Common polymorphism in the MMP-13 gene may contribute to the risk of human cancers: a meta-analysis

Cancer was viewed to be driven by accumulating genetic abnormalities that generally include chromosomal abnormalities, mutations in tumor-suppressor genes, and oncogenes. The aim of this meta-analysis was to systematically summarize the possible associations between MMP-13 rs2252070 A>G variant and cancer risks. We systematically reviewed studies focusing on MMP-13 polymorphisms with human cancer susceptibility that were published before April 30, 2014. Relevant articles were identified through research of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases. All analyses were calculated using the Version 12.0 STATA software. Odds ratios (OR) and 95 % confidence interval (95 % CI) were calculated. Eleven independent case-control studies were included in the meta-analysis, which involved 3,465 patients with cancers and 4,073 healthy controls. The results identified a positive association between rs2252070 A>G polymorphism and susceptibility to cancer under five genetic models (all P?G polymorphism with increased risk of cancers among Asians and Caucasians in majority of the groups. Our findings suggest significant association for MMP-13 rs2252070 A>G to increased susceptibility to human cancer, especially in the progression of lung carcinoma.     

Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers

In mammalian cells, four types of sialidase have been described and found to behave in different ways during carcinogenesis. We previously demonstrated that a human sialidase associated with plasma membranes (NEU3) is up-regulated in human colon cancer and is involved in suppression of apoptosis. Here we document altered expression of another human sialidase, the recently identified NEU4, and evidence of its influence on the malignant phenotype in colon cancers. Human colon mucosa was relatively rich in NEU4, which has been observed to possess short and long isoforms, but hardly contained the latter form. In clear contrast to the NEU3 case, the levels of mRNA for this sialidase were found by quantitative RT-PCR to be markedly decreased in colon cancers. In cultured human colon cancer cells, the enzyme was up-regulated in the early stage of apoptosis induced by either the death ligand TRAIL or serum-depletion, and transfection of NEU4 resulted in acceleration of apoptosis and in decreased invasion and motility. The siRNA-mediated NEU4 targeting, on the other hand, caused a significant inhibition of apoptosis and promotion of invasion and motility. Lectin blot analyses revealed that desialylated forms of nearly 100 kDa glycoproteins were prominently increased with PNA in NEU4 transfectants, whereas only slight changes in glycolipids were detected as assessed by thin layer chromatography. These results suggest that NEU4 plays important roles for maintenance of normal mucosa mostly through desialylation of glycoproteins and that down-regulation may contribute to invasive properties of colon cancers.     

DNA repair gene ERCC1 polymorphisms may contribute to the risk of glioma

Polymorphisms in excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1) gene have been shown to affect individual susceptibility to glioma, though studies have yielded conflicting results. This meta-analysis aims to derive a more precise estimation of the association between ERCC1 C8092A and C118T polymorphisms and glioma risk. A literature search of PubMed, Embase, Web of Science, Cochrane Library, and CBM databases was conducted to identify all eligible studies published before August 5, 2013. Crude odds ratios (ORs) with their corresponding confidence intervals (95 % CIs) were used to assess the strength of this association. A meta-analysis was performed by reviewing seven studies on the C8092A polymorphism (2,978 cases and 4,051 controls) and four studies on the C118T polymorphism (1,390 Asian cases and 1,546 Asian controls). Pooled analysis yielded a significant association between the C8092A variant genotype and increased risk of glioma. As for ethnicity, the A allele was associated with increased risk of glioma in Asians, while no similar finding was observed in Caucasians. Stratified analyses by histological subtype indicated that the C8092A polymorphism showed a significant association with the risk of non-glioblastoma multiforme. For the C118T polymorphism, increased glioma susceptibility was also observed among Asians. Taken together, results from our meta-analysis support the view that common variants in ERCC1 may contribute to susceptibility to glioma, especially in Asians. However, further studies investigating the significance of these two polymorphisms as markers of susceptibility to and disease progression of glioma are still needed.     

