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 Table of Contents  
ORIGINAL ARTICLE
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
China
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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 2019 Nov 19];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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-128.  Back to cited text no. 1
[PUBMED]    
2.
O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420-5.  Back to cited text no. 2
    
3.
Vageli D, Daniil Z, Dahabreh J, Karagianni E, Vamvakopoulou DN, Ioannou MG, et al. Phenotypic mismatch repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas. Lung Cancer 2009;64:282-8.  Back to cited text no. 3
[PUBMED]    
4.
Wang J, Yu L, Cai J, Jia J, Gao Y, Liang M, et al. The role of EZH2 and DNA methylation in hMLH1 silencing in epithelial ovarian cancer. Biochem Biophys Res Commun 2013;433:470-6.  Back to cited text no. 4
[PUBMED]    
5.
Morimoto T, Mitomi H, Saito T, Takahashi M, Murakami T, Sakamoto N, et al. Distinct profile of HIF1a, PTCH, EphB2, or DNA repair protein expression and BRAF mutation in colorectal serrated adenoma. J Gastroenterol Hepatol 2014;29:1192-9.  Back to cited text no. 5
[PUBMED]    
6.
Malhotra P, Anwar M, Kochhar R, Ahmad S, Vaiphei K, Mahmood S. Promoter methylation and immunohistochemical expression of hMLH1 and hMSH2 in sporadic colorectal cancer: A study from India. Tumour Biol 2014;35:3679-87.  Back to cited text no. 6
[PUBMED]    
7.
Kanth VV, Bhalsing S, Sasikala M, Rao GV, Pradeep R, Avanthi US, et al. Microsatellite instability and promoter hypermethylation in colorectal cancer in India. Tumour Biol 2014;35:4347-55.  Back to cited text no. 7
[PUBMED]    
8.
Coppedè F, Migheli F, Lopomo A, Failli A, Legitimo A, Consolini R, et al. Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: Correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism. Epigenetics 2014;9:621-33.  Back to cited text no. 8
    
9.
Vergouwe F, Boutall A, Stupart D, Algar U, Govender D, van der Linde GD, et al. Mismatch repair deficiency in colorectal cancer patients in a low-incidence area. S Afr J Surg 2013;51:16-21.  Back to cited text no. 9
[PUBMED]    
10.
Huang Q, Huang JF, Zhang B, Baum L, Fu WL. Methylation variable position profiles of hMLH1 promoter CpG Islands in human sporadic colorectal carcinoma. Diagn Mol Pathol 2012;21:24-33.  Back to cited text no. 10
[PUBMED]    
11.
Miladi-Abdennadher I, Abdelmaksoud-Damak R, Ayadi L, Khabir A, Frikha F, Kallel L, et al. Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma. Biosci Rep 2011;31:257-64.  Back to cited text no. 11
[PUBMED]    
12.
Maeda T, Suzuki K, Togashi K, Nokubi M, Saito M, Tsujinaka S, et al. Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner. Exp Ther Med 2011;2:695-700.  Back to cited text no. 12
[PUBMED]    
13.
Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, et al. Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence. Langenbecks Arch Surg 2011;396:1017-26.  Back to cited text no. 13
[PUBMED]    
14.
Kim JW, Park HM, Choi YK, Chong SY, Oh D, Kim NK. Polymorphisms in genes involved in folate metabolism and plasma DNA methylation in colorectal cancer patients. Oncol Rep 2011;25:167-72.  Back to cited text no. 14
[PUBMED]    
15.
Auclair J, Vaissière T, Desseigne F, Lasset C, Bonadona V, Giraud S, et al. Intensity-dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles. Genes Chromosomes Cancer 2011;50:178-85.  Back to cited text no. 15
    
16.
Aoyagi H, Iida S, Uetake H, Ishikawa T, Takagi Y, Kobayashi H, et al. Effect of classification based on combination of mutation and methylation in colorectal cancer prognosis. Oncol Rep 2011;25:789-94.  Back to cited text no. 16
[PUBMED]    
17.
Ahn JB, Chung WB, Maeda O, Shin SJ, Kim HS, Chung HC, et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 2011;117:1847-54.  Back to cited text no. 17
[PUBMED]    
18.
Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, et al. Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas. World J Gastroenterol 2010;16:3553-60.  Back to cited text no. 18
[PUBMED]    
19.
Mirchev MB, Kahl P, Friedrichs N, Kotzev IA, Buettner R. DNA methylation in patients with colorectal cancer – Correlation with some clinical and morphological features and with local tumour invasion. Folia Med (Plovdiv) 2010;52:22-30.  Back to cited text no. 19
[PUBMED]    
20.
Hiraki M, Kitajima Y, Nakafusa Y, Nakamura J, Hashiguchi K, Sumi K, et al. CpG Island methylation of BNIP3 predicts resistance against S-1/CPT-11 combined therapy in colorectal cancer patients. Oncol Rep 2010;23:191-7.  Back to cited text no. 20
[PUBMED]    
21.
Menigatti M, Truninger K, Gebbers JO, Marbet U, Marra G, Schär P. Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene 2009;28:899-909.  Back to cited text no. 21
    
