ILK and PRDX1 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder.

Although the incidence of gallbladder cancers is low, they are highly aggressive tumors. Squamous cell/adenosquamous carcinoma (SC/ASC) is a rare subtype of gallbladder cancer. The clinical characteristics of SC/ASC have not been well documented, and no prognosis marker has been identified. In this study, we examined integrin-linked kinase (ILK) and peroxiredoxin-1 (PRDX1) expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) by using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. We demonstrated that positive ILK and PRDX1 expressions were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive ILK and PRDX1 expressions were closely associated with decreased overall survival in both SC/ASC (p < 0.001 and p = 0.005, respectively) and AC (p < 0.001) patients. Multivariate Cox regression analysis showed that positive ILK and PRDX1 expressions were an independent poor prognostic predictor in both SC/ASC and AC patients. We also revealed a similar significance of differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability with survival in SC/ASC and AC patients. Our study suggested that positive ILK and PRDX1 expressions are closely related to the progression and poor prognosis of gallbladder cancer.

Lentivirus-based RNA silencing of Nemo-like kinase (NLK) inhibits the CAL 27 human adenosquamos carcinoma cells proliferation and blocks G0/G1 phase to S phase.

BACKGROUND: The Nemo-like kinase (NLK) is a serine/threonine-protein kinase that involved in a number of signaling pathways regulating cell fate. Variation of NLK has been shown to be associated with the risk of cancer. However, the function of NLK in oral adenosquamous carcinoma cells line CAL-27 is unknown. METHODS: In this study, we evaluated the function of NLK in CAL-27 cells by using lentivirus-mediated RNA silence. The targeted gene expression, cell proliferation and cell cycle are investigated by RT-PCR, western-blot, MTT method, colony forming assay and flow cytometry analysis respectively. RESULTS: After NLK silencing, the number of colonies was significantly reduced (54 ± 5 colonies/well compared with 262 ± 18 colonies/well in non-infected or 226 ± 4 colonies/well in negative control group (sequence not related to NLK sequence with mismatched bases). Using crystal violet staining, we also found that the cell number per colony was dramatically reduced. The RNA silencing of NLK blocks the G0/G1 phase to S phase progression during the cell cycle. CONCLUSIONS: These results suggest that NLK silencing by lentivirus-mediated RNA interference would be a potential therapeutic method to control oral squamous carcinoma growth.

Role of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expressions in gallbladder carcinoma.

PURPOSE: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in the metabolism of 5-fluorouracil, which have been examined as possible predictive markers. We conducted this study to clarify the role of TS and DPD expressions in gallbladder carcinoma (GBC). METHODS: The subjects were 28 patients who underwent surgical resection of GBC. We examined intratumoral TS and DPD mRNA expressions, using the Danenberg tumor profile method. The expression levels were classified into two groups, based on median values. Clinicopathological variables, including prognosis, were then compared between the high and low expression groups. RESULTS: There was a significant difference in the incidence of lymph node metastasis between the high and low TS expression groups. The incidence of advanced clinical stage was higher in the low TS expression group than in the high TS expression group. However, no clear correlation was observed between the DPD mRNA expression and any clinicopathological variable. There was no significant difference in the postoperative survival rates between the groups, in accordance with the expression of TS or DPD genes. CONCLUSION: Low TS mRNA was correlated with a high incidence of lymph node metastasis and advanced clinical stage. Therefore, TS gene expression may help identify patients at increased risk of the progression of GBC.

Manganese superoxide dismutase expression as a function of genotype and lung cancer pathology.

INTRODUCTION: The aim of this study was to compare the manganese superoxide dismutase (MnSOD) expression in matched tumor and normal tissue. METHODS: One hundred lung cancer specimens and matched normal lung parenchyma from the same patient were evaluated for MnSOD expression. RESULTS: The median normal MnSOD expression was 42% with a range of 10 to 70%, which was significantly greater (p = .001) than the median MnSOD expression in the tumor samples that was 18.8% and ranged from 1.1 to 50%. CONCLUSION: MnSOD expression is significantly reduced in lung adenocarcinoma and squamous cell carcinoma compared to the matched normal lung tissue.