Cigar smoking in men and risk of death from tobacco-related cancers

BACKGROUND: Cigar consumption in the United States has increased dramatically since 1993, yet there are limited prospective data on the risk of cancer associated with cigar smoking. We examined the association between cigar smoking and death from tobacco-related cancers in a large, prospective cohort of U. S. men. METHODS: We used Cox proportional hazards models to analyze the relationship between cigar smoking at baseline in 1982 and mortality from cancers of the lung, oral cavity/pharynx, larynx, esophagus, bladder, and pancreas over 12 years of follow-up of the American Cancer Society's Cancer Prevention Study II cohort. A total of 137 243 men were included in the final analysis. Women were not included because we had no data on their cigar use. We excluded men who ever smoked cigarettes or pipes and adjusted all rate ratio (RR) estimates for age, alcohol use, and use of snuff or chewing tobacco. RESULTS: Current cigar smoking at baseline, as compared with never smoking, was associated with an increased risk of death from cancers of the lung (RR = 5.1; 95% confidence interval [CI] = 4.0-6.6), oral cavity/pharynx (RR = 4.0 [95% CI = 1.5-10.3]), larynx (RR = 10.3 [95% CI = 2.6-41.0]), and esophagus (RR = 1.8; 95% CI = 0.9-3.7). Although current cigar smokers overall did not appear to be at an increased risk of death from cancer of the pancreas (RR = 1.3; 95% CI = 0.9-1.9) or bladder (RR = 1.0; 95% CI = 0.4-2.3), there was an increased risk for current cigar smokers who reported that they inhaled the smoke (for pancreas, RR = 2.7; 95% CI = 1.5-4.8; for bladder, RR = 3.6; 95% CI = 1.3-9.9). CONCLUSIONS: Results from this large prospective study support a strong association between cigar smoking and mortality from several types of cancer.     

Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer

The FAS-FASL system plays crucial role in counterattack of cancer cell against immune system. This study examined the effects of FAS (-1377G/A and -670A/G) and FASL (-844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case-control analysis of 840 patients and 840 controls. The effects on T-lymphocyte apoptosis were determined by activation-induced cell death (AICD) of T cells ex vivo and by analyzing apoptotic tumor-infiltrating lymphocytes (TILs) in breast cancer tissue. We found moderately increased risk associated with FAS -1377AG [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05-1.59] and -1377AA (OR, 1.36; 95% CI, 1.01-1.82) genotypes compared with the -1377GG genotype and decreased risk associated with FASL -844CT (OR, 0.76; 95% CI, 0.62-0.94) and -844TT (OR, 0.66; 95% CI, 0.43-1.00) genotypes compared with the -844CC genotype. T lymphocytes with the FASL -844CC genotype had heightened FASL expression that is associated with increased AICD of the T cells stimulated by MCF-7 cells or phytohemagglutinin compared with the FASL -844TT genotype (10.38 +/- 4.09% and 24.29 +/- 1.50% versus 6.03 +/- 0.41% and 17.96 +/- 3.66%; P < 0.05 and 0.001). Breast cancer patients with the FASL -844CC genotype had higher apoptotic TILs in their cancer tissues than those with the FASL -844TT genotype (33.7 +/- 1.2% versus 19.1 +/- 2.0%; P = 0.007). These findings indicate that functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.     

AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

Amplification or overexpression of the HER-2/neu gene in breast cancers is associated with aggressive behavior and resistance to therapeutic regimens. The molecular mechanisms that contribute to therapeutic resistance/survival of HER-2/neu-overexpressing tumor cells have not been well defined. To determine if phosphatidylinositol 3-kinase/AKT signaling contributes to cell survival in HER-2/neu-positive breast cancers, we performed immunohistochemical analyses to evaluate expression of HER-2/neu and AKT in a series of 52 breast carcinomas. Elevated expression of HER-2/neu was found to correlate with overexpression of AKT2 protein and activation of AKT kinase. HER-2/neu-overexpressing breast cancer cell lines were resistant to apoptosis induced by UV treatment and hypoxia, which was suppressed in the presence of the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin, indicating a link between AKT activation and stress resistance in HER-2/neu-overexpressing cells. These observations suggest that AKT signaling augments resistance to stress-induced apoptosis in breast cancer cells overexpressing HER-2/neu.     

