The Role of Catalase C262T Gene Polymorphism in the Susceptibility and Survival of Cancers

Catalase (CAT), one antioxidant enzyme, may provide resistance against many diseases. Many previous studies reported predictive and prognostic values of CAT C262T polymorphism in cancers, with divergent results. This study aimed to summarize the overall relationships between CAT C262T polymorphism and cancer risk or survival. A total of 27 eligible publications were included in susceptibility analysis, while 8 publications contained survival outcomes. The results revealed significant relationship between CAT C262T polymorphism and cancer risk(TT + CT vs CC: OR = 1.05, 95%CI = 1.00–1.10, P = 0.036), subgroup analyses indicated the CAT C262T polymorphism was significantly correlated with an increased risk for prostate cancer (TT vs CC + CT: OR = 1.43, 95%CI = 1.20–1.70, P < 0.001) and increased risk among Caucasians (TT vs CC + CT: OR = 1.19, 95%CI = 1.09–1.31, P < 0.001), while no associations between the polymorphism and Asian or mixed population were established. In the survival analysis, no interactions were identified between this polymorphism and cancer survival (TT + CT vs CC: HR = 1.37, 95%CI = 0.70–2.70, P = 0.36). In conclusion, the CAT C262T polymorphismmay be a candidate markerfor cancer risk with type-specific and population-specific effects but not a fine prognostic factor for cancer survival.

The molecular mechanisms of carcinogenesis have not been wellunderstood, but growing studies have reported that oxidative stress played a significant role in the progression of many diseases, including cancers 1 . Oxidative stress could contribute to imbalance between the reactive oxygen species (ROS) and antioxidant defense system 2 . When present at high and/or sustained level, ROS may induce severe DNA damage and chromosomal aberrations [3][4][5] , which may be followed by abnormal expression of proto-oncogenes and tumor suppressor genes. However, antioxidant defense system could prevent or combat the negative effects caused by ROS, including myeloperoxidase (MPO), glutathione peroxidase (GPX), catalase (CAT), and mitochondrial manganese superoxide dismutase (MnSOD) [6][7][8] .
Catalase is an important endogenous antioxidant enzyme thatcatalyzes hydrogen peroxide into oxygen and water, thus neutralizing the deleterious effects of ROS 9 . The CAT gene, which is located on chromosome11p13, consists of 12 introns and 13 exons 10 . There are several single nucleotide polymorphisms (SNPs) identified in the CAT gene, of which the rs1001179 polymorphism (C262T) was the most extensively studied 11,12 . The CAT C262T polymorphism is encoded on the promoter region, influencing transcriptional and splicing regulation 13 . In comparison with the variant C allele, the variant T allele of the CAT C262T polymorphism has been reported to indicate lower enzyme activity, thus raising the levels of ROS and might lead to cancer development or progression 14 . Recently, a series of studies has demonstrated the associations between the CAT C262T polymorphism and risk for multiple cancers, such as breast cancer 15 , prostate cancer 16 , hepatocellular carcinoma 11 , chronic myeloid leukemia 17 , etc. So far, some studies have indicated the CAT C262T polymorphismcould increase prostate cancer risk 6,16,18 . However, the final results were not consistent or conclusive. In terms of survival, no studies confirmed whether the CAT C262T polymorphism could be a prognostic factor of cancer patients. Here, we conducted this updated meta-analysis to comprehensively estimate the relationships between the CAT C262T polymorphism and susceptibility or survival of cancers.
Publication bias and sensitivity analysis. We didn't detect any significant publication bias by Begg' test (Pr > |z| = 0.775 Fig. 3a) or Egger' test (P > |t| = 0.548 Fig. 3b), which indicated the reliability of our meta-analysis. Furthermore, no significant change was detected when we sequentially dropped out each included study and thus the results of our study were stable. Discussion ROS are naturally generated fromaerobic metabolism 3 . The human body develops a sophisticated set of antioxidant molecules to prevent the toxic accumulation of these species 43 . CAT belongs to the antioxidant molecules and is present in all aerobic cells while the highest levels of the enzyme are found in the liver, kidneyand erythrocytes 44 . CAT is a heme enzyme that plays a very important role in avoiding hydrogen peroxide concentration by converting H 2 O 2 into H 2 O and O 2 , and protects cells from detrimental effects of oxidative stress 45 . Allelic variants of CAT gene may contribute to lower CAT enzymatic activity and higher sensitivity to ROS, and alter ROS detoxification and increase oxidative stress, thereby implicating oxidative DNA damage and modulating disease risk 46 . 245 CAT SNPs have been identified, with most studies investigating the relationships between multiple diseases and rs1001179, a C > T substitution at position − 262 from the transcription start site 44 . Previous studies indicated thatCAT C262T gene polymorphism had an influence on transcription factors binding thus altering the basal transcription and consequent expression of this enzyme and hence influenced the oxidative status of cells and its microenvironment 25,26 . Consequently, this polymorphism was believed to play a key role in the pathogenesis of cancer 25,26 . The growing studies investigated the relation of CAT C262T gene polymorphism to breast cancer, lung cancer, diabetic neuropathy, non-Hodgkin lymphoma, liver cancer and colorectal cancer 43 , however, these results did not reach an agreement. A meta-analysis is a useful strategy because it potentially investigates a large number of individuals and could evaluate the effect of a genetic factor oncancer risk. We performed the current meta-analysis to combine the eligible studies and data to precisely estimate the role of CAT C262T polymorphism in the susceptibility and survival of cancers. The present meta-analysis, including 15531 cancer patients and 41816 controls from 35 case-control or cohort studies, investigated the association between the CAT C262T polymorphism and cancer risk. Based on current accessible evidences, the individuals who carry the TT homozygote have 17% increased risk of cancer compared with the C allele carriers, revealing that the CAT C262T gene polymorphism may be a risk factor for cancer 47 . For tumor origin could influence the results from meta analysis, we performed subgroup analyses by cancer type. However, we did not find any positive relationship in the studies of breast cancer, head and neck cancer, hematological malignancies, digestive system cancer or brain cancer. Interestingly, the significant association between the CAT C262T gene and prostate cancer 6,7,16,18,25,26 was the opposite in most genetic models. The relationships between the CAT C262T gene and skin cancer 31 or cervical cancer 12 were opposite in part genetic models. Meanwhile, in the stratified analysis by ethnicity, significantly elevated cancer risks were indicated in Caucasian group but not in Asian population. The underlying genetic backgrounds and/or environmental and social factors may account for the ethnic discrepancy.
It is worth mentioning that the current study was the first meta-analysis to investigate the survival outcomes. While the TT genotype was associated with increased cancer risk especially in prostate cancer and Caucasian population, however, neither of TT or CT genotype contributed to poorer survival of cancer patients. These results indicated that CAT C262T polymorphism might only influence susceptibility to cancer instead of cancer prognosis. In addition, the association between C262T polymorphism and treatment efficiency such as chemotherapy and radiotherapy remained unclear and those data were insufficient to reach a pooled result. Further studies could focus on the role of CAT C262T polymorphism on treatment strategy. The exact mechanisms of the C262T polymorphism on cancer development and progression were warranted to investigate in future.
In interpreting the current results, several limitations of the meta-analysis should be addressed. Only if literatures that were indexed by the selected databases were included for the current study, and some relevant published studies or unpublished studies with null results were missed or ongoing studies were not sought, which might have influenced our results. Secondly, the numbers of published studies were not large to identify possible associations, especially in survival analysis. Thirdly, part studies investigated several cases with the same control, which might reduce the statistical power to identify possible associations. Fourthly, lacking the original data of    the reviewed studies limited our further evaluation of the potential interaction. However, our current study also had some merits. On one hand, over 30 case-control or cohort studies from different publications significantly increased statistical power of the analyses. On the other hand, on the basis of our studies, we find a novel mechanism to predict cancer risk. In addition, the current study is the first to investigate the survival outcomes.
To sum up, the results from the current study suggest that the CAT C262T polymorphism may contribute to genetic susceptibility to cancer, supporting the hypothesis that the polymorphism serves as a potential susceptibility tumor marker. However the CAT C262T polymorphismmay not be a fine prognostic factor for cancer survival. Further well-designed, multicenter epidemiological studies including a wider spectrum of subjects should be performed to investigate the role of this functional polymorphism in other populations and biological mechanism of CAT C262T polymorphism, which should lead to better, comprehensive interpretation of the association between the CAT C262T polymorphism and cancer risk.

