Effect of GSTM1 polymorphism on risks of basal cell carcinoma and squamous cell carcinoma: a meta-analysis

Glutathione S-transferases are important enzymes in the detoxification of a wide range of reactive oxygen species produced during melanin synthesis and oxidative stress processes. Glutathione S-transferase M1 (GSTM1) null genotype may be a candidate genetic polymorphism with a role in susceptibility to skin cancer such as basal and squamous cell carcinomas. We conducted a systematic review and meta-analysis to define the effect of GSTM1 null polymorphism on skin cancer risk. We searched the PubMed, Embase, and Web of Science databases to identify published case–control studies investigating the association between GSTM1 null genotype and skin cancer risk. Between-study heterogeneity was assessed using the I ² statistic. Odds ratios (OR) with corresponding 95 % confidence intervals (95 % CI) from individual studies were pooled using fixed and random effects models. Nineteen case–control studies (4,275 cases and 4,255 controls) were considered eligible and included in the meta-analysis, and 11 of which were on basal cell carcinoma; ten, on melanoma, and seven, on squamous cell carcinoma. Overall, the GSTT1 null genotype was not associated with the risk of skin cancer (OR, 1.01; 95 % CI 0.93–1.11; P?=?0.76). Subgroup analysis by histological types showed that GSTT1 null genotype was not associated with risks of basal cell carcinoma (OR, 1.06; 95 % CI 0.92–1.21; P?=?0.42), squamous cell carcinoma (OR, 0.97; 95 % CI 0.76–1.24; P?=?0.80), and cutaneous malignant melanoma (OR, 1.00; 95 % CI 0.88–1.14; P?=?0.60). Therefore, this meta-analysis suggests that GSTM1 null polymorphism is not associated with risks of basal and squamous cell carcinomas.     

Association of cyclin D1 polymorphism with increased susceptibility to oral squamous cell carcinoma

We have examined the association of the CCND1 A/G870 polymorphism with susceptibility and outcome in 174 German patients with oral SCC (OSCC). The CCND1 G870 allele frequency was increased in cases (G870=0.65) when compared to controls (n=155, G870=0.54) and the distribution of CCND1 genotypes were significantly different (p=0.014). Using logistic regression, correcting for age, gender and tobacco consumption, an increased frequency of the CCND1 GG870 genotype was observed in the OSCC cases (p=0.025, OR 3.37, 95% CI 1.61-9.80). No significant associations were observed between CCND1 A/G870 and tumour histological factors. Our data suggests that the CCND1 GG870 genotype is associated with increased susceptibility to OSCC. The involvement of cyclin D1 polymorphism in mechanisms of SCC development may differ in the different sub-sites of the head and neck.     

Genetically high susceptibility to oral squamous cell carcinoma in terms of combined genotyping of CYP1A1 and GSTM1 genes

An association of oral squamous cell carcinoma (SCC) susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene and GSTM1 polymorphism were reported in our previous study (Sato M, Sato T, Izumo T, Amagasa T. Genetic polymorphism of drug-metabolizing enzymes and susceptiblility to oral cancer. Carcinogenesis 1999;20:1927-31). We report here that genetic risk for oral SCC was associated with another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of CYP1A1, and combined genotyping of CYP1A1 and GSTM1 genes in relation to the cumulative cigarette-smoking dose. The genetic polymorphisms of CYP1A1 and GSTM1 genes in oral cancer susceptibility were assessed by examining polymorphic prevalences in 142 oral SCC patients and 142 healthy controls who were individually matched to the patients with respect to sex and age (+/-1 year). Individuals with a combined genotype of Val/Val and GSTM1(-) were at an increased risk for oral SCC compared with other combined genotypes, in particular, at a low dose level of cigarette smoking.     

Bag-1 proteins in oral squamous cell carcinoma

Bag-1 is an anti-apoptotic protein that exhibits altered expression in many malignancies, including oral squamous cell carcinoma. The bag-1 gene gives rise to different protein products with different subcellular localisations through alternative translational initiation sites. In oral squamous cell carcinoma, cytoplasmic expression has been associated with metastasis to regional lymph nodes and poor prognosis. In contrast, the longest Bag-1 isoform is nuclear and may regulate differentiation in oral epithelium. In this review, the functions of the three isoforms of Bag-1 expressed in oral epithelial cells are discussed in relation to their contribution to oral carcinogenesis.     

Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose.

The genetic polymorphisms of CYP1A1 and GSTM1 genes among 100 Japanese patients with oral squamous cell carcinomas (SCC) were investigated to evaluate the role of genetic susceptibility in carcinogenesis of the oral cavity. The presence of the rare homozygote of CYP1A1, m2/m2, was significantly more frequent in the patient group (15.0%) than the control group (8.0%) (Odds ratio (ORs) = 3.6 95% Confidential Interval (CI): 1.4-9.5). The heterozygotic variant, m1/m2, was also frequently seen in oral SCC patients. This meant that the m2 allele was observed in more than half of the patients. The null genotype of GSTM1 was found in 43.0% of the patient group. This was not significantly different from the controls (40.0%). When the life time cigarette consumption dose of the patients was considered with respect to genotypes of CYP1A1, the mean smoking index (SI) of oral SCC patients with m2/m2 was found to be less than half of the mean SI among the patients with m1/m1 genotype (P < 0.02). The ORs of the m2/m2 genotype was found to be significantly high in a comparison of various subsites of the oral cavity, except for the floor of the mouth. Our results indicate that the rare homozygote of CYP1A1, m2/m2, is associated with increased risk of oral SCC, in particular, at low cigarette dose levels. The results also suggested that the involvement of such susceptibility in oral carcinogenesis might be different between the subsites of the oral cavity.     

Genetic polymorphism in myeloperoxidase but not GSTM1 is associated with risk of lung squamous cell carcinoma in a Chinese population

Myeloperoxidase (MPO), an enzyme derived from neutrophils, metabolically activates a wide range of carcinogens, whereas glutathione S-transferase M1 (GSTM1) detoxifies various electrophilic metabolites. A -463G-->A polymorphism in the promoter region of the MPO gene diminishes the expression of MPO and has been consistently shown to be associated with reduced risk of lung cancer in different ethnic populations. In our study, we have assessed the role of this polymorphism in lung cancer risk in a Chinese population. Genotypes of MPO and GSTM1 were determined by PCR-SSCP and multiplex PCR in 314 patients with lung cancer and 320 frequency-matched controls. The allele frequency for MPO -463A was found to be 0.155 in controls and 0.114 in cases. Subjects with the MPO -463GG genotype were at an increased risk of squamous cell carcinoma (SCC) of the lung compared to those having at least one -463A variant allele (adjusted odds ratio [OR] 2.35; 95% confidence interval [CI] 1.40-3.94). Stratified analysis suggested an interaction between heavy smoking (> or =26 pack-years) and the MPO-463GG genotype. The adjusted OR of lung SCC for those having MPO-463GG genotype and smoked > or =26 pack-years was 20.50 (95% CI 5.58-75.33) compared to 6.22 (95% CI 1.72-22.47) for those smoked > or =26 pack-years but having at least one variant A allele (p = 0.023, test for homogeneity). This effect of the MPO polymorphism was not observed in lung adenocarcinoma. GSTM1 deletion was quite common in both controls (49.4%) and cases (50.3%) but was not associated with risk of lung cancer alone or in combination with the MPO polymorphism. Our results confirm the previous reports showing that the variant A allele of MPO has a protective effect against risk of lung cancer.     

