Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation

Most testicular germ cell tumors are curable using cisplatin-based chemotherapy, and cell lines from these tumors are unusually sensitive to cisplatin and other DNA-damaging agents. It has been suggested that this might be caused by a lower-than normal nucleotide excision repair (NER) activity. Previous studies found that cell lines from testicular germ cell tumors have on average about one-third the level of the NER protein XPA in comparison to cell lines from other tumors. We asked whether over-expression of XPA protein would alleviate the cellular sensitivity and increase the DNA repair capacity of a testis tumor cell line. Increasing XPA levels in 833K cells by 10-fold did not increase resistance to UV irradiation. XPA was localized to the cell nucleus in all cell lines, before and after exposure to UV-radiation. 833K cells were proficient in removing UV radiation-induced photoproducts from the genome and increased XPA did not enhance the rate of removal. Further, over-expressing functional XPA protein did not correlate with increased resistance of 833K testis tumor cells to cisplatin. Thus, although the amount of XPA in this testis tumor cell line is lower than normal, it is sufficient for NER in vivo. The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells.     

Platinum-sensitive and platinum-resistant ovarian cancer tissues show differences in the relationships between mRNA levels of p53, ERCC1 and XPA

We investigated the association between p53 mRNA expression and clinically relevant surrogates of nucleotide excision repair (ERCC1 and XPA) in 28 ovarian cancer specimens. We observed that platinum-resistant tumors showed higher mRNA levels of p53, ERCC1, and XPA than platinum-sensitive tumors; mRNA expression patterns in responders differed substantially from nonresponders; and p53 expression showed a strong correlation with the expression of ERCC1, and of XPA in platinum-sensitive tumor tissues, but not with platinum-resistant tumors. 47% of the mutations from p53 sequence analysis were not related to clinical response to chemotherapy. We conclude that the p53 influence on DNA repair in human malignancy may vary substantially from tumor to tumor, and that such differences are not necessarily related to the mutational status of p53.     

Applications of genomics in NSCLC

Cisplatin-based chemotherapy has long been the cornerstone of non-small cell lung cancer (NSCLC) management. However, median survival rarely exceeds 1 year. The identification of molecular markers can help to predict response, leading to a broad implementation of the new concept of customized chemotherapy. ERCC1 is an excision nuclease within the nucleotide excision repair pathway that forms a heterodimer with XPF. As a unit, they execute the 5' incision into the DNA strand relative to the site of DNA damage. The 5' excision is the last of several steps that are specific to excision of a platinum DNA lesion. In mouse models, normal ERCC1 function is critical to normal aging and brain development. Numerous studies indicate that ERCC1 influences the repair of platinum DNA damage. We report here our accumulated experience of ERCC1 mRNA expression and outcome in cisplatin-treated NSCLC patients and the preliminary confirmatory data on a prospective ERCC1 mRNA customized docetaxel-cisplatin trial, in which low ERCC1 mRNA levels in the tumor correlate with significantly better response. ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance.     

Excision repair cross complementation group 1 immunohistochemical expression predicts objective response and cancer-specific survival in patients treated by Cisplatin-based induction chemotherapy for locally advanced head and neck squamous cell carcinoma.

PURPOSE: To assess the correlation of excision repair cross complementation group 1 (ERCC1) immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous cell carcinoma treated with cisplatin-based induction chemotherapy. EXPERIMENTAL DESIGN: The initial cohort was composed of 107 patients who were treated from 1992 to 1996 by an induction chemotherapy regimen for locally advanced head and neck squamous cell carcinoma. p53 mutations had previously been studied. Pretherapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 immunohistochemical expression. RESULTS: Of 96 patients, 68 (71%; 95% confidence interval, 61-79%) had tumors that expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 (29%) patients with tumors expressing ERCC1 at lower levels had a 4-fold greater odds of benefiting from an objective response to chemotherapy (odds ratio, 4.3; 95% confidence interval, 1.4-13.4; P = 0.01) compared with the group of 68 patients with high ERCC1 expression. ERCC1 and p53 status, but not their interaction, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on age, TNM stage, tumor differentiation, and tumor localization, ERCC1 low expression was associated with a lower risk of cancer death (risk ratio, 0.42; 95% confidence interval, 0.20-0.90; P = 0.04) whereas p53 status had no prognostic value. CONCLUSION: Our results suggest that those patients characterized by low ERCC1 expression are more likely to benefit from cisplatin induction chemotherapy compared with patients with high ERCC1 expression.     

Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses

BackgroundMost non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit.Patients and methodsDNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression).ResultsIn patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs.ConclusionHere predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.     

ERCC1 protein expression predicts the response of cisplatin-based neoadjuvant chemotherapy in non-small-cell lung cancer

The excision repair cross-complementation group 1 (ERCC1) and BRCA1 have been identified as predictors of clinical outcomes among patients with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. In this study, we immunohistochemically examined the ERCC1 and BRCA1 protein expression levels in 35 patients with metastatic mediastinal lymph nodes obtained prior to treatment as retrospective study. These patients had been enrolled in our studies on neoadjuvant chemotherapy with cisplatin and irinotecan (15 patients) or chemoradiotherapy with cisplatin and docetaxel plus concurrent thoracic radiation (20 patients). The relations between the ERCC1 or BRCA1 protein expression and the clinical outcomes of the patients were then examined. The rates of radiological response and pathological effectiveness were significantly higher among patients with ERCC1-negative tumors, compared with those with positive tumors in the neoadjuvant chemotherapy group (radiological response rates; 100% vs. 42.8%, P=0.013; pathological effectiveness; 100% vs. 47.1%, P=0.038), but no associations were observed in the neoadjuvant chemoradiotherapy group. Regarding survival, no significant differences in overall survival or disease-free survival were observed between patients with ERCC1-negative and positive tumors in both the neoadjuvant chemotherapy and chemoradiotherapy groups. In summary, we showed that a ERCC1-negative protein status was significantly related to tumor responsiveness to neoadjuvant chemotherapy with cisplatin and irinotecan, but such a status was not a clear prognostic predictor to cisplatin-based neoadjuvant therapy in NSCLC patients. Further study is needed to clarify the value of molecular predictors for customizing therapy for patients with NSCLC.     

Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs

In this review, we focus on the discrepant roles of the DNA repair complex ERCC1/XPF in the prevention of cancer and in the resistance of cancer to chemotherapy. ERCC1/XPF is essential for nucleotide excision repair (NER) incising DNA 5' to the lesion. NER deficiency results in the skin cancer-prone inherited disease xeroderma pigmentosum (XP). The ERCC1/XPF complex is also involved in recombination, double strand break (DSB) and interstrand crosslink (ICL) repair cutting DNA overhangs around a lesion. In telomere maintenance ERCC1/XPF degrades 3' G-rich overhangs. In some types of cancer, high levels of ERCC1/XPF mRNA and protein correlate with poor overall survival and resistance to platinum-based chemotherapeutic treatments. Therefore, the ERCC1/XPF complex makes an attractive target for prediction of outcome for treatment in cancer patients as well as a novel drug target.     

The NER proteins are differentially expressed in ever smokers and in never smokers with lung adenocarcinoma

Background: The expression levels of excision repair cross-complementation group 1 (ERCC1), replication protein A (RPA) and xeroderma pigmentosum group F (XPF) nucleotide excision repair proteins may be important in the response to platin-based therapy in lung cancer patients. It is not known whether ERCC1, RPA and XPF expression levels differ between ever smokers (ES) and never smokers (NS).Patients and methods: ERCC1, RPA and XPF expression levels were immunohistochemically evaluated in 125 patients with resected lung adenocarcinoma (AC) and carefully reviewed smoking status.Results: ERCC1 was correlated with XPF (P = 0.001), but not with RPA (P = 0.11). In the univariate analysis, ERCC1 and XPF levels were higher in NS compared with ES (P = 0.004 and P = 0.003, respectively). In the multivariate analysis, the smoking status was predictive of the ERCC1 level [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.03–6.2] after adjustment for variables linked to the smoking status, including age and the presence of bronchioloalveolar (BAC) features. The smoking status was also predictive of both RPA (OR 6.7, 95% CI 1.5–33.3) and XPF levels (OR 12.5, 95% CI 2.9–50) after adjusting for age, sex and BAC features.Conclusion: In patients with resected lung AC, ERCC1, RPA and XPF expression levels are higher in NS compared with ES.     

