Journal of Cancer Research and Clinical Oncology

, Volume 141, Issue 12, pp 2147–2158 | Cite as

Association between MutL homolog 1 polymorphisms and the risk of colorectal cancer: a meta-analysis

  • Haiyan Chen
  • Zhujing Shen
  • Yeting Hu
  • Qian Xiao
  • Dikai Bei
  • Xiangfeng Shen
  • Kefeng Ding
Original Article – Cancer Research

Abstract

Purpose

As one of the most essential components of mismatch repair system, MutL homolog 1 (MLH1) plays an increasingly implicated role in initiation and promotion of colorectal carcinogenesis, with germ-line mutations in different loci. However, whether a single genetic variant in MLH1 could predict the risk of cancer was still under doubt and recent studies yielded inconsistent results. Therefore, this meta-analysis aimed at investigating the association between MLH1 single-nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) risks.

Methods

A systematic literature search of PubMed, MEDLINE, Web of Science and BIOSIS databases was performed to obtain all available SNPs and studies. We focused on three SNPs (rs1800734, rs1799977 and rs63750448) with the most included studies and conducted overall and subgroup analyses after data extraction.

Results

A total of 37,347, 29,114 and 2722 patients in case and control groups were meta-analyzed in four genetic models (AA vs. BB, AB vs. BB, AA+AB vs. BB and AA vs. BB+AB) for each SNP. The overall results suggested that the mutation in rs63750447 predicted a higher CRC risk (AB vs. BB: OR 2.283, 95 % CI 1.612–3.232, P = 0.000; AA+AB vs. BB: OR 2.291, 95 % CI 1.618–3.244, P = 0.000), while rs1800734 and rs1799977 were not associated with CRC risks. Subgroup analysis according to study area, quality score and genotyping technique revealed the similar results.

Conclusions

As the first meta-analysis reporting the association between rs63750448 and CRC risk, the A allele substitution might be a risk factor for CRC. Additionally, there was no persuasive evidence showing that SNPs of rs1800734 and rs1799977 were related to CRC susceptibility.

Keywords

MLH1 Polymorphism Colorectal cancer Meta-analysis 

Notes

Acknowledgments

This work was partly supported by grants from National Natural Science Foundation of China (Nos. 81272455, 81472664) and Zhejiang Provincial Natural Science Foundation of China (No. R2100071).

Conflict of interest

None.

Supplementary material

432_2015_1976_MOESM1_ESM.tif (4.6 mb)
FigS1ORs for the relation of MLH1 rs1800734 polymorphism and CRC risk with four genetic models (A, B, C and D). No statistical difference was observed (TIFF 4685 kb)
432_2015_1976_MOESM2_ESM.tif (5.7 mb)
FigS2ORs for the relation of MLH1 rs1799977 polymorphism and CRC risk with four genetic models (A, B, C and D). No statistical difference was observed (TIFF 5831 kb)
432_2015_1976_MOESM3_ESM.tif (14.4 mb)
FigS3Begg’s funnel plot for MLH1 rs1800734 polymorphism and CRC risk with four genetic models (A, B, C and D) (TIFF 14789 kb)
432_2015_1976_MOESM4_ESM.tif (10.2 mb)
FigS4Begg’s funnel plot for MLH1 rs1799977 polymorphism and CRC risk with four genetic models (A, B, C and D) (TIFF 10466 kb)
432_2015_1976_MOESM5_ESM.tif (5 mb)
FigS5Begg’s funnel plot for MLH1 63750447 polymorphism and CRC risk with AB VS BB and AA+AB VS BB genetic models (A and B, respectively). They suggested low risk of publication bias (TIFF 5160 kb)
432_2015_1976_MOESM6_ESM.docx (102 kb)
Supplementary material 6 (DOCX 103 kb)

