Prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) 8473T>C polymorphism associated with prognosis for patients with colorectal cancer treated with capecitabine and oxaliplatin

Purpose  The present study analyzed the polymorphisms of apoptosis-related genes and their impact on the response to chemotherapy and survival of patients with colorectal cancer. Patients and methods  A total of 76 patients with recurrent or metastatic colorectal cancer treated with capecitabine and oxaliplatin (XELOX) combination chemotherapy were enrolled in the present study. The single nucleotide polymorphisms of 15 apoptosis-related genes (TP53, BCL2L, TNFRSF10B, AKT1, PTGS2/COX2, BID, RIPK1, FAS, FASL, caspase 3, and caspase 6-10) were determined using a PCR-RFLP assay. Results  No significant association between the polymorphisms and the response was found for any of the genes analyzed. However, the T/T genotype of PTGS2 8473T>C (rs5275) was significantly correlated with a better progression-free survival (PFS) and overall survival (OS) when compared to the combined T/C and C/C genotype (Hazard ratio [HR] = 0.47; P value = 0.046 and HR = 0.16; P = 0.013, respectively) in a multivariate analysis adjusted for age, sex, performance status, disease status and curative resection. No association was noted between the other polymorphisms and survival. Conclusion  The PTGS2 8473T>C polymorphism was found to be correlated with PFS and OS in patients with advanced colorectal cancer treated with XELOX chemotherapy.     

Interleukin-10 promoter polymorphism is associated with decreased breast cancer risk

Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. A [TCATA] haplotype formed by polymorphisms at positions –3575, –2763, –1082, –819 and –592 in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the –592C > A polymorphism. Aim of the present study was to analyze the role of the IL-10 [TCATA] haplotype for breast cancer. We performed a case–control study including 500 female patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The –592C > A polymorphism was determined by a 5-nuclease assay (TaqMan). Frequency of the homozygous –592 AA genotype, indicating homozygosity for the [TCATA] haplotype, was 4.2% among patients and 7.3% among controls (p=0.038; odds ratio 0.56; 95% confidence interval 0.32–0.97). IL-10 genotypes were not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. Therefore we conclude that the IL-10 –592C > A promoter polymorphism may be associated with a reduced breast cancer risk.     

Catechol-O-methyltransferase polymorphism is not associated with ovarian cancer risk.

A valine-108-methionine polymorphism in exon 4 of the catechol-O-methyltransferase (COMT) gene causes a 3- to 4-fold reduction in enzyme activity and has been associated with an increased risk of breast cancer. This increased risk may be attributable to a decreased ability of the protein encoded by the low-activity allele (COMT(L)) to methylate and inactivate catechol estrogens, which have been implicated in estrogen carcinogenesis. Because estrogens have also been implicated in the etiology of ovarian cancer, we analyzed 108 cases and 106 controls from a case-control study conducted in Mainz, Germany, to test the hypothesis that COMT(L) is associated with ovarian cancer risk. No significant association was found between the COMT genotype and ovarian cancer risk (for the intermediate-activity COMT genotype versus the high-activity COMT genotype, OR, 1.29; 95% CI, 0.63-2.64; for the low-activity COMT genotype versus the high-activity COMT genotype, OR, 1.17; 95% CI, 0.52-2.61). We also hypothesized that women who were both low-activity COMT genotype- and glutathione S-transferase (GST) M1- and/or T1 null would be at higher risk for ovarian cancer because the combination of these genotypes could theoretically lead to higher catechol estrogen exposure. However, the association between the COMT polymorphism and ovarian cancer risk was similar across GSTM1 and GSTT1 genotypes (Ptrend > 0.40, for all strata). Because of the small sample size of this study population, odds ratios of a small magnitude could not be completely ruled out; however, the results presented do not support a strong association between the COMT polymorphism and the risk of ovarian cancer.     

Endothelial nitric oxide synthase (eNOS) 894 G>T polymorphism is associated with breast cancer risk: a meta-analysis

Nitric oxide (NO) is known to be critically involved in breast carcinogenesis. Genetic polymorphisms of the gene encoding for endothelial nitric oxide synthase (eNOS), the enzyme catalyzing the production of the NO, are known to predispose to malignant disease. Increasing evidences showed that eNOS plays a significant role in the development of breast cancer. However, published data on the association between eNOS 894 G>T polymorphism and breast cancer risk are inconclusive. In order to derive a more precise estimation of this relationship, a meta-analysis including 11 studies was performed. Crude odds ratios (ORs) with 95% confidence interval (CIs) were used to estimate the strength of the association. The results showed that there was a significant association with breast cancer risk in TT versus GG (OR = 1.22, 95% CI = 1.02–1.44, P = 0.272) and recessive model TT versus GG/GT (OR = 1.21, 95% CI = 1.02–1.42, P = 0.223). In summary, this meta-analysis primarily suggests that eNOS 894G>T polymorphism is associated with breast cancer.     

Estrogen receptor beta polymorphism is associated with prostate cancer risk.

