|Year : 2013 | Volume
| Issue : 3 | Page : 410-415
Excision repair cross-complementation group 1 codon 118 polymorphism, micro ribonucleic acid and protein expression, clinical outcome of the advanced gastric cancer response to first-line FOLFOX-4 in Qinghai-Tibetan plateau population
Yu-Juan Qi1, Sen Cui2, Ying-Zhong Yang3, Jing-Qi Han2, Bao-Jia Cai2, Cun-Fang Sheng2, Yan Ma3, Tana Wuren3, Ri-Li Ge3
1 Research Center for High Altitude Medicine, Qinghai University School of Medicine; Department of Oncology, Qinghai University Affiliated Hospital, Xining 810001, Qinghai, China
2 Department of Oncology, Qinghai University Affiliated Hospital, Xining 810001, Qinghai, China
3 Research Center for High Altitude Medicine, Qinghai University School of Medicine, Xining 810001, Qinghai, China
|Date of Web Publication||8-Oct-2013|
No 16 Kunlun Road, Cheng Xi District, Xining 810001, Qinghai
Source of Support: None, Conflict of Interest: None
Context: The excision repair cross-complementation group 1 (ERCC1) codon 118 C/T polymorphism has been associated with clinical outcome in cancer patients treated with platinum chemotherapy. Ethnic differences in the frequency of this polymorphism have been observed in Caucasian and African populations.
Aim: The aim of this study was to evaluate the frequency and survival benefit of the ERCC1 codon 118 C/T polymorphism in a high-altitude population with advanced gastric cancer.
Materials and Methods: Polymerase chain reaction-restriction fragment length polymorphism was used to determine the frequency of ERCC1 118 codon C/T polymorphism in 206 advanced gastric cancer patients residing in the high-altitude Qinghai-Tibetan plateau. The influence of the ERCC1 codon 118 C/T polymorphism on its micro ribonucleic acid (mRNA) and protein expression, clinicopathological features; response to the platinum-based combination chemotherapy, and the outcome was evaluated.
Statistical Analysis: The Kaplan-Meier method was used for survival analysis. The correlation of ERCC1 codon 118 polymorphism with ERCC1 mRNA and protein expression, clinicopathological characteristics, and first-line oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX-4) response was determined by χ2 -test.
Results and Conclusions: ERCC1 codon 118 C/T polymorphism was not associated with ERCC1 mRNA and protein expression, FOLFOX-4 response, and progression-free survival (PFS) or overall survival (OS). High ERCC1 mRNA and protein expression levels were associated with significantly lower FOLFOX-4 responses, PFS, and OS. ERCC1 codon 118 C/T polymorphism is not an important prognostic marker for advanced gastric cancer. Determination of ERCC1 mRNA and protein levels may be beneficial in predicting the response and outcome of FOLFOX-4 therapy in gastric cancer.
Keywords: Advanced gastric cancer, excision repair cross-complementation group 1 micro ribonucleic acid and protein expression, excision repair cross-complementation group 1 polymorphism, FOLFOX-4, Qinghai-Tibetan plateau
|How to cite this article:|
Qi YJ, Cui S, Yang YZ, Han JQ, Cai BJ, Sheng CF, Ma Y, Wuren T, Ge RL. Excision repair cross-complementation group 1 codon 118 polymorphism, micro ribonucleic acid and protein expression, clinical outcome of the advanced gastric cancer response to first-line FOLFOX-4 in Qinghai-Tibetan plateau population. J Can Res Ther 2013;9:410-5
|How to cite this URL:|
Qi YJ, Cui S, Yang YZ, Han JQ, Cai BJ, Sheng CF, Ma Y, Wuren T, Ge RL. Excision repair cross-complementation group 1 codon 118 polymorphism, micro ribonucleic acid and protein expression, clinical outcome of the advanced gastric cancer response to first-line FOLFOX-4 in Qinghai-Tibetan plateau population. J Can Res Ther [serial online] 2013 [cited 2018 Aug 16];9:410-5. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/410/119319
| > Introduction|| |
Gastric cancer currently ranks as the third most common cancer in China and will remain a significant cancer burden during the next decade. In 2005, gastric cancer accounted for approximately 400,000 new cases and 300,000 deaths in China.  The incidence of gastric cancer in China accounts for approximately 42% of cases world-wide. The mortality rate of gastric cancer in China is 4 to 8 times higher than in European and American countries. The Qinghai-Tibetan plateau is one of the most ethnically diverse Chinese provinces composed of Han, Mongol, Tibetan, and Hui ethnic groups. Hans account for 54% of the total Qinghai population, Mongols, Tibetans, and Huis together account for 46% of the total population. The Qinghai province has the highest morbidity of gastric cancer in China with a mortality rate of 40.62/100,000 men and women per year.