Polymorphisms of the XPC gene may contribute to the risk of head and neck cancer: a meta-analysis

Polymorphisms of the XPC gene have been reported to be associated with an increased risk of head and neck cancer (HNC), though the exact biological effect is still unclear. Genetic association studies (GAS) investigating the associations between three common polymorphisms (PAT, Lys939Gln, and Ala499Val) of the XPC gene and HNC risk have produced contradictory and inconclusive results. The aim of this meta-analysis is to evaluate the contributions of these polymorphisms to the risk of HNC. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases to indentify eligible studies. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to evaluate the strength of the associations under a fixed- or random-effect model according to heterogeneity test. Twelve case-control studies were included in this meta-analysis with a total of 3,078 HNC patients and 4,311 healthy controls. For XPC PAT, a significant overall association was found under all major genetic models. Stratified analyses further indicated significant associations in the Caucasian, population-based, non-PCR-RFLP, esophageal cancer and oral cancer subgroups. For XPC Lys939Gln, few significant results were found in either the overall analysis or stratified analyses. For XPC Ala499Val, the combined results revealed a significantly increased risk of HNC for carriers of the 499Val allele. This meta-analysis shows that the XPC PAT and Ala499Val polymorphisms may be associated with an increased risk of HNC, while XPC Lys939Gln may not be associated with HNC risk. Despite some limitations, this meta-analysis establishes solid statistical evidence for an association between XPC genetic polymorphisms and HNC risk that warrants further validation.     

Complementary and alternative medicine use is associated with an increased perception of breast cancer risk and death

Purpose. Complementary and alternative medicines (CAMS) are frequently used by patients with breast cancer and their use may be related to the presence of psychosocial distress. The objective of this study is to assess the presence of anxiety and depression in breast cancer patients who use CAM and assess how they perceive their risks of recurrence and dying from breast cancer compared to non-users.Methods. Breast cancer patients attending ambulatory clinics at a single cancer center were approached by their oncologist. Participants completed a self-administered survey regarding CAM usage, beliefs associated with CAM, views of their risks of developing recurrent cancer, and of dying of breast cancer. The presence of anxiety and depression was scored using the Hospital Anxiety and Depression Scale (HADS). Responses were scored and compared between CAM users and non-users.Results. A total of 251 patients completed the survey. CAM usage was reported by 43% of patients. Individuals who used CAM were younger [53.1 versus 63.0 year (p < 0.001)], had higher education (p < 0.001), were more likely to have full time employment [25.7 versus 16.3% (p < 0.001)] and have private insurance for medications (76 versus 60%, p=0.007) compared to non-users. CAM users perceived their risk of recurrence (p = 0.011) and death from breast cancer (p=0.0001) as being significantly greater than non-users. There were no significant differences in anxiety or depression scores between CAM and non-users.Conclusion. CAM use is associated with an increased perception of breast cancer recurrence and of breast cancer-related death. There was no association between the presence of anxiety or depression and CAM use. Improved patient understanding of actual risks of recurrence and death are required such that women will be able to make more informed decisions about using CAMs.     

Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4). Thus, genetic alterations within the candidate tumour suppressor gene DR4 would be expected to provoke a deficient apoptotic signalling thereby facilitating the development of cancer. The DR4 variants Thr209Arg and Glu228Ala were genotyped in a series of 521 breast cancer cases and 1100 control subjects from Germany, determining their impact on breast cancer risk. Neither Thr209Arg (626C>G) nor Glu228Ala (683A>C) alone were significantly associated with breast cancer risk [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.65-1.08, P = 0.18 and OR = 0.89, 95% CI = 0.72-1.12, P = 0.30]. However, haplotype analysis revealed a 3.5-fold risk for carriers of the 626C-683C haplotype (OR = 3.52, 95% CI = 1.45-8.52, P = 0.003).     