PURPOSE: After cloning of the second estrogen receptor, estrogen receptor beta (ERbeta) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ERbeta is thought to exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ERbeta gene are associated with prostate cancer risk. EXPERIMENTAL DESIGN: We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ERbeta gene from the promoter to the 3'-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects. RESULTS: There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen. CONCLUSION: We found an association with a SNP located in the promoter region of the ERbeta gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ERbeta is of importance for risk of prostate cancer.     

FASLG polymorphism is associated with cancer risk

Many studies have reported the association between the FASLG –844T/C polymorphism and cancer risk, but the data are remaining controversial. A pooled analysis was performed to assess this relationship comprehensively. Medline, PubMed, Embase and Web of Science were searched, and data were extracted and cross-checked independently by three authors. A total of 18 published studies including 22389 subjects were involved in this analysis. Overall, the –844C allele was associated with a significantly increased cancer risk (for CC versus TT: OR = 1.23, 95% confidence interval (CI) = 1.04–1.45; for CC + TC versus TT: OR = 1.15, 95% CI = 1.01–1.30; for CC versus TT + TC: OR = 1.20, 95% CI = 1.05–1.38). In the subgroup analysis by ethnicity, significantly elevated risks were found among Asians (for CC versus TT: OR = 1.61, 95% CI = 1.37–1.89; for CC + TC versus TT: OR = 1.36, 95% CI = 1.16–1.60; for CC versus TT + TC: OR = 1.44, 95% CI = 1.22–1.70). In the subgroup analysis by study design, significantly increased risks were found among population-based case-control studies (for CC versus TT: OR = 1.40, 95% CI = 1.06–1.84; for CC + TC versus TT: OR = 1.25, 95% CI = 1.01–1.55; for CC versus TT + TC: OR = 1.31, 95% CI = 1.06–1.61). These findings indicate that the FASLG –844C allele is emerging as a low-penetrant cancer susceptibility allele for cancer development. However, more comprehensive understanding of the association would certainly have an immense prospect in the promising field of individualised preventive care.     

A genetic polymorphism in prostaglandin synthase 2 (8473, T-->C) and the risk of lung cancer

Prostaglandin synthase 2 (PTGS2) mediated production of prostaglandins is an important step in the inflammatory response. In a population-based case-cohort study, we investigated the relationship between lung cancer and a polymorphism in PTGS2 at site 8473. Among 54,220 cohort members, 265 lung cancer cases and a comparison group of 272 individuals were identified. We found no overall significant association between the PTGS2 polymorphism and lung cancer risk, though the results indicated a lower risk in subjects carrying one copy (RR 0.87; 95% CI 0.61-1.25) or two copies (RR 0.58; 95% CI 0.30-1.12) of the variant allele compared with subjects carrying two copies of the wildtype allele. This tendency seemed to be strongest among the youngest subjects (50-55 years) with a RR on 0.48 (0.19-1.22) in carriers of one variant allele and 0.21 (0.04-1.07) in carriers of two variant alleles, and a significant trend (P=0.04). These results indicate that PTGS2 could be implicated in the development of lung cancer.     

Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50

In a population-based case-control study for breast cancer before the age of 51 years, 554 cases and 559 age-matched controls were genotyped for the polymorphic progesterone receptor allele PROGINS. Breast cancer risk was decreased in women carrying the PROGINS allele. The odds ratio adjusted for age and study region was 0.76 [95% confidence interval (CI), 0.58-1.00]. Compared with wild-type A1/A1 homozygotes, the odds ratio for A1/A2 heterozygotes and A2/A2 homozygotes was 0.82 (95% CI, 0.62-1.08) and 0.27 (95% CI, 0.10-0.74), respectively, suggesting a gene dosage effect of the A2 allele. There was suggestive evidence for a differential effect by menopausal status (P = 0.07) and by family history of breast cancer (P = 0.15).     

C282Y polymorphism in the HFE gene is associated with risk of breast cancer

The C282Y and H63D polymorphisms in the HFE gene have been implicated in susceptibility of breast cancer, but a number of studies have reported inconclusive results. The aim of this study is to investigate the association between the C282Y and H63D polymorphisms in the HFE gene and breast cancer risk by meta-analysis. We searched PubMed and Embase databases, covering all related studies until March 2, 2013. Statistical analysis was performed using STATA 10.0. A total of 7 studies including 1,720 cases and 18,296 controls for HFE C282Y polymorphism and 5 studies including 942 cases and 1,571 controls for HFE H63D polymorphism were included in the meta-analysis. The results showed that HFE C282Y polymorphism was significantly associated with increased risk of breast cancer under homozygotes vs. wild-type model (OR?=?2.06, 95%CI?=?1.19–3.58) and recessive model (OR?=?1.98, 95%CI?=?1.14–3.44) but not under heterozygotes vs. wild-type model (OR?=?0.97, 95%CI?=?0.70–1.35), dominant model (OR?=?1.00, 95%CI?=?0.72–1.40) and multiplicative model (OR?=?1.04, 95%CI?=?0.76–1.42). However, we did not find any association between HFE H63D polymorphism and breast cancer risk under all genetic models. This current meta-analysis suggested that C282Y polymorphism rather than H63D might be associated with increased risk of breast cancer.     