In five phase II studies, first-line oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX-4) combination chemotherapy was well tolerated and yielded median survival times of 9.6-11.4 months in gastric cancer patients. ,,, Oxaliplatin, a platinum-based chemotherapeutic drug, exerts its cytotoxic effects through the formation of deoxyribonucleic acid (DNA) adducts.  Differential chemotherapy responses and survival rates may be related to individual genomic variations, which may alter the expression and/or function of enzymes related to drug metabolism.  Excision repair cross-complementation group 1 (ERCC1), a key component of the nucleotide excision repair pathway, ,, enhances DNA repair and DNA damage tolerance, which may lead to platinum drug resistance. , Clinical and preclinical studies indicate that overexpression of ERCC1 protein or micro ribonucleic acid (mRNA) is associated with resistance to platinum-based chemotherapy in various cancer types. ,,,,
Impaired DNA repair within tumor cells can decrease the removal of platinum-DNA adducts to increase the clinical response to platinum chemotherapy. ,, Single nucleotide polymorphisms may contribute to inter-individual variability in DNA repair capacity and therefore predict the outcome of platinum chemotherapy. A common single nucleotide polymorphism of ERCC1 at codon 118 causes a C > T change that codes for the same amino acid, asparagine, but a trend toward higher ERCC1 mRNA levels as the number of T alleles increase.  The ERCC1 codon 118 C/T polymorphism has been associated with altered ERCC1 mRNA levels and clinical outcome in cancer patients treated with platinum chemotherapy. ,,,,
The aim of the present study was to investigate the association of ERCC1 118 C/T polymorphism on FOLFOX-4 response and survival in advanced gastric cancer patients residing in the high altitude Qinghai-Tibetan plateau.
| > Materials and Methods|| |
A total of 206 gastric cancer patients from Qinghai University Affiliated Hospital who had received FOLFOX-4 between June 2008 and December 2010 were enrolled in the study. Patient characteristics are shown in [Table 1]. All patients had resided in the Qinghai province for more than 10 years. Huis, Tibetans, and Mongols accounted for only 20, 11, and 5 of the cases; therefore, these ethnic groups were combined with the Hans for analysis. All patients had histologically confirmed gastric cancer.
|Table 1: Clinicopathological features of advanced gastric cancer patients with or without ERCC1 codon 118 C/T polymorphism (n=206)|
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Treatment and response evaluation
After primary tumor resection, all patients received FOLFOX-4, according to the following regimen : o0 xaliplatin (85 mg/m 2 ), leucovorin (200 mg/m 2 ), and 5-fluorouracil (5-FU; 400 mg/m 2 intravenous bolus) on day 1 and 2 followed by a 22-h continuous infusion of 5-FU (600 mg/m 2 ) that was repeated every 2 weeks. Treatment response was evaluated according to response evaluation criteria in solid tumors. Patients with a complete response, partial response or stable disease remained in the protocol until the progressive disease was documented. Survival was calculated from the date of diagnosis to the date of last follow-up or death from any cause. Chest radiography, abdominal ultrasonography or computed tomography was conducted every 2 months during the treatment. Patient follow-up was performed at 3-month intervals after chemotherapy at out-patient clinics or by routine phone calls. An institutional review board approved this study and informed consent was obtained from all patients before blood genotyping.
