Predictive Value of ERCC1, ERCC2, and XRCC Expression for Patients with Locally Advanced or Metastatic Gastric Cancer Treated with Neoadjuvant mFOLFOX-4 Chemotherapy.

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant mFOLFOX-4 chemotherapy were enrolled between January 2009 and January 2018. We analyzed clinicopathological features and ERCC1, ERCC2, and XRCC1 expression to identify potential predictors of clinical response. Among the 58 patients, 16 (27.6%) were categorized into the response group (partial response) and 42 into the nonresponse group (stable disease in 24 patients and progressive disease in 18 patients). A multivariate analysis showed that ERCC1 overexpression (P = 0.003), ERCC2 overexpression (P = 0.049), and either ERCC1 or ERCC2 overexpression (P = 0.002) were independent predictors of response following mFOLFOX-4 neoadjuvant chemotherapy. Additionally, ERCC1 and ERCC2 overexpression did not only predict the response but also progression-free survival (both P < 0.05) and overall survival (both P < 0.05). ERCC1 and ERCC2 overexpression are promising predictive biomarkers for patients with locally advanced or metastatic GC receiving neoadjuvant mFOLFOX-4 chemotherapy and the potential clinical implication is mandatory for further investigation.

ERCC1 and ERCC2 as predictive biomarkers to oxaliplatin-based chemotherapy in colorectal cancer patients from Egypt.

BACKGROUND: The impact of Excision repair cross-complementation group 1 (ERCC1) and group 2 (ERCC2) expression levels on the efficacy of oxaliplatin-based chemotherapy is still controversial. The present study was conducted to determine the predictive value of these molecular biomarkers in stage III and IV colorectal cancer (CRC) patients receiving oxaliplatin (OX)-based chemotherapy as first-line treatment. METHODS: The study included 80 CRC patients who received first line oxaliplatin based chemotherapy The expression levels of ERCC1 and ERCC2-mRNA and proteins were determined in the primary tumors by quantitative real time reverse transcription polymerase chain reaction(RT-qPCR) and immunohistochemistry (IHC); respectively. The results of mRNA expression were correlated with patients' characteristics, response to treatment, overall- and event free survival (OS & EFS). RESULTS: Sixty four out of the 80 patients were legible for assessment of ERCC1 and ERCC2 expression. The cut-off levels of ERCC1and ERCC2-RNA were 3.8×10-3& 4.6×10-3; respectively. Reduced ERCC1 and ERCC2 RNA expressions were detected in 50 (78.1%) and 48 (75%) cases, respectively whereas reduced proteins were detected in 48 cases (75%) for ERCC1 and ERCC2. After The median follow up period was 30.5months (range: 7-104months), Patients with low mRNAERCC1levels showed significantly longer OS (p=0.011) and EFS (p˂0.001). However, no significant relation was found between ERCC2 levels and OS or EFS. In multivariate analysis performance status (PS), stage of the disease and ERCC1-mRNA expression were independent prognostic factors for EFS whereas tumor histology and stage of the disease were independent factors for OS. CONCLUSIONS: ERCC1 expression levels may help in selecting patients who benefit from oxaliplatin chemotherapy in stage III & IV CRC. Further large trials are needed to validate these data.

Xeroderma pigmentosum, complementation group D expression in H1299 lung cancer cells following benzo[a]pyrene exposure as well as in head and neck cancer patients.

DNA repair genes play critical roles in response to carcinogen-induced and anticancer therapy-induced DNA damage. Benzo[a]pyrene (BaP), the most carcinogenic polycyclic aromatic hydrocarbon (PAH), is classified as a group 1 carcinogen by International Agency for Research on Cancer. The aims of this study were to (1) evaluate the effects of BaP on DNA repair activity and expression of DNA repair genes in vitro and (2) examine the role of xeroderma pigmentosum, complementation group D (XPD) mRNA expression in human head and neck cancers. Host cell reactivation assay showed that BaP inhibited nucleotide excision repair in H1299 lung cancer cells. DNA repair through the non-homologous end-joining pathway was not affected by BaP. Real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot demonstrated that XPD was downregulated by BaP treatment. BaP exposure did not apparently affect expression of another 11 DNA repair genes. BaP treatment increased the DNA damage marker γ-H2AX and ultraviolet (UV) sensitivity, supporting an impairment of DNA repair in BaP-treated cells. XPD expression was also examined by quantitative RT-PCR in 68 head and neck cancers, and a lower XPD mRNA level was found in smokers' cancer specimens. Importantly, reduced XPD expression was correlated with patient 5-year overall survival rate (35 vs. 56%) and was an independent prognostic factor (hazard ratio: 2.27). Data demonstrated that XPD downregulation was correlated with BaP exposure and human head and neck cancer survival.