Harmol induces apoptosis by caspase-8 activation independently of Fas/Fas ligand interaction in human lung carcinoma H596 cells.

The beta-carboline alkaloids are naturally existing plant substances. It is known that these alkaloids have a wide spectrum of neuropharmacological, psychopharmacological, and antitumor effects. Therefore, they have been traditionally used in oriental medicine for the treatment of various diseases including cancers and malaria. In this study, harmol and harmalol, which are beta-carboline alkaloids, were examined for their antitumor effect on human lung carcinoma cell lines, and structure-activity relationship was also investigated. H596, H226, and A549 cells were treated with harmol and harmalol, respectively. Apoptosis was induced by harmol only in H596 cells. In contrast, harmalol had negligible cytotoxicity in three cell lines. Harmol induced caspase-3, caspase-8, and caspase-9 activities and caspase-3 activities accompanied by cleavage of poly-(ADP-ribose)-polymerase. Furthermore, harmol treatment decreased the native Bid protein, and induced the release of cytochrome c from mitochondria to cytosol. The apoptosis induced by harmol was completely inhibited by caspase-8 inhibitor and partially inhibited by caspase-9 inhibitor. The antagonistic antibody ZB4 blocked Fas ligand-induced apoptosis, but had no effect on harmol-induced apoptosis. Harmol had no significant effect on the expression of Fas. In conclusion, our results showed that the harmol could cause apoptosis-inducing effects in human lung H596 cells through caspase-8-dependent pathway but independent of Fas/Fas ligand interaction.

KIT activation in uterine cervix adenosquamous carcinomas by KIT/SCF autocrine/paracrine stimulation loops.

OBJECTIVES: Uterine adenosquamous carcinoma (ASC) is an uncommon, yet, one of the most aggressive cervical cancer subtype. The successful treatment of some tumors, such as gastrointestinal stromal tumors (GISTs), by anti-KIT inhibitors fosters the study of this receptor tyrosine kinase in other malignancies. In the present study, we intended to molecularly characterize KIT in ASC. METHODS: In a series of 30 cases, we studied KIT (CD117), KIT phosphorylated/activated form, as well as KIT ligand, stem cell factor (SCF), by immunohistochemistry. We further screened for KIT hotspot mutations (exon 9, 11, 13 and 17) by PCR-SSCP and for KIT gene amplification by Quantitative real-time PCR in CD117 positive cases. RESULTS: We observed CD117 expression in approximately 13% of cases, with approximately 7% co-expressing SCF, which resulted in KIT phosphorylation/activation. No KIT activating mutations or gene amplification were found, despite the presence of 4q aneuploidy in one case. CONCLUSIONS: This is the first study assessing KIT activation and molecular alterations in a large series of rare ASC. Our findings showed the absence of KIT molecular alterations and suggested the presence of KIT activation in a small proportion of cases through KIT/SCF co-expression.

HPV+ cervical carcinomas and cell lines display altered expression of caspases.

OBJECTIVE: Loss of expression of apoptotic regulatory proteins in many neoplasias might result in defective or delayed apoptosis, thus facilitating tumor growth or survival. We analyzed here, the basal expression of precursors of apoptotic Caspases in normal cervical epithelium, HPV+ cervical tumor samples and HPV+ tumor-derived cell lines. METHODS: Expression of initiator and effector Caspases was analyzed by immunochemistry in normal cervical epithelium and three types of cervical tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma) whereas expression of Caspases in HeLa, SiHa and CaSki cells was by immunofluorescence, Western blot and RT-PCR. Besides, the effect of the HPV-16 E6/E7 oncogenes on Caspases expression in cervical cells was evaluated by transfecting C33-A (HPV-) cells. RESULTS: Expression of Caspases 3 and 9 was undetectable in adenocarcinoma and adenosquamous cell carcinoma, respectively. Whereas in squamous cell carcinoma, the expression of Caspases was similar those observed in normal samples. Expression of Caspases 3 and 6 was low in HeLa and CaSki cells, while Caspase 8 was low in SiHa and it was not detected in C33-A cells. All Caspases were detected in the cytoplasm and nucleus of the cells. We did not observe an effect of the E6/E7 oncogenes on the expression of Caspases in C33-A cell. CONCLUSION: Our results showed a differential expression of several Caspases in carcinoma samples and cell lines, suggesting multiple alterations of the Caspase pathways in cervical cancer.

