Combined analysis of mRNA expression of ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 to predict prognosis in patients with non-small cell lung cancer who received adjuvant chemotherapy
© Leng et al; licensee BioMed Central Ltd. 2012
Received: 17 January 2012
Accepted: 23 March 2012
Published: 23 March 2012
The aim of this study was to investigate prognostic value of excision repair cross-complementing 1 (ERCC1), BCL2-associated athanogene (BAG-1), the breast and ovarian cancer susceptibility gene 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and class III β-tubulin (TUBB3) in patients with non-small cell lung cancer (NSCLC) who received platinum- based adjuvant chemotherapy.
Messenger RNA expressions of these genes were examined in 85 tumor tissues and 34 adjacent tissue samples using semi-quantitative RT-PCR. The expressions of these five genes were analyzed in relation to chemotherapy and progression-free survival (PFS) and overall survival (OS). Seventy-four patients were enrolled into chemotherapy.
Patients with ERCC1 or BAG-1 negative expression had a significantly longer PFS (P = 0.001 and P = 0.001) and OS (P = 0.001 and P = 0.001) than those with positive expression. Patients with negative ERCC1 and BAG-1 expression benefited more from platinum regimen (P = 0.001 and P = 0.002). Patients with BRCA1 negative expression might have a longer OS (P = 0.052), but not PFS (P = 0.088) than those with BRCA1 positive expression. A significant relationship was observed between the mRNA expression of ERCC1 and BAG-1 (P = 0.042). In multivariate analysis, ERCC1 and BAG-1 were significantly favorable factors for PFS (P = 0.018 and P = 0.017) and OS (P = 0.027 and P = 0.022).
ERCC1 and BAG-1 are determinants of survival after surgical treatment of NSCLC, and its mRNA expression in tumor tissues could be used to predict the prognosis of NSCLC treated by platinum.
Lung cancer is a common malignant tumor, and was the first ranked cause of cancer death in both males and females . As one of the most prevalent malignant tumors in China, lung cancer has been highlighted with emphasis for cancer prevention and treatment. Recently, the combinations of cytotoxic agents (such as gemcitabine, vinorelbine, and taxane) and platinum become new standard for non-small-cell lung cancer (NSCLC). But the resistance to these drugs causes unsatisfactory of overall survival rate. Therefore, it is very important to understand the molecular markers of resistance to chemotherapeutic drugs.
The excision repair cross-complementing 1 (ERCC1) is a DNA damage repair gene that encodes the 5' endonuclease of the NER complex, and is one of the key enzymes of the nucleotide excision repair (NER) pathway which is essential for the removal of platinum-DNA adducts. Clinical studies have found that high ERCC1 expression is associated with resistance to platinum-based chemotherapy and worse prognosis in patients with advanced NSCLC . The human BAG-1 gene is located in chromosome 9 and encodes three major BAG-1 isoforms, BAG-1S (p36), BAG-1 M (p46), and BAG-1 L (p50), which are generated via alternate translation mechanisms from the same mRNA . BAG-1 is a multifunctional binding protein involved in differentiation, cell cycle, and apoptosis. BAG-1 has recently been found to bind and interact with the anti-apoptotic gene Bcl-2, thereby inhibiting apoptosis . Because of its affect on apoptosis, BAG-1 may play an important role in lung cancer. Further study showed that BAG-1 could be a target for lung cancer treatment of cisplatin . The breast and ovarian cancer susceptibility gene1 (BRCA1) was the first breast cancer susceptibility gene identified in 1990 and was primary cloned in 1994. It has multiple roles not only in DNA damage repair but also in cell cycle regulation, transcriptional control, ubiquitination and apoptosis. In NSCLC, chemotherapeutic treatment can damage DNA through various mechanisms, the lack of functional BRCA1 can lead to increased sensitivity of the tumor cells to molecular damage, demonstrating that BRCA1 represents a predictive marker of chemotherapy response in NSCLC .
