|Year : 2016 | Volume
| Issue : 2 | Page : 699-704
rs61764370 polymorphism of Kras and risk of cancer in Caucasian population: A meta-analysis
Shi-Yan Zhang, Jing Shi
Department of Clinical Laboratory, Affiliated Fuding Hospital, Fujian University of Traditional Medicine, Fuding, Fujian, China
|Date of Web Publication||25-Jul-2016|
Department of Clinical Laboratory, Fuding Hospital, Fujian University of Traditional Medicine, 120 South Road of Old City, Fuding
Source of Support: None, Conflict of Interest: None
Background: Kras is an important oncogene that plays a pivotal role in carcinogenesis. Rs61764370 polymorphism in Kras 3'-untranslated region is a candidate factor for contributing susceptibility to cancer. However, the results of emerging studies concerning association between rs61764370 and cancer risk remain elusive.
Materials and Methods: The association between rs61764370 and risk of cancer was evaluated in 30 studies including 14936. cases and 15168 controls.
Results: Meta-analysis result showed that genotype. GT/GG of rs61764370 was not associated with cancer in Caucasian population. After stratifying the overall population into cancer type subgroups, no significant association was observed between genotype. GT/GG and ovarian, breast, colorectal, non.-small cell lung cancer or head-neck carcinoma in Caucasian population, respectively.
Conclusion: These results indicated that genotype. GT/GG of rs61764370 was not a genetic susceptible risk factor for cancer, and rs61764370 could not be used as a biomarker for estimating cancer risk in Caucasian population.
Keywords: Cancer, Kras, Let-7, rs61764370
|How to cite this article:|
Zhang SY, Shi J. rs61764370 polymorphism of Kras and risk of cancer in Caucasian population: A meta-analysis. J Can Res Ther 2016;12:699-704
| > Introduction|| |
It is reported that cancer is one of the most important diseases affecting human health worldwide. Hundreds of thousands of people was diagnosed as new cancer patients and the death rate continues to increase, particular in developing cancer. According to survey of Chinese Cancer Registry Annual Report 2013, 3.09 million persons were newly diagnosed as cancer cases, cancer morbidity in women was significantly increased in 2012 and the growth rate was higher than it in developed country. Meanwhile, the 2012 American cancer report showed approximately 1.6 million new cancer cases and 0.58 million cancer deaths were projected to occur. Cancer is a multifactor disorder affected by environmental and genetic factor as well as interaction between them. One of the most important factors is maintained the balance between oncogenes and cancer suppressed genes in human. Genetic variation of these genes, such as mutation, single nucleotide polymorphism (SNP) and copy number variation (CNV) were verified to activate oncogenes or silence cancer suppressor, resulting in dysregulation of cancer-related genes and carcinogenesis.
Kras is an important oncogene that plays an essential role in carcinogenesis. It belongs to Ras gene family, and encodes a GDP/GTP-binding protein that is a member of small GTPase superfamily acting as an intracellular signal transducer in carcinogenesis. Recently, 10 microRNA Let-7 complementary binding sites (LCS) in 3'-untranslated region (3'-UTR) of Kras had been successfully identified, and LCS-SNP in Kras 3'-UTR had been demonstrated to be associated with cancer risk, prognosis as well as drug efficacy.,,
Rs61764370 is a variant of allele T alters to allele G which is located in LCS6 of Kras 3'-UTR. It can attenuate the binding capability of mature Let-7 to target Kras mRNA, leading to up-regulating activity of Kras. Moreover, a significant lower expression of Let-7 was found in tumor from patients harboring the G allele in comparison with T allele. These findings indicated that rs61764370 was associated with aberrant expression of Kras and level of Let-7. Hence, this locus might be associated with cancer and considered as a candidate-susceptible locus for cancer risk. Accumulating studies had reported the association between rs61764370 and risk of cancer,,, but these studies displayed contradictory conclusions. Kjersem et al. reported no significant association between genotype GT/GG of rs61764370 and colorectal cancer. However, study conducted by Chin et al. indicated that allele G of rs61764370 was significantly associated with increased risk for among moderate smokers.
In our study, we comprehensively searched eligible studies and conducted a meta-analysis to explore the precise relationship of rs61764370 and cancer risk.
| > Materials and Methods|| |
The following retrieval expressions, “rs61764370 and cancer”, “LCS6 and cancer” as well as “Kras polymorphism and cancer”, were used to search relevant studies in databases of PUBMED and CNKI with deadline of June of 2014 in English and Chinese language. In addition, manual retrieval was also used to obtain substantial relevant studies.