References

  1. Abuli A, Bujanda L, Munoz J et al (2014) The MLH1 c.1852_1853delinsGC (p. K618A) variant in colorectal cancer: genetic association study in 18,723 individuals. PLoS One 9(4):e95022PubMedCentralCrossRefPubMedGoogle Scholar
  2. Allan JM, Shorto J, Adlard J et al (2008) MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer. Int J Cancer 123(10):2456–2459CrossRefPubMedGoogle Scholar
  3. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 1088–1101Google Scholar
  4. Berndt SI, Platz EA, Fallin MD et al (2007) Mismatch repair polymorphisms and the risk of colorectal cancer. Int J Cancer 120(7):1548–1554CrossRefPubMedGoogle Scholar
  5. Campbell PT, Curtin K, Ulrich CM et al (2009) Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Gut 58(5):661–667PubMedCentralCrossRefPubMedGoogle Scholar
  6. Cannavo E, Gerrits B, Marra G et al (2007) Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J Biol Chem 282(5):2976–2986CrossRefPubMedGoogle Scholar
  7. Cejka P, Stojic L, Mojas N et al (2003) Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J 22(9):2245–2254PubMedCentralCrossRefPubMedGoogle Scholar
  8. Chao EC, Lipkin SM (2006) Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res 34(3):840–852PubMedCentralCrossRefPubMedGoogle Scholar
  9. Chen H, Taylor NP, Sotamaa KM et al (2007) Evidence for heritable predisposition to epigenetic silencing of MLH1. Int J Cancer 120(8):1684–1688CrossRefPubMedGoogle Scholar
  10. Christensen LL, Madsen BE, Wikman FP et al (2008) The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population. BMC Med Genet 9:52PubMedCentralCrossRefPubMedGoogle Scholar
  11. Cunningham JM, Christensen ER, Tester DJ et al (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58(15):3455–3460PubMedGoogle Scholar
  12. De Graeff P, Crijns A, de Jong S et al (2009) Modest effect of p53, EGFR and HER-2/neu on prognosis in epithelial ovarian cancer: a meta-analysis. Br J Cancer 101(1):149–159PubMedCentralCrossRefPubMedGoogle Scholar
  13. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefPubMedGoogle Scholar
  14. Egger M, Smith GD, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634PubMedCentralCrossRefPubMedGoogle Scholar
  15. Ehsani L, Osunkoya AO (2004) Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis. Tumour Biol 35:8743CrossRefGoogle Scholar
  16. Gao L-B, Pan X-M, Li L-J et al (2011) RAD51 135G/C polymorphism and breast cancer risk: a meta-analysis from 21 studies. Breast Cancer Res Treat 125(3):827–835CrossRefPubMedGoogle Scholar
  17. Hinrichsen I, Ernst BP, Nuber F et al (2014) Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1. Mol Cancer 13:11PubMedCentralCrossRefPubMedGoogle Scholar
  18. Ioannidis JP, Patsopoulos NA, Evangelou E (2007) Uncertainty in heterogeneity estimates in meta-analyses. BMJ 335(7626):914PubMedCentralCrossRefPubMedGoogle Scholar
  19. Ito E, Yanagisawa Y, Iwahashi Y et al (1999) A core promoter and a frequent single-nucleotide polymorphism of the mismatch repair gene hMLH1. Biochem Biophys Res Commun 256(3):488–494CrossRefPubMedGoogle Scholar
  20. Kanao R, Hanaoka F, Masutani C (2009) A novel interaction between human DNA polymerase eta and MutLalpha. Biochem Biophys Res Commun 389(1):40–45CrossRefPubMedGoogle Scholar
  21. Kim JC, Roh SA, Koo KH et al (2004) Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer 3(2):129–137CrossRefPubMedGoogle Scholar
  22. Koessler T, Oestergaard MZ, Song H et al (2008) Common variants in mismatch repair genes and risk of colorectal cancer. Gut 57(8):1097–1101CrossRefPubMedGoogle Scholar
  23. Kunkel TA, Erie DA (2005) DNA mismatch repair*. Annu Rev Biochem 74:681–710CrossRefPubMedGoogle Scholar
  24. Loeb LA, Loeb KR, Anderson JP (2003) Multiple mutations and cancer. Proc Natl Acad Sci 100(3):776–781PubMedCentralCrossRefPubMedGoogle Scholar
  25. Mac Partlin M, Homer E, Robinson H et al (2003) Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX. Oncogene 22(6):819–825CrossRefPubMedGoogle Scholar
  26. McDaid J, Loughery J, Dunne P et al (2009) MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea. Br J Cancer 101(3):441–451PubMedCentralCrossRefPubMedGoogle Scholar
  27. Mei Q, Yan HL, Ding FX et al (2006) Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients. Cancer Genet Cytogenet 171(1):17–23CrossRefPubMedGoogle Scholar
  28. Muniz-Mendoza R, Ayala-Madrigal ML, Partida-Perez M et al (2012) MLH1 and XRCC1 polymorphisms in Mexican patients with colorectal cancer. Genet Mol Res 11(3):2315–2320CrossRefPubMedGoogle Scholar
  29. Niv Y (2007) Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer. World J Gastroenterol 13(12):1767PubMedCentralCrossRefPubMedGoogle Scholar
  30. Ohsawa T, Sahara T, Muramatsu S et al (2009) Colorectal cancer susceptibility associated with the hMLH1 V384D variant. Mol Med Rep 2(6):887–891PubMedGoogle Scholar