Increased cyclooxygenase-2 (COX-2) expression is associated with chemotherapy resistance and outcome in ovarian cancer patients.

BACKGROUND: Cyclooxygenase-2 (COX-2) expression is associated with aggressive clinicopathological parameters and unfavourable prognosis in several human malignancies. The aim of this study was to investigate the expression of COX-2 and its association with clinicopathological parameters, response to treatment, and clinical outcome in ovarian cancer patients. PATIENTS AND METHODS: COX-2 expression was analysed by immunohistochemistry in 87 primary ovarian carcinomas from patients with measurable disease after primary laparotomy. RESULTS: COX-2 immunoreaction was observed in 39 (44.8%) cases, and did not differ in distribution according to age, FIGO stage, debulking at time of surgery, presence of ascites, histotype or tumour grade. Both in patients cytoreduced at first surgery and in those undergoing only explorative laparotomy, the percentage of COX-2 positivity was significantly higher in non-responding than in patients responding to treatment (P = 0.043 and P = 0.0018, respectively). In multivariate analysis, only COX-2 positivity and older age retained an independent role in predicting a poor chance of response to treatment. There was no significant difference of clinical outcome according to COX-2 status in patients undergoing primary debulking while, in the subgroup of patients who underwent explorative laparotomy, COX-2-positive cases showed a shorter time to progression (P = 0.025) and overall survival (P = 0.025). CONCLUSIONS: The assessment of COX-2 status could provide additional information in order to identify ovarian cancer patients with a poor chance of response to chemotherapy and potentially candidates for more individualised treatments.     

XRCC2 Arg188His polymorphism is not directly associated with breast cancer risk: evidence from 37,369 subjects

Several common single-nucleotide polymorphisms (SNPs) within the XRCC2 gene have been identified as potential breast cancer susceptibility loci and a coding SNP in exon 3 (Arg188His, rs3218536) has been extensively studied, though the results were inconclusive. We, in this study, performed a more convincing and precise estimation of the relationship between Arg188His and breast cancer by meta-analyzing the currently available evidence from literature. A total of 16 studies involving 18,341 cases and 19,028 controls (37,369 subjects) were identified for meta-analysis. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. When all the studies were pooled into meta-analysis, there was no evidence of a significant association between Arg188His and breast cancer risk in any genetic models. Notably, Arg188His tended to be related to breast cancer in a fixed-effects, dominant model (OR = 0.922, 95% CI: 0.870–0.978, P = 0.007); however, since there was a between-study heterogeneity (P _h = 0.014), we assessed the association using a random-effects model instead and no significance was observed (OR = 0.932, 95% CI: 0.852–1.020, P = 0.128). Subgroup analysis by ethnicity did not change the results. In summary, the present meta-analysis suggests that the XRCC2 Arg188His is not directly associated with breast cancer risk. However, considering that susceptibility is likely to be the result of a complex interplay between genetic variation and environmental factors, we cannot rule out the possibility of interactions between Arg188His and other variants. Further investigation on the influence of this SNP in modifying the relationship between environment exposures and breast cancer risk is still needed.     

Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors

Background  

Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade.     

HER2 polymorphism and breast cancer risk in Portugal.

Breast cancer is a major public health problem around the world, and its carcinogenesis is not yet well understood. The human epidermal growth factor Receptor 2 (HER2) seems to play an important role in the development of this neoplasia, and genetic alterations in this gene, such as point mutations and polymorphisms have been detected in breast cancer patients. We analysed the frequency of a single nucleotide polymorphism in the HER2 gene in blood samples from 152 breast cancer patients and 146 healthy controls using the polymerase chain reaction methodology, followed by restriction fragment length polymorphism (PCR-RFLP). We found a twofold increase in risk of breast cancer in women who are carriers of a Val allele genotype-Ile/Val and Val/Val genotypes [odds ratio (OR)=2.00; 95% confidence interval (CI) 1.23-3.25; P=0.005]. Our results indicate an association between the presence of the Val allele in the HER2 polymorphism and the risk of breast cancer. Further studies are needed to evaluate the role of this polymorphism in the behaviour of breast cancer.     

A novel polymorphism in the promoter region of ERBB4 is associated with breast and colorectal cancer risk.

PURPOSE: The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer. EXPERIMENTAL DESIGN: We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG -1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression. RESULTS: We identified five new germ line variants -815 A>T, -782 G>T, -638 insTC, -267 C>G, and -219 del10bp. Two variants showed in vitro functional effects. The -782T allele showed lower protein binding affinity and lower promoter activity compared with the -782G allele, however, the -815T allele showed higher protein binding affinity and higher promoter activity. The -782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively). CONCLUSION: The ERBB4 -782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.