Heparanase expression in gallbladder carcinoma and its correlation to prognosis.

BACKGROUND AND AIM: Heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate and has been implicated in tumor angiogenesis and metastasis. The present study was to analyze the expression of and explore the prognostic value of heparanase and two important transcriptional factors, namely hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear transcriptional factor kappa B p65 (NF-kappaB p65) in gallbladder cancer. METHODS: Heparanase, HIF-1alpha and NF-kappaB p65 protein levels in 38 patients with gallbladder carcinoma were detected by immunohistochemistry and analyzed for clinicopathological significance. RESULTS: The heparanase, HIF-1alpha and NF-kappaB p65 proteins were found in 24 (63.2%), 13 (34.2%) and 22 (57.9%) specimens, respectively. High heparanase expression was closely related to advanced TNM stage (P = 0.007), depth of tumor invasion (P = 0.016), lymph node metastasis (P = 0.040) and decreased postoperative survival at 3 years (50.0% vs 20.8%, P = 0.001). Both HIF-1alpha and NF-kappaB p65 proteins were correlated with tumor size (P = 0.039 and P = 0.027, respectively) and patients positive for HIF-1alpha expression had a decreased survival rate compared with those negative for HIF-1alpha expression (40.0% vs 15.4%, P = 0.035). In addition, heparanase-positive cases had high expression of NF-kappaB p65 compared with the heparanase-negative cases (P = 0.047). CONCLUSION: Heparanase and HIF-1alpha are frequently expressed in gallbladder carcinoma and are associated with decreased survival. High expression of heparanase, combined with NF-kappaB p65, may contribute to the highly invasive and metastatic behavior of gallbladder carcinoma.

Expression of glutathione S-transferase pi and glutathione synthase correlates with survival in early stage non-small cell carcinomas of the lung.

The glutathione S-transferase (GST) family of genes encode for detoxification enzymes that protect against reactive oxygen species and influence host susceptibility to carcinogens, including tobacco smoke. It has not been determined whether isoenzyme GST-pi or glutathione synthase (GSH2) expression by tumor cells bears a relationship to survival. A total of 201 non-small cell lung cancers (NSCLC) with long-term follow-up were immunostained with antibodies to GST-pi and GSH2 using standard immunostaining techniques. Results were graded semiquantitatively using a scale of 0 to 3 (0 < or = 10%; 1 = 10%-50%; 2 = 51%-80%; 3 > or = 80%) for both nuclear and cytoplasmic staining. Results were correlated with patient survival using Kaplan-Meier analysis. Nuclear staining with GST-pi in greater than 10% of the cells was closely associated with decreased survival (P = .02) in stage I and II squamous cell carcinomas (n = 40). Cytoplasmic staining showed a similar trend that did not reach statistical significance. No significant correlation between GST-pi staining and survival was determined for other histologic types of NSCLC. Cytoplasmic GSH2 staining in greater than 80% of tumor cells was associated with a trend toward improved survival for stage I adenocarcinoma (P = .08) but did not show a relationship to survival for other histologic types of NSCLC. GST-pi expression predicts prognosis in stage I and II squamous cell lung carcinoma, and GSH2 expression may indicate better survival in early stage adenocarcinoma of the lung. Manipulation of GST-pi and GSH2 may be a potential basis for treatment of some NSCLC.