Increased expression of ERCC2 gene in head and neck cancer is associated with aggressive tumors: a systematic review and case-control study.

INTRODUCTION: The excision repair cross-complementation group 2 (ERCC2) ATP-dependent helicase is an essential member of the DNA repair pathway. It has been observed to be differentially expressed in different cancers, which shows its involvement in carcinogenesis. AIM: In the present study we have tried to determine the association of expression patterns of this gene with head and neck carcinogenesis. METHOD: We first carried out a systematic review of the available studies on the role of ERCC2 in head and neck cancer (HNC). In order to test the hypothesis that the expression patterns of XPD/ERCC2 play a critical role in HNC pathogenesis, we then conducted a population based case-control study on 81 head and neck tumor samples and adjacent normal-tissue control samples. Reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative polymerase chain reaction (qPCR) were used to assess ERCC2 deregulation at the mRNA level. RESULT: Expression analysis showed that the ERCC2 expression level was significantly upregulated (p<0.05) in HNC tissues compared with adjacent normal tissues. Furthermore, the expression pattern of ERCC2 was correlated with the expression pattern of Ki-67 and a significant correlation (r = 0.230, p<0.03) was observed between ERCC2 and Ki-67. Spearman's correlation also showed a significant correlation between ERCC2 expression and tumor stage (r = 0.271, p<0.02) and grade (r = 0.228, p<0.02) of HNC. CONCLUSIONS: Our data suggest that deregulation of ERCC2 in HNC has the potential to predict a more aggressive cancer phenotype and may be considered a possible biomarker for improved diagnosis and prognosis of HNC.

A Systematic Review and Meta-Analysis of Three Gene Variants Association with Risk of Prostate Cancer: An Update.

PURPOSE: Prostate cancer (PCa) is one of the most commonly diagnosed male malignancies. Nu­merous studies have investigated the role of genetic variants in PCa risk. However, the results re­main unclear. The purpose of this study was to evaluate the relationship between single-nucleo­tide polymorphism (SNP) rs2228001 in xeroderma pigmentosum group C (XPC), SNP rs4073 in interleukin 8 (IL8), and SNP rs2279744 in mouse double minute 2 (MDM2) homolog gene with PCa susceptibility. MATERIALS AND METHODS: Electronic database of PubMed, Medline, and Embase were searched for eligible articles published between January 2000 and April 2014. The odd ra­tio (OR) with its 95% confidence interval (CI) were calculated to estimate the strength of association. RESULTS: A total 18 case-control studies, including 5725 PCa cases and 5900 healthy controls, were screened out. Six studies were eligible for each SNP. For XPC 939A/C polymorphism, no significant association was found with PCa risk in the whole population (P > .05). No relationship in subgroup analysis was found by ethnicity. For IL8 -251T/A variant, the A allele was not related with PCa risk in any genetic models when compared with those individuals without A allele. For MDM2 -309T/G mutation, the G allele was not as­sociated with the increased risk of PCa in total population and subgroup analysis by ethnicity as well. CONCLUSION: Our study demonstrated that all these three genetic polymorphisms were not associated with an in­creased risk of developing PCa, which might also provide an insight into the future research. Further large-scale studies with concerning the gene-gene and gene-environment interactions are needed to elucidate final conclusion.

Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy.

OBJECTIVES: To determine the correlation between expression of three DNA repair genes and early failure/clinical outcome of stage III colorectal cancer (CRC) patients administrated with FOLFOX-4, including the excision repair cross-complementation group 1 (ERCC1), the excision repair cross-complementing 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1). MATERIALS AND METHODS: We retrospectively analyzed clinicopathological features and ERCC1, ERCC2, XRCC1 expressions by immunohistochemical staining in 180 stage III CRC patients undergoing curative resection and treated with FOLFOX-4 chemotherapy to identify predictors of postoperative early failure. RESULTS: Among 180 CRC patients, 44 patients were classified into early failure group, and 136 patients were categorized into non-early failure group. A multivariate logistic regression analysis showed that ERCC1 overexpression (P = 0.005), and high postoperative carcinoembryonic antigen (CEA) levels (P = 0.001) were independent predictors of early failure. Additionally, ERCC1 overexpression was not only a predictor of early failure but also for disease-free survival (P < 0.001) and overall survival (P < 0.001). However, no predictive roles of ERCC2 and XRCC1 expression among these analyzed patients. CONCLUSIONS: ERCC1 overexpression is an important predictor of early failure in patients with stage III CRC administrating FOLFOX-4 adjuvant chemotherapy and this marker may help identify patients who would benefit from intensive follow-up and enhance therapeutic programs.