Genotyping of ERCC1 codon 118 C/T polymorphism
The ERCC1 codon 118 C/T polymorphism was examined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as previously described. Genomic DNA was extracted from leukocytes using the Gentra Puregene Blood kit (Qiagen, Germany). PCR amplification of genomic DNA (50 ng) was performed using ERCC1-specific primers (forward 5'-GCA GAG CTCACCTGA GGA AC-3' and reverse 5'-GAG GTG CAA GAAGAG GTG GA-3'). After initial denaturation at 95°C for 2 min, the following PCR protocol was performed for 35 cycles : d0 enaturation at 96°C for 20 s, annealing at 60°C for 30 s, and extension at 72°C extensions for 30 s. After BsrD1 restriction enzyme (New England BioLabs, USA) digestion at 60°C for 16 h, PCR products were separated on 2.5% ethidium bromide-stained agarose gels.
ERCC1 reverse transcription (RT)-PCR
Archival primary tumor tissue was available as formalin fixed, paraffin embedded tissue blocks from 60 patients. The intra-tumoral ERCC1 mRNA expression was determined by semi-quantitative RT-PCR. Quantification of relative gene expression was performed using the comparative gradation value method using β-actin as an endogenous control. Total RNA was extracted and purified from tumor tissue using Tri-Reagent (Molecular Research Center Inc., USA) according to the manufacturer's protocol. Primers were designed according to human ERCC1 (NM_202001) and β-actin (NM_001101) cDNA sequences using Primer3 Input (version 0.4.0). The following primers were used: ERCC1, forward: 5'-GCC TCC GCT ACC ACA ACC T-3' and reverse: 5'-TCT TCT CTT GAT GCG GCG A-3' and β-actin, forward: 5'-CGG GAC CTG ACT GAC TAC CTC-3' and reverse: 5'-TCG TCA TAC TCC TGC TTG CTG-3' (Invitrogen, USA). RT reactions were performed according to the manufacturer's protocol (Promega, USA). The PCR conditions were as follows : a0 n initial denaturation at 95°C for 2 min, followed by 35 cycles of denaturation at 96°C for 20 s, annealing at 60°C for 30 s, and extension at 72°C for 30 s. The PCR product from each reaction tube was separated by electrophoresis (2 V/cm) using a 1.5% agarose gel (TAE buffer, pH 8.3) containing ethidium bromide. PCR products were visualized using the UVP GDS8000 System (UVP Inc., USA) and band intensities were analyzed densitometrically with Lab works software (UVP Inc., USA). ERCC1 amplification products were calculated as a ratio of the gray scale of ERCC1 to that of β-actin.
Tumor tissue sections were stained with anti-ERCC1 mouse monoclonal antibody (ab43, Abcam, USA) using a streptavidin biotin-immunoperoxidase kit (Santa Cruz Biotechnology, USA) according to the manufacturer's instructions. The intensity and distribution of immunohistochemistry (IHC) staining were analyzed microscopically by an experienced pathologist. Only nuclear immunoreactivity was considered positive for ERCC1. The staining intensity was graded on a scale of 0-3. The percentage of stained tumor cells (0-100%) was determined, and the final semi-quantitative scores on a scale of 0-300 were calculated by multiplying staining intensity by the percentage of stained tumor cells. The median value was used as the cutoff point for separating ERCC1-positive from ERCC1-negative tumors.
All statistical analyzes were performed using the SPSS software (version 18.0; SPSS Inc., USA). Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method, and the log-rank test was used for survival comparisons among subgroups. The correlation of ERCC1 codon 118 polymorphism with ERCC1 mRNA and protein expression, clinicopathological characteristics, and FOLFOX-4 response was determined by χ2 -test. A two-sided P value 0.05 was considered significant.
| > Results|| |
ERCC1 Codon 118 polymorphism genotyping
PCR-RFLP analysis of the resultant 208-bp fragment led to C/C (208 bp), C/T (208, 128, 80 bp), and T/T (128, 80 bp) genotypes [Figure 1]. The allelic discrimination data from PCR-RFLP assay were confirmed by direct sequencing of representative PCR products [Figure 2]. The frequencies of the C/C, C/T, and T/T genotypes were 52.4% (108/206), 40.8% (84/206), and 6.8% (14/206), respectively. The allele frequencies of C and T were 72.8% and 27.2%, respectively. Distribution of ERCC1 codon 118 polymorphism genotypes was consistent with the Hardy-Weinberg equilibrium among patients (χ2 = 0.185).
