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Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 851-855

Promoter methylation of human mutL homolog 1 and colorectal cancer risk: A meta-analysis

1 Combine Traditional Chinese and Western Medicine of Oncology, Henan Tumor Hospital, Zhengzhou 450008, Henan, China
2 Department of Oncology, Henan Tumor Hospital, Zhengzhou 450008, Henan, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Qilong Gao
No. 127 Dongming Road, Zhengzhou 450008, Henan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.172587

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 > Abstract 

Aims: Several studies suggested that promoter methylation of human mutL homolog 1 (hMLH1) was associated with the risk of colorectal cancer (CRC). However, other studies did not indicate the same results. To derive a more comprehensive estimation of the association between hMLH1 methylation and CRC risk, we conducted a meta-analysis.
Materials and Methods: We searched in the PubMed, EMBASE, and WanFang Medicine databases. The strength of the associations was measured by odds ratios (ORs) with 95% confidence intervals (CIs).
Results: A total of 47 studies with 4296 cases and 2827 controls were included. A statistically significant association between hMLH1 methylation and CRC risk was found (OR = 9.25; 95% CI, 5.65–15.53; P < 0.001). The heterogeneity was significant (P < 0.001). In the subgroup analysis of race, Asian and Caucasian with hMLH1 methylation had increased CRC risk (OR = 12.19; 95% CI, 7.02–23.42; P < 0.001 and OR = 6.38; 95% CI, 2.17–19.64; P < 0.001). In the subgroup analysis of sample source, only the sample from tissue showed increased CRC risk (OR = 10.46; 95% CI, 6.12-17.90; P < 0.001). The Egger's test did not find publication bias (P = 0.176).
Conclusions: In conclusion, this meta-analysis suggested that hMLH1 methylation was associated with an increased CRC risk.

Keywords: Association, colorectal cancer, meta-analysis, methylation

How to cite this article:
Shi B, Chu J, Gao Q, Tian T. Promoter methylation of human mutL homolog 1 and colorectal cancer risk: A meta-analysis. J Can Res Ther 2018;14:851-5

How to cite this URL:
Shi B, Chu J, Gao Q, Tian T. Promoter methylation of human mutL homolog 1 and colorectal cancer risk: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2020 May 28];14:851-5. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/851/172587

 > Introduction Top

Colorectal cancer (CRC) is one of the most common cancers in the world, and it has high death ratio, which ranks as the fourth deadliest malignancy after lung, stomach, and liver cancer. Clinically, more than 1 million people were diagnosed as CRC every year, and the number of deaths grew rapidly from 490,000 in 1990 to 715,000 in 2012.[1] In the United States, the 5-year survival rate is 93.2% for stage I as opposed to only 8.1% for stage IV.[2] Therefore, early diagnosis is of vital importance for the treatment and prognosis of CRC patients.

Human mutL homolog 1 (hMLH1) is the most important member of mismatch repair (MMR) genes encoding a number of DNA repair enzymes and thus cooperating to recognize and repair DNA mismatches.[3] hMLH1 methylation has been found in ovarian, and CRC cell lines for resistance to cisplatin and restoration of MMR activity in these cells are sufficient to re-establish susceptibility to chemotherapy.[4] Several studies suggested that hMLH1 methylation was associated with the risk of CRC. However, other studies did not confirm the result.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51] Therefore, to derive a more comprehensive estimation of the association between hMLH1 methylation and CRC risk, we conducted a meta-analysis.

 > Materials and Methods Top

Selection of published studies

We searched in the PubMed, EMBASE, and WanFang Medicine databases for studies assessing the association between hMLH1 methylation and CRC risk. The literature strategy used the following keywords: (“Human mutL homolog 1,” “hMLH1”) and (“colorectal cancer” or “CRC”). The references of the retrieved articles were also hand searched at the same time to identify additional published articles. The references of eligible studies and relevant reviews were also checked for other literature not indexed into common databases. There was no language restriction applied in this meta-analysis. The inclusion criteria of eligible studies were as following: (1) Case-control or cohort study; (2) the cases were patients with CRC; (3) the controls were cancer-free individuals; (4) reported the frequencies of hMLH1 methylation in both cases and controls or the odds ratio (OR) and its 95% confidence interval (95% CI) of the association between hMLH1 methylation and CRC risk. Family-based studies and studies containing overlapping data were all excluded.