GSTP1, ERCC1 and ERCC2 polymorphisms, expression and clinical outcome of oxaliplatin-based adjuvant chemotherapy in colorectal cancer in Chinese population.

AIM: Platinum agents have shown to be effective in the treatment of colorectal cancer. We assessed whether single nucleotide polymorphisms (SNPs) in GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln might predict the overall survival in patients receiving oxaliplatin-based chemotherapy in a Chinese population. METHODS: SNPs of GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln in 335 colorectal cancer patients were assessed using TaqMan nuclease assays. RESULTS: At the time of final analysis on Nov. 2011, the median follow-up period was 37.7 months (range from 1 to 60 months). A total of 229 patients died during follow-up. Our study showed GSTP1 Val/Val (HR=0.44, 95% CI=0.18-0.98), ERCC1 C/C (HR=0.20, 95% CI=0.10-0.79) and ERCC2 G/G (HR=0.48, 95% CI=0.19-0.97) to be significantly associated with better survival of colorectal cancer. GSTP1 Val/Val, ERCC1 C/C and ERCC2 G/G were also related to longer survival among patients with colon cancer, with HRs (95% CIs) of 0.41 (0.16-0.91), 0.16 (0.09-0.74) and 0.34 (0.16-0.91), respectively. CONCLUSION: GSTP1, GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln genotyping might facilitate tailored oxaliplatin-based chemotherapy for colorectal cancer patients.

Nucleotide excision repair gene subunit XPD is highly expressed in cervical squamous cell carcinoma.

One of the subunits in the mammalian transcription factor II H complex, XPD (TFIIH p80), plays a significant role in the nucleotide excision repair pathway. Events such as abnormal DNA excision repair may be involved in the cervical carcinogenesis process. Expression of the human XPD protein was examined using immunohistochemistry in 84 normal cervical tissues and 148 cervical squamous cell carcinoma samples. Additionally, qRT-PCR was performed to analyse the XPD mRNA expression in 69 fresh normal cervical tissues and 110 cervical carcinoma samples. The relationships between XPD expression and various clinicopathological features (including age, FIGO stage, tumor size, stroma involvement, lymph node metastasis and histologic grade) were assessed. The XPD (TFIIH p80) protein was detected primarily in the cytoplasm. We found a statistically significant difference in XPD expression level in cervical carcinoma versus normal cervical tissue (Z = -7.302, P = 0.000). Notably, XPD mRNA was significantly over-expressed in cervical carcinoma tissues but not in normal cervix tissues (t = 6.942, P = 0.000). However, no statistically significant relationship was found regarding XPD expression and age, FIGO stage, tumor size, stroma involvement, lymph node metastasis or histologic grade (P = 0.089, 0.953, 0.809, 0.275, 0.421, 0.387 respectively). Our results showed that XPD was highly expressed in cervical squamous cell carcinoma tissues. A poorly understood change may occur during the XPD transcription process, resulting in the abnormal enrichment seen from mRNA to the protein level, thus leaving the protein unable to perform the normal function of excision repair. There is a need for further research in order to elucidate the specific mechanism involved.

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins.

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD(+) tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase ß, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.

mRNA expression of RRM1, ERCC1 and ERCC2 is not associated with chemosensitivity to cisplatin, carboplatin and gemcitabine in human lung cancer cell lines.

BACKGROUND AND OBJECTIVE: Expression of genes involved in DNA repair and/or DNA synthesis, including ribonucleotide reductase M1 (RRM1) and excision repair cross-complementation 1 (ERCC1) has been reported to be associated with chemosensitivity to platinum agents and gemcitabine. The aim of this study was to test whether similar associations would be seen between mRNA expression for the RRM1, ERCC1 and ERCC2 genes and in vitro chemosensitivity in lung cancer. METHODS: Using a panel of 20 lung cancer cell lines, including 15 NSCLC and 5 small cell lung cancers (SCLC), the mRNA expression levels for the RRM1, ERCC1 and ERCC2 genes were examined by quantitative real-time reverse transcription PCR. The in vitro cytotoxicity of cisplatin, carboplatin and gemcitabine was assessed using a tetrazolium-based colorimetric assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) assay). RESULTS: Significantly, higher RRM1 mRNA expression was found in SCLC compared with NSCLC. However, there were no correlations between mRNA expression of the ERCC1, ERCC2 and RRM1 genes and chemosensitivity to cisplatin, carboplatin or gemcitabine. CONCLUSIONS: These in vitro results suggest that further studies are needed to evaluate the expression of the RRM1, ERCC1 and ERCC2 genes as predictive biomarkers for sensitivity to platinum agents and gemcitabine.