Ribonucleotide reductase subunit M1 (RRM1) is located on chromosome segment 11p15.5, it is a region with a frequent loss of heterozygosity in NSCLC. It is a component of ribonucleotide reductase, which is required for deoxynucleotide production and is also the predominant cellular determinant of the efficacy of gemcitabine, which make it to be the molecular target of gemcitabine [7, 8]. Along with the use of antitubulin agents such as taxanes and vinorelbine, study shows there are a number of tubulin isotypes in humans, and found that class III β-tubulin (TUBB3) among them is expressed in a proportion and related to clinical outcome . The expression of TUBB3 is associated with resistance of paclitaxel and docetaxel, no matter in vitro or in clinical research [10, 11].
Changes of gene mRNA expression during carcinogenesis may lead impact of the diagnosis, treatment, and prevention of NSCLC, it is important to understand these changes. So, in this study, we use RT-PCR to examine the expression of ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 in tumor samples from patients with resected NSCLC not receiving adjuvant chemotherapy. We analyzed the relationships of these genes expression in tumors about survival time and response to chemotherapy to determine whether the expression of these molecules could be used as prognostic factors of progression-free and overall survival in this cohort of patients.
Baseline characteristics of 85 patients with NSCLC
Well and moderate
I + II
III + IV
Chemotherapy status(74 cases)
ECOG Performance status
RNA isolation and cDNA synthesis
Fresh frozen specimens of tumor and adjacent tissues were obtained from 85 patients. Collection time from resection to freezing was required 20 minutes or less for all specimens. The fresh frozen specimens were processed for RNA isolation and reverse-transcriptase polymerase chain reaction (RT-PCR) in detecting expression analysis for the ERCC1, BAG-1, BRCA1, RRM1, and TUBB3 genes. Specimens were microscopically examined to assess quality and to verify the histopathology.
Primers for gene analysis
The data were analyzed using SPSS 17.0 software package. The correlation of gene expression with different clinical characteristics was analyzed with chi-square test or Fisher's exact test. Correlation between gene mRNA levels was evaluated by Spearman correlation coefficients. The Kaplan-Meier method and Log-rank test were used to analyze the correlation of patient survival with gene expression. Factors with significant influence on survival in univariate analysis were further analyzed by multivariate Cox regression analysis. A significance level of P < 0.05 was used.
Expression of ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 mRNA after surgical resection
Correlation between ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 expression and clinical features
The expression of five genes in different clinical features were compared and summarized. It showed that the difference of these five genes were only significant between some parts of clinical features. Correlations were observed between ERCC1 expression and TNM stage (P = 0.006), metastasis of lymph node (P = 0.01), and TUBB3 expression and TNM stage (P = 0.004). No Correlation was observed between ERCC1, TUBB3 expression and other clinical features. Besides, No Correlation was observed between BAG-1, BRCA1, RRM1 expression and gender, age, nationality, histology, differentiation of tumor, metastasis of lymph node, TNM stage, chemotherapy status or performance status.
Association between gene expression and survival after surgical resection
Univariate analysis of Clinicopathological features, tumor markers, and patient survival
PFS HR (95% CI)
OS HR (95% CI)
Gender (Male vs. Female)
Age (≤ 60 vs.>60)
Nationality (The Han vs. The Zhuang)
Histology (Squamous carcinoma vs. Adenocarcinoma)
Differentiation (Well and moderate vs. Poor)
Metastasis lymphatics (Yes vs. No)
TNM stage (I+II vs. III+IV)
ERCC1 (positive vs. negative)
BAG-1 (positive vs. negative)
BRCA1 (positive vs. negative)
RRM1 (positive vs. negative)
TUBB3 (positive vs. negative)
Multivariate analysis of Clinicopathological features, tumor markers, and patient survival
PFS HR (95% CI)
OS HR (95% CI)
ERCC1 (positive vs. negative)
BAG-1 (positive vs. negative)
Metastasis lymphatics (Yes vs. No)
TNM stage (I + II vs. III + IV)
Multivariate Cox regression analysis was also performed for the overall survival. In addition to ERCC1, BAG-1, TNM stage and metastasis of lymph node were included in the Cox models. The other gene of TUBB3, BRCA1 and RRM1, together with the rest of patients' and clinical characteristics were not included. Negative ERCC1 and BAG-1 expression were independent and significant predictor of favorable outcome for overall survival (P = 0.027 and P = 0.022), with a hazard ratio of ERCC1 was 0.447 (95% CI: 0.219-0.911); for BAG-1, with a hazard ratio of 0.486 (95% CI: 0.262-0.901), whereas TNM stage and metastasis of lymph node had no significant association. The reason that TNM staging and lymph node were not associated with survival in the multivariate analysis might be the statistical significance of the two characteristics with survival contained in the other variables (ERCC1 and BAG-1). The other explanatory reason might be the limit of sample size.