Cytokeratin alteration in oral leukoplakia and oral squamous cell carcinoma

Intermediate filaments are involved in cell migration and intracellular signal transduction pathways. In a variety of organs, the expression of distinct intermediary filaments are further associated with distinct steps of malignant transformation. In this study, we seeked to define the cytokeratin (Ck) expression pattern in oral leukoplakia and oral squamous cell carcinoma (OSCC). One hundred and ninety-two patients with OSCC, 117 patients with oral leukoplakia without dysplasia (OL) and 23 with oral leukoplakia with dysplasia (squamous intraepithelial neoplasia) (OLD) of the oral cavity were investigated for the immunohistochemical expression of Ck 5-6, Ck 8/18, Ck 1 Ck 10, Ck 14, Ck 19 using the tissue microarray technique. Correlations between clinical features and the expression of cytokeratins were evaluated statistically by chi2 tests. The expression of Ck 8/18, Ck 19 and Ck 1 was seen in 3.1% (Ck 8/18), 12.5% (Ck 19), 75.4% (Ck 1) of all leukoplakias, 1.0% (Ck 8/18), 9.4% (Ck 19), 76.8% (Ck 1) in OL, 13.0% (Ck 8/18), 27.3% (Ck 19), 68.4% (Ck 1) in OLD and was significantly associated with the degree of dysplasia (Ck 8/18 p<0.01; Ck 19 p<0.01; Ck 1 p<0.01) and the acquisition of invasive growth properties. The highest frequencies were observed in invasive squamous cell carcinomas. The expression of Ck 8/18 and Ck 19 in transformed oral lesions can be regarded as an early feature in the pathogenesis of invasive OSCC. However, the aberrant expression of Ck 8/18 and Ck 19 in an even higher frequency in invasive carcinomas characterizes the expression of typical glandular cytokeratins as a general progression marker in squamous cell carcinomas. These results can be interpreted as first hints that oral leukoplakias with an expression of Ck 8/18 or 19 independent of dysplasia, should be resected totally since they might indicate an increased progression potential.     

Diagnosis and therapy of oral squamous cell carcinoma

Oral squamous cell carcinoma ranks among the top ten most common cancers worldwide. Despite the success in diagnosis and therapy during the past 30 years, oral squamous cell carcinoma still belongs to the tumor types with a very unfavorable prognosis. In an effort to identify genomic alterations with prognostic relevance, we applied the comparative genomic hybridization technique on oral squamous cell carcinoma. The tumors exhibited from five up to 47 DNA copy number alterations, indicating a considerable degree of genomic imbalance. Out of 35 tumors, 19 showed a gain of chromosome band 7p12. Genomic imbalances were investigated by hierarchical cluster analysis and clustered image mapping to investigate whether genomic profiles correlate with clinical data. Results of the present investigation show that profiling of genomic imbalances in general, and especially of the epidermal growth factor receptor (EGFR) on 7p12, may be suitable as prognostic factors. In order to identify small-molecule inhibitors for EGFR, we established a database of 531 natural compounds derived from medicinal plants used in traditional Chinese medicine. Candidate compounds were identified by correlation analysis using the Kendall tau-test of IC50 values of tumor cell lines and microarray-based EGFR mRNA expression. Further validation was performed by molecular docking studies using the AutoDock program with the crystal structure of EGFR tyrosine kinase domain as docking template. We estimate these results will be a further step toward the ultimate goal of individualized, patient-adapted tumor treatment based on tumor molecular profiling.     

A case of oral squamous cell carcinoma responding to S-1

A 76-year-old patient with oral squamous cell carcinoma was treated by chemotherapy with S-1. S-1 (100 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course. The primary lesion markedly decreased at 7 days after the beginning of S-1 treatment, and disappeared after one course of S-1. After two courses, the primary lesion was assessed to show a complete response (CR),and no tumor cells were identified as a result of biopsy. In addition, the value of tumor marker SCC decreased from 2.13 ng/mL before treatment to 0.68 ng/mL after two courses of S-1. Although the patient is still taking UFT, she is well with no signs of recurrence 50 months from the initial treatment.     

Caveolin-1 in oral squamous cell carcinoma microenvironment: an overview

Caveolin-1 plays an important role in the pathogenesis of oncogenic cell transformation, tumorigenesis, and metastasis. Increased expression of caveolin-1 in an array of tumors has confirmed its value in prognosis. It has been established that oxidative stress is the main cause for loss of stromal caveolin-1 via autophagy in the tumor microenvironment. In this overview, we attempt to abridge the relationship between caveolin-1 and oral squamous cell carcinoma, taking all the established theories into consideration.     