Abnormal MGMT promoter methylation may contribute to the risk of esophageal cancer: a meta-analysis of cohort studies

This meta-analysis was conducted aiming to evaluate the relationship between abnormal O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and the risk of esophageal cancer (EC). A range of electronic databases was searched: Web of Science (1945?~?2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966?~?2013), EMBASE (1980?~?2013), CINAHL (1982?~?2013), and the Chinese Biomedical Database (CBM) (1982?~?2013) without language restrictions. Meta-analysis was performed with the use of the STATA 12.0 software. In the present meta-analysis, 9 clinical cohort studies with a total of 861 EC patients were included. The pooled results revealed that the frequency of MGMT promoter methylation in cancer tissues was significantly higher than in adjacent and normal tissues (cancer tissues vs adjacent tissues, odds ratio (OR)?=?6.73, 95 % confidence intervals (95 % CI) 4.75?~?9.55, P?P?MGMT promoter methylation also exhibited a higher frequency in all these subgroups (all P?MGMT promoter methylation may contribute to the risk of EC. Thus, detection of MGMT promoter methylation may be utilized as a valuable diagnostic marker for EC.     

c-Myc induction of programmed cell death may contribute to carcinogenesis: a perspective inspired by several concepts of chemical carcinogenesis

The c-Myc protein, encoded by c-myc gene, in its wild-type form can induce tumors with a high frequency and can induce massive programmed cell death (PCD) in most transgenic mouse models, with greater efficiency than other oncogenes. Evidence also indicates that c-Myc can cause proliferative inhibition, i.e. mitoinhibition. The c-Myc-induced PCD and mitoinhibition, which may be attributable to its inhibition of cyclin D1 and induction of p53, may impose a pressure of compensatory proliferation, i.e. regeneration, onto the initiated cells (cancer progenitor cells) that occur sporadically and are resistant to the mitoinhibition. The initiated cells can thus proliferate robustly and progress to a malignancy. This hypothetical thinking, i.e. the concurrent PCD and mitoinhibition induced by c-Myc can promote carcinogenesis, predicts that an optimal balance is achieved between cell death and ensuing regeneration during oncogenic transformation by c-Myc, which can better promote carcinogenesis. In this perspective, we summarize accumulating evidence and challenge the current model that oncoprotein induces carcinogenesis by promoting cellular proliferation and/or inhibiting PCD. Inspired by c-myc oncogene, we surmise that many tumor-suppressive or growth-inhibitory genes may also be able to promote carcinogenesis in a similar way, i.e. by inducing PCD and/or mitoinhibition of normal cells to create a need for compensatory proliferation that drives a robust replication of initiating cells.     

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP-PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP-PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.     

Computer-based quality of life questionnaires may contribute to doctor-patient interactions in oncology

It is well recognized that oncologists should consider patients' quality of life and functioning when planning and delivering anticancer treatment, but a comprehensive assessment of how a patient feels requires a thorough inquiry. A standardized measurement of patients' quality of life may support clinicians in identifying important problems for discussion during the limited time of the medical consultations. The aim of this study was to assess the feasibility of computer-administered individual quality of life measurements in oncology clinics with immediate feedback of results to clinicians and to examine the impact of the information on consultations. The study employed a prospective non-randomized design with pre-test post-test within subjects comparisons and involved three medical oncologists and 28 cancer patients receiving chemotherapy. The intervention consisted of completion of quality of life questionnaires before the consultations and informing clinicians of the results. The main outcome measures were patients' perceptions of the content of baseline and intervention consultations and satisfaction with communication. A qualitative analysis of clinicians' interviews was performed. When clinicians had the quality of life results they enquired more often about daily activities (Z= -2.71, P=0.007), emotional problems (Z= -2.11, P=0.035) and work related issues (Z= -1.89, P=0.058). There was an increase in the number of issues discussed during the intervention consultation (Z= -1.89, P=0.059). Patients were highly satisfied with both consultations. The computer measurement was well accepted by patients who felt that the questionnaires were a useful tool to tell the doctors about their problems. The clinicians perceived that the quality of life data broadened the range of the clinical inquiry and helped them identify issues for discussion. Having symptoms and functional problems expressed quantitatively on a scale was useful for detection of change over time.