Correlations between ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 expression and the kind of adjuvant chemotherapy
74 of 85 patients received at least two cycles of adjuvant chemotherapy, of whom 66 (89.2%) finished at least 4 cycles. The main chemotherapy regimens included gemcitabine (GEM, 45.9%), vinorelbine (NVB, 39.2%) and paclitaxel (PTX, 14.9%) combined with cisplatin (DDP)/carboplatin (CBP).
Correlation of ERCC1 and BAG-1 expression
Correlation between expression of ERCC1 and BAG-1
Along with the development of theory and practice in treatment of chemotherapy with resected NSCLC, we have already known the combination of two cytotoxic drugs, like a platinum and a non-platinum agent, is the standard first-line treatment of NSCLC patients . However, because of the high rate of toxicity observed and associated with drug resistance, treatment response rate and median overall survival are not satisfactory. This appears to be gene of chemoresistance, which plays an important role in the after surgery treatment. So, some markers detection is a key for chemotherapy in NSCLC patients.
Platinum drugs mainly exert their cytotoxicity by forming bulky intra-strand platinum-DNA adducts and inter-strand cross-link of the two DNA strands. Removal of these adducts from genomic DNA and repair of inter-strand cross-links in DNA and recombination processes are mediated by components of different DNA repair pathways. ERCC1 is a key factor involved in nuclear excision repair (NER) for platinum induced adducts . There is observation of platinum resistance in lung cancer A549 cells lines with high expression of ERCC1 , and increased clinical evidence that overexpression of ERCC1 in NSCLC inhibits platinum efficacy. In addition to ERCC1 negative tumors appear to benefit from cisplatin based chemotherapy, it also gains benefit from overall survival as a prognostic factor [2, 15, 16]. As a predictive factor, a phase III trial in NSCLC showed better PFS and OS in the low genotypic than in the high genotypic group, and the patients in the low genotypic group also had a trend toward a lower risk of progression than those in the control arm . Although it had been identified that ERCC1 positive could be associated with resistance to platinum based chemotherapy, however, some studies reported that ERCC1 expression had correlation with improved prognosis [18, 19]. This discrepancy may be due to differences of experimental processing, regional disparity or technical issues. In our study, expression of ERCC1 in stage III + IV was higher than stage I + II (P = 0.006). This was also happened in lymph node metastasis compared to no metastasis (P = 0.01), which like Ota et al. reported . The available data indicate ERCC1 positive patients might present a poor prognosis, and ERCC1 expression might appear to be an advanced stage event.
The BAG-1, as an anti-apoptotic function, exhibits positive expression in many malignant tumors. It binds to the cytosolic domain of the growth factor receptors on the cell surface, enhancing the protection from cell death triggered by these receptors. However, it binds to Bcl-2 and heat shock protein (HSP) and modulates their function in the cytosol, and it binds to nuclear hormone receptors for inhibiting hormone-induced apoptosis in the nucleus . Further exploration shows overexpression of BAG-1 suppresses activation of caspases and apoptosis induced by chemotherapeutic agents . As expected, experiment performed in lung cancer cells indicates silencing of BAG-1 gene can sensitize lung cancer cells to cisplatin-induced apoptosis . In this study, the positive BAG-1 expression correlated significantly with progression-free and overall survival in patients treated by platinum. As we described, current research has proven expression of BAG-1 indicates poor prognosis . Whereas, Rorke et al.  reported high expression of BAG-1 may correlate to better prognosis in NSCLC. The difference between findings may be due to different choices of treatment and different components of data.