Expression of ERCC1 predicts clinical outcome in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy

The aim of the present study was to evaluate the correlation between excision repair cross-complementation group 1 (ERCC1) protein with the clinical outcome of nasopharyngeal carcinoma (NPC) patients treated with cisplatin-based induction chemotherapy. One hundred one Stage III-IVB nonkeratinizing NPC patients who were treated with cisplatin (DDP)+fluorouracil (5-Fu) induction chemotherapy were recruited. Pre-treatment tumor biopsy specimens were analyzed for ERCC1 by immunohistochemistry. The relationship of ERCC1 expression and chemotherapy response and survival of these NPC patients was analyzed. The objective response to induction chemotherapy of NPC patients with low ERCC1 expression compared with high ERCC1 expression was 88.2% vs. 72% (P=0.041). The 5-year distant failure-free survival (D-FFS) of NPC patients with low ERCC1 expression compared with high ERCC1 expression was 73.5% vs. 51.3% (P=0.037). ERCC1 expression was a significant prognostic factor for overall survival and D-FFS using Cox regression analysis. High tumor ERCC1 expression predicts low chemotherapy response and poor survival mainly caused by more metastasis in locoregionally advanced NPC treated with cisplatin-based induction chemotherapy.     

Absence of evidence for allelic loss or allelic gain for ERCC1 or for XPD in human ovarian cancer cells and tissues

We have previously reported on mRNA expression of ERCC1, XPA and XPD in human ovarian cancer cells and tissues. Several factors can influence mRNA expression for any given gene. Alterations in gene copy number for ERCC1 and/or XPD have been reported to occur in malignant glioma specimens. Human ovarian cancer cell lines and tissues were therefore examined for evidence of altered gene copy number in selected genes within the nucleotide excision repair (NER) pathway. Six ovarian cancer cell lines were studied: A2780, A2780/CP70, SKOV3, MCAS, QvCar3 and Caov4. Cellular sensitivity to cisplatin varies by more than 1 log between some of these cells. In each of these cell lines, the genes examined included ERCC1, XPA, XPB, XPD, XPG, CSB and p53. Genomic DNA was also extracted from ovarian cancer specimens taken from 22 patients and assessed for evidence of allelic loss and/or allelic gain for ERCC1 and XPD. Twelve of the clinical specimens were from patients with platinum-sensitive tumors and ten were from patients with platinum-resistant tumors. In no case could we demonstrate a reproducible variation in gene copy number in any cell line. Among the human tissues studied, there was one case of allelic gain out of 22 specimens. We therefore conclude that alterations in gene copy number is not a common event in human ovarian cancer. Other mechanisms must be invoked to explain differences in mRNA expression for these genes.     

Polymorphisms of DNA repair genes and risk of non-small cell lung cancer

Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean.     

Microarray-based expression of DNA repair genes does not correlate with growth inhibition of cancer cells by natural products derived from traditional Chinese medicine

Drug resistance represents a major obstacle in cancer chemotherapy. As chemically characterized compounds derived from plants used in traditional Chinese medicine (TCM) may have molecular targets different from those of standard antitumor drugs, they might be attractive candidates for novel therapeutics with improved pharmacological features. DNA repair is frequently involved in the development of resistance to established anticancer drugs, e.g. alkylating agents. Using a database of 531 chemically characterized TCM compounds from medicinal plants recently established by us, the IC50 values of 60 N.C.I. tumor cell lines for these 531 natural products were tested for correlation with the microarray-based mRNA expression of six genes involved in nucleotide excision repair (ERCC1, XPA, XPC, DDB2, ERCC4, ERCC5). No compound correlated with the expression of these genes, indicating that mRNA expression of these genes is not associated with resistance of the cell lines to these TCM compounds. The same is true for another six genes of the base excision repair pathway (MPG, APEX1, OGG1, XRCC1, LIG3, POLB). Microarray-based COMPARE analyses were performed to identify other candidate genes that are able to predict responsiveness of tumor cells to TCM-derived natural products. As an example, diallyl disulfide from garlic (Allium sativum L., Chinese name: dashuan) was chosen. Eighteen genes were identified whose mRNA expression predicted sensitivity or resistance to diallyl disulfide in hierarchical cluster analyses. Apart from some genes with still unknown function, genes were identified from different functional groups, e.g. signal transducers, regulators of GTPase activity, those associated with cytoskeleton formation and regulation, constituents of the ribosome. Remarkably, none of these genes have been described to be involved in DNA repair. In conclusion, our data indicate that TCM-derived natural products are worth being further investigated as novel compounds to eradicate tumors which reveal resistance to established anti-cancer drugs.     