Two investigators (Shi-Yan Zhang and Jing Shi) were simultaneously identified title and abstract of each searched study to obtain relevant studies. Then, eligible study was carefully identified from relevant study by reading the full text. Relevant study was considered as an eligible study if it conformed to the following inclusion criteria: A. case-control designed study concerning rs61764370 and risk of cancer; B. study provided the sufficient data to calculate Odds ratio (OR) and 95% confidence interval (95% CI); C. genotype distribution in control group should be fitted for Hardy-Weinberg equilibrium (HWE); D. The quality assessment of study should be higher than 20 score; E. cases of study should be solid cancer patients and controls should be healthy individuals. Whereas, review, meta-analysis, letter, comment, communication, and single group-designed study, duplicative data published study or low quality score assessed study were excluded from our study.
Quality assessment was performed in each eligible study according to the STROBE quality score systems, which included 30 items. One item means one score, and score of 10, 20 and 30 are considered as low, moderate and high levels of quality, respectively.
The following baseline characteristics data were extracted from eligible study: The first author's name or abbreviation of study name, published year, country or region, race, case and control group, genotyping method, genotype data as well as OR and 95% CI. Two investigators independently assessed the quality score of eligible articles and extracted the data. Any assessment results with disagreement were dealt with by discussion.
Meta-analysis was performed using Stata software (Version 12.0, College Station, TX, USA). The overall effect was established by Z test and the significantly difference was considered when P value was lower than 0.05. The crude OR and 95% CI were used as common measurements for estimating the strength of the association between rs61764370 polymorphism and cancer risk. The heterogeneity test was assessed using Q test and estimated I 2 and P < 0.1 was set up to consider significant difference. The fixed model was used when the P value of Q test was more than 0.1, otherwise the random model was choose to estimate the finally results. Sensitivity analysis was performed to assess the stability of meta-analysis by omitting the eligible studies successively or changing the regression model. The Begg's funnel plot and Egger's test were used to evaluate the possible publication bias and P < 0.05 was considered as the existence of publication bias.,
| > Results|| |
In all, 395 articles were found from above the databases by retrieving. According to inclusion and exclusion criteria, 86 duplicated retrieval articles, 255 unrelated articles, 44 review, letter and comment were excluded from this study. As a result, 10 original articles, including 30 studies were recruited to estimate the association between rs61764370 and risk of cancer.,,,,,,,,, The detailed flow of search and screen was listed in [Figure 1]. The baseline characteristics of each including article are shown in [Table 1].
|Table 1: Characteristics of eligible studies concerning rs61764370 and cancer risk in the present meta-analysis|
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The comparison was done in 30 studies, including 14,936 cases and 15,168 controls. The results of the heterogeneity test and meta-analysis for overall and subgroups are summarized in [Table 2]. As shown in [Table 2], the result of Q test of rs61764370 was 0.033 in Caucasian population, thus the random model was choose to evaluate the overall effects. As a result, GT/GG genotype of rs61764370 was not associated with cancer in Caucasian population (OR = 1.05, 95% CI = 0.97-1.14) [Figure 2]. After stratification according to cancer type, the P values of Q test for rs61764370 polymorphism in ovarian cancer, breast cancer, colorectal cancer, non-small cell lung cancer and head-neck carcinoma subgroup were 0.008, 0.997, 0.501, 0.055 and 0.404, respectively. The fixed model was used for breast cancer, colorectal cancer and head-neck carcinoma subgroups, and the random model was applied for ovarian cancer and non-small cell lung cancer subgroups to evaluate the overall effects. However, GT/GG genotype was not observed to be associated with ovarian cancer (OR = 1.06, 95% CI = 0.95-1.19), breast cancer (OR = 0.99, 95% CI = 0.83-1.19), colorectal cancer (OR = 1.13, 95% CI = 0.84-1.54), non-small cell lung cancer (OR = 0.93, 95% CI = 0.60-1.43) or head-neck carcinoma (OR = 1.17, 95% CI = 0.50-1.52), respectively.
|Table 2: Results of meta-analysis of genotype GT/GG of rs61764370 and cancer risk|
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|Figure 2: Result of meta-analysis concerning genotype GT/GG of rs61764370 and cancer risk|
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Sensitivity analysis was conducted to evaluate the influence of eligible studies successively or changing the regression model on the pooled OR and overall effect. The results are showed in [Table 2]. When changing the regression model or omitting each article, the P values of overall effect and ORs in comparison of genotype GT/TT vs. GG were similar in overall population and each cancer subgroups, suggesting that the results were stable in these groups.