BRCA1 is implicated in NER, which was discussed in the part of ERCC1, it also associates with double-strand break repair and mismatch repair, indicating its crucial role in DNA repair . It has been indicated that BRCA1 presents different sensitivity to different chemotherapy agent in vitro study. The negative expression of BRCA1 results in high sensitivity to cisplatin, whereas its positive expression increases sensitivity to antimicrotubule agents . In clinical research, it was found that patients whose tumors had BRCA1 expression would have significantly poorer survival and should be candidates for adjuvant chemotherapy . Median survival was 11 months for 38 patients with low BRCA1, treated with cisplatin plus gemcitabine; 9 months for 40 patients with intermediate BRCA1, treated with cisplatin plus docetaxel; and 11 months for 33 patients with high BRCA1, treated with docetaxel alone. Two-year survival was 41.2%, 15.6% and 0%, respectively, which had manifested the potential predictive role of BRCA1 in a recent non-randomized phase II clinical trial . Our findings indicate that BRCA1 expression might correlate with OS and platinum treatment based OS, however, there was no statistical significance (P = 0.052 vs. P = 0.073). Nevertheless, the results tend to migrate to statistical significant directions accompanied extension of follow-up time and expansion of sample size.
In addition, as the gene sensitive to cisplatin or other DNA damaging agents, expression of ERCC1 is closely related to BRCA1, no matter in breast cancer or in NSCLC [29, 30]. But there is not much more studies indicate correlations between BAG-1. Our findings demonstrate a strong correlation between ERCC1 and BAG-1. Therefore, it is plausible that patients with the expression of ERCC1 and BAG-1 present a poor prognosis and the lack of its expression would receive more benefit from non platinum based chemotherapy.
As one of the targets of gemcitabine, RRM1 also have roles in DNA repair systems like ERCC1 and BRCA1. It encodes the regulatory subunit of ribonucleotide reduction of ribonucleoside diphosphates to the corresponding deoxyribonucleotides . In earlier study, it suggested continuous exposure of lung cancer cell lines to increasing amounts of gemcitabine resulted in increased expression of RRM1 . In addition, another research showed reduced RRM1 expression increased sensitivity to gemcitabine in lung cancer cell lines, and found RRM1 expression in tumor is a major predictor of disease response to gemcitabine chemotherapy during a prospective phaseII clinical trial with NSCLC . TUBB3 is investigated and recognized as a role in resistance to antitubulin agents. The report shows TUBB3 is expressed in high levels in lung cancer cell lines, and by using RNAi technology, it was found that TUBB3 mediates sensitivity to paclitaxel in NSCLC cells, and high levels of TUBB3 expression are associated with paclitaxel and docetaxel resistance in vitro [11, 33, 34]. Our result showed that TUBB3 was more frequently observed in stage I + II than in stage III + IV patients (P = 0.004). But Recent data suggested expression of TUBB3 was related to advanced stage NSCLC . In this study, no correlation of chemotherapy between RRM1 and TUBB3, or the survival of the patients was found. It might be caused by the limitation of different cycles of adjuvant chemotherapy taken by patients and other interferences like number of samples and only one clinical center involved in our study.
In summary, to better overcome the problems related to drug resistance and to improve the clinical outcome of advanced NSCLC patients, relationship between drug resistance caused by gene expression and prognosis of patients received adjuvant chemotherapy must be investigated. Our findings indicate ERCC1 and BAG-1 are prognostic factors for progression-free and overall survival, and may be predictive biomarkers for platinum based chemotherapy in NSCLC patients. Accompanied by enlargement of sample size, BRCA1 might also be an indicator the above-mentioned. Although the approach of RT-PCR has a better feasibility and repeatability, and we have quality control of the laboratory. It remain has many factors influence the experimentation to cause the false positive results. Moreover, 85 patients were certainly few and follow-up time was short to be able to conclude firmly on any of the findings in our study, particularly using multivariate analysis. However, because of patients with negative expression of these genes indeed receive more benefit from platinum based chemotherapy in our study, the combined detection of the mRNA expression of these genes might better individualize the efficacy of chemotherapy and improve survival in this common and vital cancer.
This research was supported by Guangxi Scientific research and technology development projects (Grant No. 10124001A-44)
This research was supported by Guangxi Scientific research and technology development projects (Grant No. 10124001A-44). Thanks for data sorting and processing by Guang-Yao Ma and Man-Hong Li.
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