Data extraction

Relevant data were extracted from all the eligible studies independently by two reviewers, and disagreements were settled by discussion and the consensus among all reviewers. The main data extracted from the eligible studies were as following: The first author, year of publication, ethnicity, gender of the cases, sample source, and total numbers of cases and controls.

Statistical analysis

The strength of the associations between hMLH1 methylation and CRC risk was measured by ORs with 95% CIs. Between-study heterogeneity was assessed by Chi-square test, and was quantified using the I2 statistic (ranging from 0% to 100%), which was defined as the percentage of the observed between-study variability that is due to heterogeneity rather than chance. When the result of the Q-test and I2 statistics suggested heterogeneity (P ≤ 0.05 and I2 > 50%), a random-effects model (DerSimonian-Laird method) was used; otherwise, fixed-effects model (Mante-Haenszel method) was adopted. The Egger's test was used to assess publication bias statistically. All statistical tests were performed by using STATA 11.0 software (Stata Corporation, College Station, TX, USA). P < 0.05 was considered significant. All the P values were two-sided.

 > Results Top

Study characteristics

A total of 47 studies with 4296 cases and 2827 controls were included based on the search criteria. All these studies were conducted in Asians and Caucasians. One was performed in Africans. The samples were collected from tissue or blood. The main study characteristics are summarized in [Table 1].
Table 1: Characteristics of studies included in the meta-analysis

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Quantitative data synthesis

A statistically significant association between hMLH1 methylation and CRC risk was found (OR = 9.25; 95% CI, 5.65–15.53; P < 0.001). In the subgroup analysis of race, Asian and Caucasian with hMLH1 methylation had increased CRC risk (OR = 12.19; 95% CI, 7.02–23.42; P < 0.001 and OR = 6.38; 95% CI, 2.17–19.64; P < 0.001). In the subgroup analysis of sample source, only the sample from tissue showed increased CRC risk (OR = 10.46; 95% CI, 6.12–17.90; P < 0.001). All the results are shown in [Table 2]. The Egger's test did not find publication bias (P = 0.176).
Table 2: Meta-analysis results and subgroup analyses

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 > Discussion Top

Many articles have published results for hMLH1 methylation and CRC risk. However, the results were not same. To clarify the effect of hMLH1 methylation as a prognostic biomarker, the data from the studies providing independent assessments of hMLH1 methylation in CRC were systematically evaluated and synthesized. In this meta-analysis, we found a significant association between hMLH1 methylation and CRC risk. In addition, we found Asians and Caucasian with hMLH1 methylation had a higher risk of CRC.

DNA methylation has been extensively studied in CRC.[52] CRC can be divided into subsets according to DNA methylation patterns: CpG Island methylator phenotype positive (CIMP+) and CIMP- group.[53] CIMP+ cancers show distinct clinicopathologic features including female preponderance, older age, proximal colon location, mucinous, and poorly differentiated histology. Hu et al. elucidated the mutation spectrum and frequency of hMLH1 gene in sporadic CRC.[54] Wang et al. suggested that common variants in hMLH1 may serve as a predictor of CRC survival.[55]

Our study has some advantages. First, this is the most comprehensive meta-analysis which investigated the association between hMLH1 methylation and CRC risk. Second, heterogeneity and publication bias were investigated. However, we cannot find the main source of heterogeneity. This meta-analysis has some limitations. First, due to lacking of the original data of the eligible studies, we could not perform other subgroup analyses based on gender, and so on. Second, the numbers of published studies were not sufficient for a comprehensive analysis, particularly for Africans. Third, this study is a meta-analysis of case-control study and cohort study. Confounding should be considered.

 > Conclusion Top

This meta-analysis suggested that hMLH1 methylation was associated with an increased CRC risk, especially the sample from tissue. Further studies with a larger sample size are needed to further, assess the presence of an association.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Table 1], [Table 2]


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