Enzymatic activities of uridine and thymidine phosphorylase in normal and cancerous uterine cervical tissues.

In this study, the preliminary analyses were conducted of enzymatic activities of uridine phosphorylase (UP) and thymidine phosphorylase (TP) in normal tissues and cancer tissues of the uterine cervix. The study was performed on 27 patients of cervical cancer, treated first in our hospital. Normal cervical tissues obtained from 15 patients undergoing hysterectomy for benign diseases were used as controls. The supernatant of the homogenated cervical tissues and the stroma (5-FU and ribose-1-P or deoxyribose-1-P) were analyzed by high performance liquid chromatography, and then the UP and TP activities calculated. TP activity was significantly greater than UP activity (P < 0.0001). Both UP and TP showed significantly greater activity in cancer tissues than in normal tissues (P < 0.0001). In the TP activity of the cancer tissues, there was no significant difference among the histological types, while the TP activity tended to be significantly higher in the cases with lymph node metastasis. These results showed that the TP-mediated route seemed important as the 5FU metabolic pathway in the uterine cervical tissues, and TP enzymatic activity might be associated with lymph node metastasis.

Overexpression of cyclooxygenase-2 in carcinoma of the pancreas.

The level of cyclooxygenase (COX)-2 has been investigated recently in various human carcinomas. In the present study, we examined the distribution and extent of COX-2 protein in human pancreatic tumors using immunohistochemistry. A strong expression of COX-2 protein was present in 23 of 52 (44%) pancreatic carcinomas, a moderate expression was present in 24 of 52 (46%) pancreatic carcinomas, and a weak expression was present in 5 of 52 (10%) pancreatic carcinomas. In contrast, benign tumors showed weak expression or no expression of COX-2, and only islet cells displayed COX-2 expression in normal pancreatic tissues. Overexpression of COX-2 in carcinoma tissues was also confirmed by Western blot analysis. Furthermore, consistent with the results at protein levels, reverse transcription-PCR analyses indicated that COX-2 mRNA was overexpressed in 7 of 13 (54%) carcinomas, but in none of 3 benign tumors. Our findings suggest that COX-2 inhibitors might be potentially effective against pancreatic carcinomas and that COX-2 may be involved in certain biological processes in pancreatic islets.

Cyclooxygenase-2 is overexpressed in human cervical cancer.

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.

Significance of cathepsin-D expression in uterine tumours.

Cathepsin-D (Cath-D) expression was evaluated by an immunoradiometric assay in 67 primary endometrial carcinomas and 70 cervical cancers. In the endometrial tumours, an inverse correlation was observed between Cath-D levels and stage (P = 0.027) and myometrial invasion (P = 0.046). A significant correlation between Cath-D levels and hormone receptor status was demonstrated (P < 0.05). In cervical cancer, no differences in the distribution of Cath-D levels according to clinicopathological parameters and hormone receptors were observed. However, patients not responding to neoadjuvant chemotherapy had significantly lower Cath-D values than those showing complete or partial response (P = 0.011). As far as prognostic significance is concerned, it appears that Cath-D expression might have a different role in the two uterine neoplasias. While our preliminary data in endometrial cancer suggest that high Cath-D levels may be a favourable prognostic indicator, cervical cancer patients with Cath-D+ tumours had a shorter disease-free survival than those with Cath-D- tumors (P = 0.017).

Expression of telomerase reverse transcriptase mRNA and its quantitative analysis in human endometrial cancer.