Publication bias was estimated using Begg's test and funnel plot as well as Egger's test. As shown in [Table 2] and [Figure 3], the shape of funnel plot was symmetrical and P values of Begg's test and Egger's were 0.972 and 0.86, respectively. These results indicated that no publication bias was found in comparison of genotype GT/GG vs. TT.
| > Discussion|| |
MicroRNA (miRNA) is a class of small non-coding RNA molecular with a total length of 20-24 nt, which exists broadly in physiological and pathophysiological processes to function mainly by post-translational repression by using a RNA interference pathway in human. Let-7 is the first characterized miRNA and it plays an important role both in maintaining cell proliferation and differentiation in embryonic stem cells and in carcinogenesis and cancer progression. Let-7 can bind to the mRNA 3'-UTR of target gene, contributing to altering the stability and expression of genes. Lots of gene had been predicted and verified as its targeted gene, including Kras.Kras contains Let-7 complementary binding sites in its mRNA 3'-UTR. Emerging evidences indicated that Let-7 could repress Kras expression which played a tumor suppressor role in carcinogenesis. Moreover, Let-7 was found to be down-regulated in lung cancer, breast cancer as well as hepatocellular carcinoma.,, In addition, rs61764370 which located in LCS6 of Kras could affect the binding capacity between Let-7 and Kras mRNA 3'-UTR, resulting in further altered expression of Kras and its downstream effectors and increasing risk of cancer. So we speculate that rs61764370 may associate with cancer.
In present study, a comprehensive meta-analysis was conducted to explore the possible association between rs61764370 and cancer risk. Our result showed that genotype GT/GG of rs61764370 was not associated with cancer in Caucasian population. After stratifying the overall population into cancer type subgroups, there was still no association between genotype GT/GG of rs61764370 and ovarian, breast, colorectal, non-small cell lung cancer as well as head-heck carcinoma, respectively. These findings revealed that genotype GT/GG of rs61764370 was neither a risk susceptible factor for cancer in Caucasian population, no increased predisposition to ovarian, breast, colorectal, non-small cell lung cancer as well as head-heck carcinoma, respectively. Our findings are consistent with results reported by Ying et al. On the basis of different genetic background, frequency of mirror allele G of rs61764370 in Chinese population is significantly lower than that in Caucasian population and genotype GG is low distributed in Caucasian population. No study was found to report the relationship between the locus and risk of cancer in Chinese. Moreover, included studies concerning rs61764370 and cancer risk in Caucasian population provided the data of genotype GG combining with GT without the detail frequency of genotype GG. Thus, only the association between genotype GT/GG of rs61764370 and cancer risk was performed in Caucasian population in our study. The present study did not observe a significant association between rs61764370 and cancer risk. The reason for this is unclear, maybe the mechanism of Let-7 binds to LCS6 in 3'-UTR of Kras plays a limited role in regulating Kras transcription and expression, for 10 LCSs were identified in its mRNA 3'-UTR. For example, variation of rs61764370 of Kras in colorectal cancer cell line did not showed concomitant change in the Kras expression or modulation of the downstream mitogen activated kinase or PI3K/AKT signaling. Other possible for our null observation may lie with compensational effect of miRNAs bind to other 9 LCSs of Kras 3'-UTR, in this way, other miRNAs could repress its transcription and expression, leading to low level of Kras.
The meta-analysis, to our knowledge, is the first time to comprehensively estimate the association between rs61764370 and risk of cancer in Caucasian population, and it is more reliable than previous single case-control study because it includes the largest of sample size. However, several limitations of this study should be addressed. We searched the eligible studies only in PUBMED and CNKI databases, which might miss some other relevant case-control articles, and might subsequently lead to selection bias. Although the sample size in our study was the largest by now, it was not large enough for a comprehensive meta-analysis in cancer subtype groups. No sufficient data was provided in each eligible study, and our findings were not based on adjusted OR to estimate.
In summary, this meta-analysis demonstrated rs61764370 is not a genetic susceptible locus for cancer risk in Caucasian population. Considering the limitations of this study, the further well-designed epidemiological studies are strongly recommended to validate the role of rs61764370 on cancer risk.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]