 51% Bcl-2 positive NSCLC tumors and 62% and 63% positive squamous cell carcinomas for the training and validation cohorts respectively. Bcl-2 has been found to mediate the anti-apoptotic effect of nicotine in lung cancer [44] and we observed higher Bcl-2 expression in tumors of smokers (n = 265) compared to non smokers (n = 29; mean ± SE 30.8 ± 2.1 and 22.7 ± 2.96 respectively; data not shown) however this did not reach statistical significance due to small number of non smokers.…”

“…Meta-analysis of 13 immunohistochemical studies assessing Bcl-2 with the same antibody clone as used in this study revealed that Bcl-2 was associated with better survival for NSCLC patients (HR = 0.71, 95% CI 0.61-0.83) however this study was biased in favor of positive trials [22]. Bcl-2 has also been reported to be a negative prognostic marker [32,33,35,36,43] whereas the majority of studies on Bcl-2 expression show no impact on survival [20,21,27,28]. Methodology differences in immunohistochemistry, different thresholds for Bcl-2 and use of conventional semi-qualitative, subjective pathologist-scoring systems, lack of reproducibility and lack of independent validation of the results preclude firm conclusions based on the current literature.…”

“…Bcl-2 has been found to be upregulated in a series of tumor types including squamous cell carcinomas of the lung and the potential of Bcl-2 to predict survival for NSCLC patients has been assessed by immunohistochemistry, with different studies demonstrating varying degrees of correlation between Bcl-2 expression and outcome [19-28]. A meta-analysis of 28 clinical studies showed that Bcl-2 positivity was associated with improved survival with a combined hazard of 0.71[22], however numerous individual studies suggest that Bcl-2 has no prognostic value for NSCLC [20,21,27-31] while others report a correlation with poor prognosis [32-36].…”

The prognostic role of Bcl-2 mRNA expression in curatively resected non-small cell lung cancer (NSCLC)

“…Our data showing that non-smokers have lower Bcl-2 mRNA expression than smoking NSCLC patients suggests the hypothesis that part of the pre-disposition of smokers for lung cancer may be due to an up-regulation of Bcl-2 expression by some component(s) of the smoke. However, other studies have not reported an association between smoking and Bcl-2 expression [21,30]. Even though in our study Bcl-2 expression and smoking were associated, smoking was no prognostic factor in NSCLC after curative resection.…”

Absence of gene mutations in KIT-positive thymic epithelial tumors

“…However, mutation status of KIT was not examined in that study. Regarding the KIT expression in lung cancer, Yaren et al [19] have reported that KIT immunostaining was relatively rarely positive in squamous cell carcinoma of the lung (2 of 36 cases; 5.6%) and in adenocarcinoma of the lung (2 of 28 [11]. They reported that 19 of 22 thymic cancers revealed positive staining for KIT, whereas none of 110 thymomas contained positive cells.…”