|Figure 1: Polymerase chain reaction (PCR) products digested with BsrDI separated by gel electrophoresis. The length of the PCR products was 208 bp. The codon 118 T allele was cleaved by BsrDI in two fragments, while the C allele was not cleaved. The restriction fragment length polymorphism analysis of the resultant 208-bp fragment led to C/C (208 bp), C/T (208, 128, 80 bp) as well as T/T (128, 80 bp) genotypes|
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|Figure 2: Sequencing results of polymerase chain reaction (PCR) amplification fragment containing excision repair cross-complementation group 1 codon 118 polymorphism sites. The single-nucleotide polymorphism (SNP) sites are indicated by the arrowhead. The results were completely matched to the corresponding results derived from PCR-restriction fragment length polymorphism|
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FOLFOX-4 response and survival rates
C/C genotype patients had a higher response (complete and partial responses) to FOLFOX-4 treatment compared with C/T and T/T genotype patients (47.2% vs. 32.6%; P = 0.033) [Table 2]. C/C with C/T and T/T polymorphism was not associated with FOLFOX-4 response, PFS (7.19 months vs. 6.41 months), or OS (11.81 months vs. 11.09 months) [Figure 3]a.
|Figure 3: (a) Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) for patients with the excision repair cross-complementation group (ERCC1) (118 C/T genotype (b and c) Kaplan-Meier estimates of PFS and OS for patients with the ERCC1 messenger ribonucleic acid (mRNA) and protein levels|
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|Table 2: Response to FOLFOX-4 treatment in advanced gastric cancer patients with different ERCC1 codon 118 status (n=206)|
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ERCC1 mRNA expression levels
The intra-tumoral expression of ERCC1 mRNA is shown in [Figure 4]a. A marked inter-individual variation in ERCC1 mRNA expression was observed: ERCC1/β-actin ratios ranged from 0.160 to 0.821 with a median value of 0.290. The median value was assigned as the cut-off value to classify the patients into high and low ERCC1 mRNA expression groups. ERCC1 mRNA expression was unaffected by ERCC1 codon 118 genotypes (0.305 for C/C and 0.260 for C/T + T/T; Z = −1.148; P = 0.251) [Figure 4]b. However, high ERCC1 mRNA expression was associated with lower PFS (6.30 months vs. 7.32 months, P = 0.032) and OS (10.43 months vs. 11.70 months, P = 0.034) [Figure 3]b.
|Figure 4: The expressions of excision repair cross-complementation group 1 (ERCC1) messenger ribonucleic acid (mRNA) and Relationship with codon 118 polymorphism. A marked inter-individual variation in ERCC1 mRNA expression in the 60 samples was observed: ERCC1/β- actin ratios ranged from 0.160 to 0.821 with a median value of 0.290. The median value was assigned as the cut-off value to divide those 60 patients into two groups with high or low ERCC1 mRNA values. No significant relationship was found between ERCC1 mRNA expression and ERCC1 codon 118 genotypes (the median ERCC1 expression was 0.305 for C/C and 0.260 for C/T + T/T; Z = -1.148, P = 0.251).|
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ERCC1 protein expression levels
IHC of ERCC1 protein expression is shown in [Figure 5]a and b. Intense nuclear signals were detected, indicative of positive ERCC1 staining. ERCC1 codon 118 polymorphism did not influence ERCC1 protein level [Table 3]. High ERCC1 protein expression levels were associated with lower PFS (6.24 months vs. 7.23 months; P = 0.039) and OS (10.33 months vs. 11.85 months; P = 0.031) [Figure 3]c.