Upregulation of thioredoxin reductase 1 in human oral squamous cell carcinoma

Lymphoma is not a common focus for viral therapy as many researchers do not consider lymphoma as a suitable target for viral vectors. In the present study, the infection, replication and cytotoxicity of herpes simplex virus (HSV) and adenovirus vectors were screened and evaluated in different lymphoma cell lines. Three recombinant viruses, BAC-HSV-1-eGFP, Adv-eGFP and an NV1020-like oncolytic HSV-1 virus strain named BAC-HSV-1-eGFP-delIRs, inserted with green fluorescent protein (GFP) as a reporter, were applied to evaluate the efficiency of viral infection and replication and cytotoxicity to lymphoma cells. Four types of lymphoma cell lines (SNK-6, Jurkat, Raji and Hut 78) were examined. We found that the HSV-1 vector, BAC-HSV-1-eGFP, was able to infect and replicate in the three lymphoma cell lines (Jurkat, Raji and Hut 78) and inhibit the growth of these cells more efficiently than adenovirus vector Adv-eGFP. The sensitivity of the four types of lymphoma cell lines to the viral vectors was different. The human cutaneous TL cell line Hut 78 was more sensitive to the viral vectors than the other cell lines. However, the human NK/T lymphoma cell line SNK-6 was not infected by any of the viral vectors and did not allow replication of the viruses. In conclusion, lymphoma may be a potential target for HSV-1 vector-mediated viral therapy.     

Expression of protease-activated receptor 1 in oral squamous cell carcinoma.

Protease-activated receptor 1 (PAR-1) is a G-coupled membrane protein. In this study, we analyzed the expression of PAR-1 in oral squamous cell carcinomas (SCCs). PAR-1 was expressed in oral SCCs, but the level of PAR-1 protein was lower in non-metastatic cells than in metastatic cells. Thrombin stimulated the growth of metastatic cells, and both thrombin and thrombin receptor activation peptide (TRP) enhanced the adhesion of these cells to fibronectin, but had no effect on non-metastatic cells. Thrombin and TRP also induced matrix metalloproteinase (MMP)-2 and MMP-9 activities in metastatic cells. These results suggest that PAR-1 may contribute to the growth and invasive potential of oral SCC.     

Survivin expression in oral squamous cell carcinoma

A series of 110 cases of oral squamous cell carcinoma (SCC) together with six lymph node and one distant metastatic lesions was analysed for expression of survivin, a recent apoptosis inhibitor, by immunohistochemistry and Western blotting. In total, 91 cases (82.7%) of carcinoma and all metastasis (seven cases, 100%) were positive for survivin expression, with weighted survivin scores ranging from 1 to 4. In contrast, normal oral epithelium did not express survivin. There was no significant correlation between survivin expression and age, sex, tumour size, the presence of lymph node and distant metastases. Survivin expression was increased in poorly differentiated tumours, even if differences were not statistically significant. In contrast, when analysed for prognostic significance, patients with low survivin expression had statistically significant better survival rates than the group with high survivin expression (P<0.05). These data suggest that survivin expression may identify cases of oral SCC with more aggressive and invasive phenotype.     

Human papillomavirus and oral squamous cell carcinoma: A review of HPV-positive oral squamous cell carcinoma and possible strategies for future

Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Besides tobacco use and alcohol consumption, human papillomavirus (HPV) infection has also been identified as a risk factor for OSCC recently. The OSCC incidence has increased in recent years, especially among younger women. The purpose of this article is to review clinical and epidemiological studies on the association between HPV infection and OSCCs, and the efficacy of HPV vaccine, so as to provide possible policy implications for preventing HPV-positive OSCC. It is necessary to review the present related body of knowledge to determine whether the association between HPV infection and OSCC has been thoroughly studied. The study was based on literature review. Studies were identified using electronic databases including MEDLINE, PubMed, EMBASE, etc. The inclusion and exclusion criteria were based on consultation from a panel of experts in this area and carefully designed. Based on a systematic review of literatures, HPV infection is a possible cause for the incidence of HPV-positive OSCCs. The prevalence of HPV infection possibly contributed to the increasing trends of HPV-positive OSCCs. Oral HPV infection is a form of HPV transmission. Oral sex behaviors and open-mouthed kissing are probably reasons for oral HPV infection. We also have some epidemiological evidences proving that HPV vaccine provides a possible solution for preventing oral HPV infection. Increased awareness of HPV-positive OSCCs is essential due to the severity of this problem. Biological and epidemiological data regarding the link between sexual behavior and HPV-associated cancers indicate a probable connection, although definitive data are needed. Future studies are needed to investigate the mechanisms of how HPV infection causes HPV-positive OSCCs, whether HPV vaccine provides a prevention for OSCCs, and other important issues.     