Three major components of telomerase, i.e., human telomerase RNA (hTERC), telomerase-associated protein (TEP1), and the human telomerase reverse transcriptase (hTERT), have been identified. Among them, TERT expression is very closely related to telomerase activity. The purpose of this study was to evaluate the implications of TERT expression and telomerase activity in endometrial cancer. Fresh surgical specimens of 36 endometrial carcinomas (CA group) and 9 samples of postmenopausal endometrial tissue without malignancy (NP group) were obtained at operation in our hospital. These specimens were analyzed for telomerase activity and TERT expression by TRAP assay and RT-PCR, respectively, and the detection and quantitative analysis were made. The results for endometrial cancer were compared with those for normal endometrium and with the clinical data. In the CA group, TERT expression was detected in 35/36 subjects (97.2%), whereas in 1/9 subject (11.1%) from the NP group. Relative TERT mRNA expression was 0.50 in the CA group, and this was significantly higher compared with the level of 0.10 in the NP group (p<0.05). Telomerase activity was detected in 34/36 subjects (94.4%) from the CA group and in 3/9 subjects (33.3%) from the NP group (p<0.05), while the RTA was 30.9 and 0.2, respectively (p<0.05). There was a significant correlation between the relative TERT expression and RTA (n=45, R=0.413, p<0.05). RTA was significantly higher at an advanced surgical stage (FIGO II, III or IV) than at an early stage (FIGO 0 or I) (52.4 vs. 20.4, p<0.05), but other clinical factors showed no relationship with TERT and RTA values. The detection and quantitative analysis of telomerase activity and TERT expression is helpful for distinguishing malignant from normal endometrium when the patient is postmenopausal, even if the tumor is very small or of low malignancy.

An immunohistochemical analysis of antioxidant and glutathione S-transferase enzyme levels in normal and neoplastic human lung.

Samples of normal human lung and six major types of human lung carcinomas were immunostained for antioxidant enzymes (manganese and copper, zinc superoxide dismutases, catalase, and glutathione peroxidase) and six isoenzymes of glutathione S-transferase staining was generally low in tumor cells compared with the high level of staining noted in respiratory epithelium. A notable exception was heterogeneity in immunostaining for manganese superoxide dismutase in lung adenocarcinoma, which showed both positive and negative cells in the same tumor. Tumor stromal cells (fibroblast-appearing cells) often showed strong immunostaining for manganese superoxide dismutase, while stromal cells were negative for other antioxidant and glutathione S-transferase enzymes. None of the carcinomas studied had significant levels of catalase or glutathione peroxidase; this finding has potential clinical relevance since it indicates that these tumors cannot detoxify hydrogen peroxide. The low levels of antioxidant and glutathione S-transferase enzymes in tumor cells is consistent with the hypothesis that these enzymes are markers of cell differentiation.

Lifestyle-related biomarkers and endometrial cancer survival: elevated gamma-glutamyltransferase as an important risk factor.

BACKGROUND: Lifestyle seems to play an important role in endometrial cancer mortality, but it remains unclear which biomarkers are involved. The aim of this study was to assess the extent of the association between lifestyle-related biomarkers and the survival of endometrial cancer patients. METHODS: A sub-cohort of 242 endometrial cancer patients, from a population-based study of the more than 90,000 female participants of the Vorarlberg Health Monitoring and Promotion Programme, was followed for a median duration of twelve years. Besides age, tumour staging, and histology, also pre-diagnostic levels of body mass index, blood pressure, triglycerides, total cholesterol, glucose, gamma-glutamyltransferase (GGT), and serum uric acid were analysed in Cox proportional hazards regression models to estimate multivariate mortality risks. RESULTS: During follow-up 89 deaths occurred of which 49 were cancer-related. Survival was associated with age, tumour stage, and histology. Of the biomarkers, log10-transformed GGT showed a large effect on cancer-related mortality (HR = 3.35, 95% CI 1.12-10.03), whereas the other parameters did not appear with significant effects after adjustment for the other factors. CONCLUSION: Elevated level of GGT, a lifestyle-related marker, was associated with poor survival among endometrial cancer patients.

Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer.