Identification and Eligibility of Relevant Studies. Two investigators performed a comprehensive and
systematic search through the databases of Pubmed, Embase and CNKI for relevant studies with the following terms: "catalase" or "CAT", "polymorphism" or "variant" or "mutation", and "cancer" or "carcinoma" or "malignancy" (Last search update December 2015). The publication language and publication date were not restricted in our search. Some potential publications were obtained from a manual search of the references of retrieved articles.
The inclusion criteria were: (1) case-control studies or cohort studies; (2) evaluating the associations between the CAT C262T polymorphism and cancer risk or survival outcomes; (3) detailed data on genotype frequency of the CAT C262T for calculating the odds ratios (ORs), available hazards ratios (HRs) and 95% confidence intervals (95%CIs). The exclusion criteria were: (1) reviews, conference abstracts, case reports, animal studies or editorials; (2)without available genotype frequency of the CAT C262T; (3) when the same or overlapped population and duplicated studies were met, only the most recent studies with sufficient information were included. Data extraction. Two investigators extracted data independently and consensus on all the items was reached after discussion. The main information included the first author, publication year, country, ethnicity, source of controls, sample, quality control, quality health, cancer type, number of cases and controls, genotype distributions of cases and controls, genotyping method, HWE of the control groups, and HR with 95%CI of this polymorphism in survival analysis. Statistical Analysis. All statistical analyses were conducted with STATA 12.0 (Stata Corp, College Station, TX, USA). The statistical heterogeneity among the studies was calculated by the I 2 statistics. If I 2 > 50%, the random-effects model was applied to analysis; otherwise, the fixed-effects model was adopted 48,49 . ORs with 95% CIs were used to stabilize risk estimates, while HRs with 95% CIs were required to predict whether the CAT C262T gene polymorphism had influence on OS of cancer patients. The following genetic models were used to evaluate the susceptibility: dominant model (TT + CT vs CC), recessive model (TT vs CT + CC), homozygote model (TT vs CC), heterozygote model (CT vs CC), and allelic contrast model (T vs C). We also performed the subgroup analyses based on cancer type and ethnicity. The significance of the pooled OR was assessed by Z test and the statistically significant outcome was defined as P < 0.05. HWE was evaluated by the chi-square test in control groups for each study, where P < 0.05 was considered significant 50 . Both Egger's and Begg's tests were used to evaluate the publication bias 51 . Sensitivity analysis, which aimed to identify whether the heterogeneity across these studies was from one individual study, was also performed to ensure the reliability of the results.