|Figure 5: Immunohistochemical staining results of excision repair cross-complementation group 1 (ERCC1) protein in gastric cancer tissues (original magnification ×100 and ×400) (a and b). Tumor tissues were stained with a mouse monoclonal anti-ERCC1 antibody, using a streptavidin-biotinimmunoperoxidase kit according to the manufacturer's instructions. Positive ERCC1 staining is defined as intense nuclear signals. The statistical difference between the correlation of ERCC1 codon 118 statuses and ERCC1 nuclear staining patterns was determined by χ2-test.|
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|Table 3: The correlations between excision repair cross-complementation group 1 (ERCC1) codon 118 statuses and ERCC1 protein expression|
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| > Discussion|| |
Compared with reported frequencies in Caucasian populations, , a significantly higher percentage of the C/C genotype was observed in gastric cancer patients residing in the high altitude Qinghai-Tibetan plateau. A higher prevalence of the C/C genotype in Caucasian populations is in agreement with previous reports. , Some research shown that the incidence of ERCC1 codon 118 C/C, C/T, and T/T genotypes was 47.6%, 39.9%, and 12.5%, respectively, and ERCC1 codon 118 C/C genotype was associated with significantly higher response rates, PFS, and OS in metastatic colorectal carcinoma patients in Taipei.  Our results are in agreement with previous reports demonstrating a benefit in treatment response in cancer patients with the C/C genotype. A survival benefit was clearly demonstrated in refractory colorectal cancer patients with the ERCC1 codon 118 C/C genotype treated with 5-FU/oxaliplatin.  PFS and OS were shorter in our study than previous studies and this may be related to the advanced-stage (stage IV) gastric cancer in our patient cohort.
In a prospective, multicenter trial, the ERCC1 codon 118 T/T genotype was independently associated with an adverse PFS in advanced gastric cancer treated with first-line FOLFOX-4.  However, other studies have reported that T/T genotype patients have higher objective response rates to 5-FU/oxaliplatin and better clinical outcomes than C/T and C/C genotype patients. , Jérô found that the ERCC1 polymorphism of metastatic colorectal cancer in France C/C, C/T, and T/T genotypes were 22%, 45%, 33%, the objective response rate was significantly higher in the T/T genotype group compared with the C/T and the C/C genotype groups (P = 0.018),  it is different with ours result. Hirotaka report the patients with pancreatic cancer treated with platinum-based chemotherapy with one or two AAT codons had a significantly longer PFS and OS than those homozygous for AA allele.  In the present study, the C/T polymorphism was not associated with FOLFOX-4 response, PFS, or OS. Steffensen et al. also found that ERCC1 118 C/T and C8092A polymorphisms did not have a significant influence on platinum resistance, PFS, or OS in ovarian cancer patients. 
In the present study, ERCC1 mRNA expression was unaffected by ERCC1 codon 118 genotypes. However, high ERCC1 mRNA expression was associated with lower PFS and OS. In agreement with our findings, Kazumi reported that high ERCC1 mRNA levels were associated with a shorter time to treatment failure in metastatic gastric adenocarcinoma.  Median survival time in patients with low ERCC1 mRNA levels was significantly longer than in those with high ERCC1 mRNA levels in advanced gastric cancer patients.  In contrast, No statistically significant relationship existed between ERCC1 mRNA expression and response to chemotherapy (P = 0.794) and No statistically significant difference in median survival was demonstrated according to ERCC1 expression (P = 0.801) in advanced non-small cell lung cancer. 
We found that ERCC1 codon 118 polymorphism did not influence ERCC1 protein level. Takenaka et al. also showed that ERCC1 genotypes were not correlated with ERCC1 protein expression in non-small cell lung cancer.  In the present study, high ERCC1 protein expression levels were associated with lower PFS and OS. In agreement with our findings, favorable 5-FU/oxaliplatin response rates and survival were observed in gastric cancer patients without ERCC1 protein expression.  Shao et al. reported that the expression of ERCC1 protein was not associated with treatment response or OS in advanced and metastatic breast cancer.  Epidemiologic evidence and a better understanding of the functional significance of the C/T change are needed to further establish the effect of this polymorphism on treatment response and survival.  In addition, multiple other mechanisms such as gene regulation (e.g., polymorphisms in the promoter region or promoter methylation), mRNA processing (e.g., splicing, modification, and turnover), and translation (e.g., mRNA induced inhibition of translation) can cause phenotypic changes.
In summary, our study suggests that ERCC1 codon 118 C/T polymorphism is not an important prognostic marker in advanced gastric cancer. Determination of ERCC1 mRNA and protein expression may useful in predicting treatment response and survival in advanced gastric cancer.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]