22.
Kawaguchi M, Yanokura M, Banno K, Kobayashi Y, Kuwabara Y, Kobayashi M, et al. Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer. Int J Oncol 2009;34:1541-7.  Back to cited text no. 22
[PUBMED]    
23.
Ramírez N, Bandrés E, Navarro A, Pons A, Jansa S, Moreno I, et al. Epigenetic events in normal colonic mucosa surrounding colorectal cancer lesions. Eur J Cancer 2008;44:2689-95.  Back to cited text no. 23
    
24.
Nagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, et al. Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 2008;134:1950-60, 1960.e1.  Back to cited text no. 24
    
25.
Mokarram P, Naghibalhossaini F, Saberi Firoozi M, Hosseini SV, Izadpanah A, Salahi H, et al. Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate/Vitamin B12 status. World J Gastroenterol 2008;14:3662-71.  Back to cited text no. 25
[PUBMED]    
26.
Kim HC, Lee HJ, Roh SA, Kim JS, Yu CS, Kim JC. CpG Island methylation in familial colorectal cancer patients not fulfilling the Amsterdam criteria. J Korean Med Sci 2008;23:270-7.  Back to cited text no. 26
[PUBMED]    
27.
Kakar S, Deng G, Cun L, Sahai V, Kim YS. CpG Island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component. Hum Pathol 2008;39:30-6.  Back to cited text no. 27
[PUBMED]    
28.
Ide T, Kitajima Y, Ohtaka K, Mitsuno M, Nakafusa Y, Miyazaki K. Expression of the hMLH1 gene is a possible predictor for the clinical response to 5-fluorouracil after a surgical resection in colorectal cancer. Oncol Rep 2008;19:1571-6.  Back to cited text no. 28
[PUBMED]    
29.
Fujiwara I, Yashiro M, Kubo N, Maeda K, Hirakawa K. Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway. Dis Colon Rectum 2008;51:1387-94.  Back to cited text no. 29
[PUBMED]    
30.
Brim H, Mokarram P, Naghibalhossaini F, Saberi-Firoozi M, Al-Mandhari M, Al-Mawaly K, et al. Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study. Mol Cancer 2008;7:68.  Back to cited text no. 30
[PUBMED]    
31.
Noda H, Mashima R, Kamiyama H, Okada S, Kawamura YJ, Konishi F. Promoter hypermethylation of tumor-related genes in sporadic colorectal cancer in young patients. J Exp Clin Cancer Res 2007;26:521-6.  Back to cited text no. 31
[PUBMED]    
32.
Leung WK, To KF, Man EP, Chan MW, Hui AJ, Ng SS, et al. Detection of hypermethylated DNA or cyclooxygenase-2 messenger RNA in fecal samples of patients with colorectal cancer or polyps. Am J Gastroenterol 2007;102:1070-6.  Back to cited text no. 32
[PUBMED]    
33.
Greenspan EJ, Cyr JL, Pleau DC, Levine J, Rajan TV, Rosenberg DW, et al. Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer. Carcinogenesis 2007;28:769-76.  Back to cited text no. 33
[PUBMED]    
34.
Zhang D, Bai Y, Ge Q, Qiao Y, Wang Y, Chen Z, et al. Microarray-based molecular margin methylation pattern analysis in colorectal carcinoma. Anal Biochem 2006;355:117-24.  Back to cited text no. 34
[PUBMED]    
35.
Ye C, Shrubsole MJ, Cai Q, Ness R, Grady WM, Smalley W, et al. Promoter methylation status of the MGMT, hMLH1, and CDKN2A/p16 genes in non-neoplastic mucosa of patients with and without colorectal adenomas. Oncol Rep 2006;16:429-35.  Back to cited text no. 35
[PUBMED]    
36.
Wallner M, Herbst A, Behrens A, Crispin A, Stieber P, Göke B, et al. Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Clin Cancer Res 2006;12:7347-52.  Back to cited text no. 36
    
37.
O'Brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E, et al. Comparison of microsatellite instability, CpG Island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 2006;30:1491-501.  Back to cited text no. 37
    