人肿瘤细胞核苷酸切除修复蛋白表达与抗癌药耐药的相关性

背景与目的：核苷酸切除修复（Nucleotide excision repair,NER）是真核细胞中的DNA修复多酶系统,它可能与人肿瘤细胞对抗癌药的耐药有关。本实验将探讨NER蛋白（XPA,XPB,XPD和ERCC1）的表达与人肿瘤细胞耐药的关系。方法：采用western blot检测美国国家癌症研究所（National Cancer Institute,NCI）用于抗癌药筛选的60株人肿瘤细胞的ERCC1,XPA,XPB XPD表达,并与170种抗癌药物的细胞毒试验结果进行相关性分析。结果：ERCC1,XPB和XPD的蛋白表达与抗癌药物敏感性呈负相关,在170种抗癌药物中分别有13,17和32种的耐药性与上述蛋白水平相关性显著或非常显著（P＜0．05）。而XPA的表达与药物敏感性无明显正／负相关。根据已确定的6种药物作用机理分析,肿瘤细胞XPD表达与其对烷化剂类抗癌药耐药相关性显著。结论：本实验结果肿瘤细胞的XPD蛋白表达与烷化剂类抗癌药的耐药相关,提示XPD在肿瘤细胞耐药过程中起重要作用。     

Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists

Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case-control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (OR(GC) = 1.1, OR(CC) = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/Gy(GG) = 1.0, 95% CI = <0, 6.0; EOR/Gy(GC/CC) = 5.9, 95% CI = 0.9, 14.4; p(het) = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/Gy(AA) = 9.1, 95% CI = 2.1-21.3; EOR/Gy(AC/CC) = 0.6, 95% CI = <0, 4.6; p(het) = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.     

ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation

The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1 expression as a predictive marker of survival in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). ERCC1 expression was assessed by immunohistochemical staining. The median age of the 45 patients analysed was 56 years (range 27-75 years), and 82% were men; 73% of all specimens showed high expression of ERCC1. The overall tumour response rate after CCRT was 89%. The median follow-up was 53.6 months (95% CI, 34.5-72.7 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 58.7 and 61.3%, respectively. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 3-year PFS (83.3 vs 49.4%, P=0.036) and OS (91.7 vs 45.5%, P=0.013) rates. Multivariate analysis showed that low expression of ERCC1 was an independent predictor for prolonged survival (HR, 0.120; 95% CI, 0.016-0.934, P=0.043). These results suggest that ERCC1 expression might be a useful predictive marker of locally advanced SCCHN in patients treated with cisplatin-based CCRT.     

Role of ERCC1 variants in response to chemotherapy and clinical outcome of advanced non-small cell lung cancer

Excision repair cross-complementation group 1 (ERCC1) and xeroderma pigmentosum-F (XPF) in the nucleotide excision repair pathway have been effectively repairing DNA damage induced by chemotherapeutic agents. We conducted a cohort study to assess the associations of ERCC1 and XPF polymorphisms with response to platinum-based chemotherapy and clinical outcome of non-small-cell lung cancer (NSCLC). One hundred eighty-seven NSCLC cases treated with platinum-based chemotherapy were prospectively analyzed. The predictive value of four SNPs in ERCC1 and two SNPs in XPF in patient's response and survival related to platinum-based chemotherapy were analyzed using χ ² tests, Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. The overall chemotherapy response rate for treatment was 51.18 %. One hundred eighty-seven patients were followed up, and the median survival time is 17.6 months (ranged from 1 to 50 months). A total of 106 patients (56.68 %) died from NSCLC during the follow-up period. Carriers of the rs3212986 AA and A allele had a borderline significantly lower response rate to the chemotherapy. In the Cox proportional hazards model, patients carrying the ERCC1 rs3212986 AA genotype were significantly associated with increased risk of death from NSCLC when compared with those with CC genotype as a reference variable. This study reported that variants in ERCC1 can be used as a prognostic maker to platinum-based chemotherapy in NSCLC patients.     