Both mutation and amplification of epidermal growth factor receptor (EGFR) in lung cancers have been reported in association with clinical responses to tyrosine kinase inhibitors. We have reported evidence implicating mutation specifically in the "terminal respiratory unit" type of adenocarcinoma, which is characterized by expression of thyroid transcription factor 1, a lineage marker of peripheral airway cells. However, little is known about the role of gene amplification in the molecular progression of lung adenocarcinoma. In this study, we examined the topographical distribution of amplification in three microdissected portions each of 48 individual lung cancers with confirmed mutations. Relative copy number of the gene was analyzed using Taq Man-based gene dosage analysis and fluorescent in situ hybridization technique. Gene amplification was found in 11 lung cancers. Strikingly, nine of the cancers showed heterogeneous distribution, and amplification was associated with higher histologic grade or invasive growth. Because it was likely that the high-grade lesions were the origin for metastases, metastatic lymph nodes corresponding to five tumors with heterogeneous distribution were analyzed. Unexpectedly, amplification status of the metastatic sites was not always associated with gene amplification of the primary tumors, suggesting that selection of the metastatic clone may be defined by other factors. We also examined 17 precursor lesions and 21 in situ lung adenocarcinomas, and found that only one in situ carcinoma harbored gene amplification. Taken together, our results show that mutation occurs early in the development of lung adenocarcinoma, and that amplification may be acquired in association with tumor progression.

Cyclooxygenase-2 and epidermal growth factor receptor expressions in different histological subtypes of cervical carcinomas.

This study was designed to evaluate the significance of cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) expression in a series of cervical adenocarcinoma (AC), cervical adenosquamous carcinoma (ASC), and cervical squamous cell carcinoma (SCC). One hundred thirty cases of cervical carcinoma (30 ASC, 50 AC, and 50 SCC) were analyzed for COX-2 and EGFR expressions using specific primary antibodies. Samples were scored semiquantitatively as follows: (-), 0% of immunoreactive cells; (+), <5% of immunoreactive cells; (++), 5% to 50% of immunoreactive cells; and (+++), >50% of immunoreactive cells. The COX-2 expression was more frequently positive than EGFR in all cervical cancers studied. The COX-2 expression was also more prominent in AC than in ASC (P = 0.003). Expression of either COX-2 or EGFR was significantly different when comparing SCC with AC (P < 0.001 and P = 0.04, respectively). There was no significant correlation between COX-2 and EGFR expressions and age at diagnosis, recurrence, distant metastasis, and/or positive status of regional lymph nodes, neither between COX-2 and EGFR coexpression and the clinical data analyzed. Nevertheless, our data support that there are significant differences between EGFR and COX-2 expressions in the 3 different histogenetic types of cervical cancer. Also, in terms of therapeutic strategies, our data can be valuable in the selection of patients eligible to receive specific EGFR/COX-2-targeted therapy.

Association of XRCC1 Arg399Gln and OGG1 Ser326Cys polymorphisms with the risk of cervical cancer in Japanese subjects.

OBJECTIVE: In this study, genetic polymorphisms, XRCC1 Arg399Gln and OGG1 Ser326Cys were examined with reference to cervical cancer risk in a population-based incident case-control study in Japan. METHODS: The cases comprised 131 cervical cancer patients: 87 cases with squamous cell carcinoma (SCC) and 44 with adenocarcinoma (ADC) or adenosquamous carcinoma (ADSC). Controls were sampled from 320 healthy women who underwent a health checkup. RESULTS: The frequency of the XRCC1 399GlnGln genotype was higher in individuals with adenocarcinoma/adenosquamous carcinoma than in the healthy controls (OR = 2.98, 95% CI = 1.11-8.01, P = 0.030). However, no association was demonstrated in SCC. Analysis of OGG1 Ser326Cys polymorphism showed no significant differences between cervical cancer patients and controls. In stratification analysis, significant elevated risk of adenocarcinoma/adenosquamous carcinoma was associated with the XRCC1 399GlnGln genotype among nonsmokers (OR = 3.85, 95% CI = 1.28-11.59, P = 0.017), but not among smokers. No gene-gene interaction was observed in our case subjects. CONCLUSION: This is the first report that the XRCC1 Arg399Gln polymorphism might be important in relation to the risk of adenocarcinoma/adenosquamous carcinoma of the cervix.