38.
Fox EJ, Leahy DT, Geraghty R, Mulcahy HE, Fennelly D, Hyland JM, et al. Mutually exclusive promoter hypermethylation patterns of hMLH1 and O6-methylguanine DNA methyltransferase in colorectal cancer. J Mol Diagn 2006;8:68-75.  Back to cited text no. 38
[PUBMED]    
39.
Derks S, Postma C, Moerkerk PT, van den Bosch SM, Carvalho B, Hermsen MA, et al. Promoter methylation precedes chromosomal alterations in colorectal cancer development. Cell Oncol 2006;28:247-57.  Back to cited text no. 39
[PUBMED]    
40.
Leung WK, To KF, Man EP, Chan MW, Bai AH, Hui AJ, et al. Quantitative detection of promoter hypermethylation in multiple genes in the serum of patients with colorectal cancer. Am J Gastroenterol 2005;100:2274-9.  Back to cited text no. 40
[PUBMED]    
41.
Ashktorab H, Smoot DT, Farzanmehr H, Fidelia-Lambert M, Momen B, Hylind L, et al. Clinicopathological features and microsatellite instability (MSI) in colorectal cancers from African Americans. Int J Cancer 2005;116:914-9.  Back to cited text no. 41
[PUBMED]    
42.
Anacleto C, Rossi B, Lopes A, Soares FA, Rocha JC, Caballero O, et al. Development and application of a multiplex PCR procedure for the detection of DNA methylation in colorectal cancer. Oncol Rep 2005;13:325-8.  Back to cited text no. 42
[PUBMED]    
43.
Anacleto C, Leopoldino AM, Rossi B, Soares FA, Lopes A, Rocha JC, et al. Colorectal cancer “methylator phenotype”: Fact or artifact? Neoplasia 2005;7:331-5.  Back to cited text no. 43
[PUBMED]    
44.
Xu XL, Yu J, Zhang HY, Sun MH, Gu J, Du X, et al. Methylation profile of the promoter CpG Islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol 2004;10:3441-54.  Back to cited text no. 44
[PUBMED]    
45.
Lee S, Hwang KS, Lee HJ, Kim JS, Kang GH. Aberrant CpG Island hypermethylation of multiple genes in colorectal neoplasia. Lab Invest 2004;84:884-93.  Back to cited text no. 45
[PUBMED]    
46.
Kim JC, Lee KH, Ka IH, Koo KH, Roh SA, Kim HC, et al. Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria. Clin Cancer Res 2004;10 (18 Pt 1):6159-68.  Back to cited text no. 46
    
47.
Arnold CN, Goel A, Compton C, Marcus V, Niedzwiecki D, Dowell JM, et al. Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer. Cancer Biol Ther 2004;3:73-8.  Back to cited text no. 47
[PUBMED]    
48.
Strazzullo M, Cossu A, Baldinu P, Colombino M, Satta MP, Tanda F, et al. High-resolution methylation analysis of the hMLH1 promoter in sporadic endometrial and colorectal carcinomas. Cancer 2003;98:1540-6.  Back to cited text no. 48
[PUBMED]    
49.
Roh SA, Kim HC, Kim JS, Kim JC. Characterization of mutator pathway in younger-age-onset colorectal adenocarcinomas. J Korean Med Sci 2003;18:387-91.  Back to cited text no. 49
[PUBMED]    
50.
Ricciardiello L, Goel A, Mantovani V, Fiorini T, Fossi S, Chang DK, et al. Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer. Cancer Res 2003;63:787-92.  Back to cited text no. 50
[PUBMED]    
51.
Kámory E, Kolacsek O, Ottó S, Csuka O. hMLH1 and hMSH2 somatic inactivation mechanisms in sporadic colorectal cancer patients. Pathol Oncol Res 2003;9:236-41.  Back to cited text no. 51
    
52.
Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG Island links ageing and neoplasia in human colon. Nat Genet 1994;7:536-40.  Back to cited text no. 52
[PUBMED]    
53.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG Island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 1999;96:8681-6.  Back to cited text no. 53
[PUBMED]    
54.
Hu F, Li D, Wang Y, Yao X, Zhang W, Liang J, et al. Novel DNA variants and mutation frequencies of hMLH1 and hMSH2 genes in colorectal cancer in the Northeast China population. PLoS One 2013;8:e60233.  Back to cited text no. 54
[PUBMED]    
55.
Wang Y, Li G, Hu F, Bi H, Wu Z, Zhao X, et al. The prognostic significance of polymorphisms in hMLH1/hMSH2 for colorectal cancer. Med Oncol 2014;31:975.  Back to cited text no. 55
[PUBMED]    



 
 
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