A truncated human xeroderma pigmentosum complementation group A protein expressed from an adenovirus sensitizes human tumor cells to ultraviolet light and cisplatin

Individuals with the genetic disease xeroderma pigmentosum (XP) have impaired nucleotide excision repair (NER). Group A XP cells are defective in the XPA protein essential for NER and serve, together with other NER proteins, as a nucleation factor for the demarcation of bulky DNA damage. Because XPA cells are extremely sensitive to UV and drugs that cause bulky DNA damage, the XPA protein is an attractive target for manipulating cellular sensitivity to certain cancer therapeutics, a concept that perhaps can be applied toward developing more effective cancer treatments. We have made a replication-defective adenovirus, AdCMV-FlagXPA(59-114), that expresses a truncated form of XPA encompassing amino acids 59-114 sufficient for binding to the excision repair cross-complementing protein 1 (ERCC1)/xeroderma pigmentosum complementation group F (XPF) nuclease essential for making an incision 5' of the damage. On the basis of previous work, it was expected that this truncated XPA protein would work as a decoy and impair NER and, thus, sensitize cells to UV and drugs that produce bulky DNA lesions. Because the truncated XPA protein is "tagged" with the Flag epitope, an anti-Flag antibody can be used to detect protein expression and to isolate proteins associated with the XPA complex. We show that relatively large quantities of truncated XPA protein are present in infected human lung carcinoma A549 cells 2-4 days postinfection. Moreover, in a pull-down assay using anti-Flag antibody, we show that ERCC1 is present in the FlagXPA complex but not in a complex isolated from cells infected with a control virus. Most importantly, cells infected with AdCMV-FlagXPA(59-114) are significantly more sensitive than control cells to UV-induced damage as determined by host-cell reactivation of UV-irradiated AdLacZ adenovirus and in a cytotoxicity assay that appears to be the result of aberrant processing of 6-4 photoproducts. Infected cells were also more sensitive to treatment with cisplatin, an important cancer drug. These results suggest that NER, and the XPA protein in particular, can be a direct target for sensitizing tumor cells to UV and cisplatin and perhaps also certain other clinically important drugs.     

Expression of xeroderma pigmentosum A protein predicts improved outcome in metastatic ovarian carcinoma

BACKGROUND: The nucleotide excision repair (NER) proteins repair DNA adducts due to xenobiotics and cancer chemotherapy. The authors hypothesized that expression of the NER protein xeroderma pigmentosum A (XPA) would be reduced in a clinically significant fashion in metastatic ovarian carcinoma. METHODS: Malignant effusion specimens were studied so that there was a uniform metastatic ovarian carcinoma population for study. XPA protein expression was analyzed by immunocytochemistry in 142 effusion specimens (109 peritoneal specimens, 33 pleural specimens) from 125 patients. Specimens were obtained at diagnosis (n = 76), and at disease recurrence (n = 66). Patients in the latter group received platinum-based chemotherapy. RESULTS: XPA was expressed in cancer cells in 136 of the 142 (96%) effusion specimens. Strongest expression occurred in leukocytes and reactive mesothelial cells. XPA expression did not correlate with treatment status, effusion site, International Federation of Gynecology and Obstetrics stage, histologic grade, or the extent of residual disease. More effusion tumor cells from patients with a complete response to chemotherapy expressed XPA compared with those with a partial or no response (P = 0.03, chi(2) test). Patients with recurrent disease with XPA expressed in > 25% of tumor cells had better progression-free survival (PFS) by univariate analysis (median = 0 vs. 11 months, P < 0.001; 95% confidence interval [CI], 1-5, 8-14) and overall survival (OS; median = 24 vs. 34 months, P = 0.04; 95% CI, 17-31, 24-44). XPA was the only predictor of PFS outcome by multivariate analysis (P = 0.03). CONCLUSIONS: The results of the current study showed that XPA was widely expressed in metastatic ovarian carcinoma effusion specimens and in the cells of the effusion microenvironment. Paradoxically, XPA expression was associated with better response to chemotherapy and predicted better PFS and OS.