  31. Pan XM, Yang WZ, Xu GH et al (2011) The association between MLH1 -93 G>A polymorphism of DNA mismatch repair and cancer susceptibility: a meta-analysis. Mutagenesis 26(5):667–673CrossRefPubMedGoogle Scholar
  32. Papadopoulos N, Nicolaides NC, Wei Y-F et al (1994) Mutation of a mutL homolog in hereditary colon cancer. Science 263(5153):1625–1629CrossRefPubMedGoogle Scholar
  33. Picelli S, Zajac P, Zhou XL et al (2010) Common variants in human CRC genes as low-risk alleles. Eur J Cancer 46(6):1041–1048CrossRefPubMedGoogle Scholar
  34. Picelli S, Lorenzo Bermejo J, Chang-Claude J et al (2013) Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility. PLoS One 8(9):e72091PubMedCentralCrossRefPubMedGoogle Scholar
  35. Raptis S, Mrkonjic M, Green RC et al (2007) MLH1 -93G > A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst 99(6):463–474CrossRefPubMedGoogle Scholar
  36. Rasmussen LJ, Heinen CD, Royer-Pokora B et al (2012) Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present, and future. Hum Mutat 33(12):1617–1625CrossRefPubMedGoogle Scholar
  37. Samowitz WS, Curtin K, Wolff RK et al (2008) The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. Genes Chromosomes Cancer 47(10):835–844PubMedCentralCrossRefPubMedGoogle Scholar
  38. Shastry BS (2002) SNP alleles in human disease and evolution. J Hum Genet 47(11):561–566CrossRefPubMedGoogle Scholar
  39. Shin KH, Shin JH, Kim JH et al (2002) Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. Cancer Res 62(1):38–42PubMedGoogle Scholar
  40. Siehler SY, Schrauder M, Gerischer U et al (2009) Human MutL-complexes monitor homologous recombination independently of mismatch repair. DNA Repair 8(2):242–252PubMedCentralCrossRefPubMedGoogle Scholar
  41. Tempfer CB, Hefler LA, Schneeberger C et al (2006) How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer? Gynecol Endocrinol 22(3):155–159CrossRefPubMedGoogle Scholar
  42. Thakkinstian A, McEvoy M, Minelli C et al (2005) Systematic review and meta-analysis of the association between β2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 162(3):201–211CrossRefPubMedGoogle Scholar
  43. Tulupova E, Kumar R, Hanova M et al (2005) Do polymorphisms and haplotypes of mismatch repair genes modulate risk of sporadic colorectal cancer? Mutat Res 648(1–2):40–45Google Scholar
  44. van Roon EH, van Puijenbroek M, Middeldorp A et al (2010a) Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition? BMC Cancer 10(1):180PubMedCentralCrossRefPubMedGoogle Scholar
  45. van Roon EH, van Puijenbroek M, Middeldorp A et al (2010b) Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition? BMC Cancer 10:180PubMedCentralCrossRefPubMedGoogle Scholar
  46. Wang Y, Friedl W, Propping P et al (1998) Val384Asp in hMLH1 gene in Chinese, Japanese and German and its etiological role in colorectal cancer. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 15(5):263–266PubMedGoogle Scholar
  47. Wang Y, Zhou J, Li Z et al (2000) One of the etiological factors of digestive tract cancers in Chinese: the missense mutation Val384Asp in the hMLH1 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 17(2):82–86PubMedGoogle Scholar
  48. Wang D, Song L, Zhang X et al (2010) Etiological role of Val384Asp in hMLH1 gene in familial colorectal cancer. Acta Univ Med Nanjing 1:1–6Google Scholar
  49. Wang T, Liu Y, Sima L et al (2012) Association between MLH1 -93G>a polymorphism and risk of colorectal cancer. PLoS One 7(11):e50449PubMedCentralCrossRefPubMedGoogle Scholar
  50. Whiffin N, Broderick P, Lubbe SJ et al (2011) MLH1-93G>A is a risk factor for MSI colorectal cancer. Carcinogenesis 32(8):1157–1161CrossRefPubMedGoogle Scholar
  51. Zhang XM, Li JT, Zhu M et al (2004) Study on the relationship between genetic polymorphism Val384Asp in hMLH1 gene and the risk of four different carcinomas. Zhonghua Liu Xing Bing Xue Za Zhi 25(11):978–981PubMedGoogle Scholar
  52. Zhang L, Cao J, Shen W et al (2011) Correlation between hMLH1-93G/A Gene Polymorphism and Colorectal Cancer. Chin J Gastroenterol 16(4):214–217Google Scholar
  53. Zhao N, Zhu F, Yuan F et al (2008) The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations. Biochem Biophys Res Commun 370(2):338–343PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Haiyan Chen
    • 1
    • 2
  • Zhujing Shen
    • 3
  • Yeting Hu
    • 1
    • 2
  • Qian Xiao
    • 1
    • 2
  • Dikai Bei
    • 1
    • 2
  • Xiangfeng Shen
    • 1
    • 2
  • Kefeng Ding
    • 1
    • 2
  1. 1.The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang ProvinceCancer InstituteHangzhouChina
  2. 2.Department of OncologyThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
  3. 3.Department of RadiologyThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina

Personalised recommendations