Preoperative chemotherapy with S-1 and low-dose cisplatin for oral squamous cell carcinoma

We investigated preoperative chemotherapy with S-1 and low-dose cisplatin for the untreated stage II-IV oral squamous cell carcinoma patients. The chemotherapy consisted of S-1 80 mg/m2/day (day 1-14) and CDDP 5 mg/m2/day (day 1-5 and day 8-12) intravenous drip (less than 1 hour). In the second phase clinical trial of 44 patients, the clinical response rate was 63.7% and the histological response rate by the Oboshi-Shimosato's evaluation was 61.4%. The main adverse events were myelosuppression and gastrointestinal disturbance such as nausea 36.4%, anorexia 27.3%, neutropenia 25% and leukopenia 25%. Grade 3 and 4 adverse events were neutropenia 11.4%, leukopenia 9.1%, thrombocytopenia 4.5% and oligochromemia 4.5%. The two-year overall survival rate was 92.6%. The advantages of this chemotherapy are high response rate, low adverse effects and not to prevent planned therapies such as surgery and radiation. These facts suggest that this chemotherapy is suitable for preoperative chemotherapy.     

PLCE1在口腔鳞状细胞癌中的表达及其临床意义

目的:探讨磷脂酶Cε1（phospholipase C epsilon－1,PLCE1)在口腔鳞状细胞癌(OSCC)组织中的表达及其与临床病理特征和患者预后的关系。方法:应用免疫组织化学方法检测PLCE1在83例OSCC组织和20例正常口腔黏膜组织中的表达,并分析 PLCE1表达与OSCC临床病理特征的关系;采用Kaplan-Meier法进行生存分析,Cox 风险比例回归模型分析影响OSCC患者预后的独立因素。结果:PLCE1在OSCC组织与口腔正常黏膜组织中高表达率分别为53.01%和15.00%,差异有统计学意义（P=0.002）。PLCE1的表达与患者年龄、性别、吸烟无相关性,而与肿瘤分化程度、T分期、临床分期、N分期有密切关系。单变量分析显示临床分期、PLCE1、T分期、N分期是影响OSCC预后的因素,双变量分析显示PLCE1是其独立预后因素。结论:PLCE1过表达与OSCC的发生、发展密切相关,可作为判断OSCC恶性程度和不良预后的参考指标。     

CXCR1、CXCR2在口腔鳞癌中的表达及意义

目的　探讨CXCR1、CXCR2的表达与口腔鳞癌生物学行为的关系及意义.方法　应用免疫组织化学技术检测57例口腔鳞癌手术切除标本和10例正常口腔黏膜标本中CXCR1、CXCR2的表达情况,分析其与病变类型及临床病理特征的关系.结果　口腔鳞癌标本中41例(71.9％) CXCR1呈阳性表达,35例(61.4％) CXCR2呈阳性表达.CXCR1与口腔鳞癌的病理分级、临床分期及淋巴结转移关系密切,CXCR2与口腔鳞癌的临床分期及淋巴结转移关系密切.结论　CXCR1、CXCR2在口腔鳞癌的发生、发展中起重要作用,是口腔鳞癌早期诊断和预后的潜在生物学参考指标.     

Marijuana use and risk of oral squamous cell carcinoma

Previous laboratory investigations, case reports, and a hospital-based case-control study have suggested that marijuana use may be a risk factor for squamous cell head and neck cancer. We conducted a population-based case-control study to determine whether marijuana use is associated with the development of oral squamous cell carcinoma (OSCC). Case subjects (n = 407) were 18-65-year-old residents of three counties in western Washington State who were newly diagnosed with OSCC from 1985 through 1995. Control subjects (n = 615), who were similar to the cases with respect to age and sex, were selected from the general population using random-digit telephone dialing. Lifetime histories of marijuana use and exposure to known OSCC risk factors were ascertained using a structured questionnaire. Information on genetic polymorphisms in glutathione S-transferase enzymes was obtained from assays on participant DNA. Odds ratios for associations with features of marijuana use were adjusted for sex, education, birth year, alcohol consumption, and cigarette smoking. A similar proportion of case subjects (25.6%) and control subjects (24.4%) reported ever use of marijuana (adjusted odds ratio, 0.9; 95% confidence interval, 0.6-1.3). There were no trends in risk observed with increasing duration or average frequency of use or time since first or last use. No subgroup defined by known or suspected OSCC risk factors (age, cigarette smoking, alcohol consumption, and genetic polymorphisms) showed an increased risk. Marijuana use was not associated with OSCC risk in this large, population-based study.