Chonnam Med J.  2008 Apr;44(1):23-30. 10.4068/cmj.2008.44.1.23.

Association Study of hMLH1 Polymorphisms with Riskof Acute Myeloid Leukemia in Korean

• Piao CZ
• Mei JX
• Kim HJ
• Juhng SW
• Choi C

• KMID: 1973387
• DOI: http://doi.org/10.4068/cmj.2008.44.1.23

Abstract

Acute myelogenous leukemia (AML) is caused by dysregulation of oncogenes, tumor suppressor genes, and DNA mismatch repair genes. Accumulating evidence has shown that genetic differences in mismatch repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. In AML and lymphoma, the promoter of hMLH1 is frequently hypermethylated. The purpose of this study is to investigate the association of hMLH1 gene polymorphisms with the susceptability to AML in Korean people. Allelic frequency of rs9311149, rs1800734, rs3774343, rs4647215, rs3774341, rs3774335, rs748766, D376D, V384D SNPs of hMLH1 was determined in 32 normal subjects by sequencing analysis. Haplotype frequency and linkage disequilibrium coefficiency of nine SNPs were estimated. The author selected and genotyped six SNPS for full-scale association study, they include one tagging SNP from neighboring six SNPs and five SNPs including two novel SNPs. One hundred and sixty eight AML cases and 255 unrelated healthy controls were used for the study. V384D was associated with increased risk of AML both in genotypes (OR=2.335; 95% CI: 1.056~5.165, p=0.032) and in allele frequency (OR=2.417; 95% CI: 1.118~5.228, p=0.021). Other SNPs except V384D were not associated with AML. The allele frequency of the SNPs between Asians, European descendants, and Africans was very significantly different (p<0.01), respectively. Among Asians, that of Koreans and Japanese was similar (p>0.05), while that between Korean and Chinese, and that between Japanese and Chinese were significantly different (p< 0.05). The data suggests that V384D polymorphism of hMLH1 might be associated with AML.

Keyword

Polymorphisms Genetic; SNP protein; Leukemias

MeSH Terms

Asian Continental Ancestry Group
DNA Mismatch Repair
Gene Frequency
Genes, Tumor Suppressor
Genotype
Haplotypes
Humans
Leukemia
Leukemia, Myeloid, Acute
Linkage Disequilibrium
Lymphoma
Oncogenes
Polymorphism, Genetic
Polymorphism, Single Nucleotide

Figure

• 

  Fig. 1 (A) Partial sequence of the hMLH1 exon10 around rs4986984. Genomic DNA from normal individual was sequenced. The arrow indicates the C/T heterozygosity of rs4986984 at position +18524 from the start of the translation site. (B) Partial sequence of the hMLH1 exon14 around CNUH-GRCHD03-209. Genomic DNA from normal individual was sequenced. The arrow indicates the A/G heterozygosity of CNUH-GRCHD03-209 at position +32178 from the start of the translation site.

Reference

1. Bond GL, Hu W, Levine A. A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res. 2005. 65:5481–5484.

2. Kim KH, Yeom KS, Choi C. Search for the cSNP frequencies of N-acetyltransferase 2 and NAD(P)H dehydrogenase, quinone 1 in DNA pool of Korean people. Chonnam Med J. 2002. 38:202–209.

3. Gu Z, Hillier L, Kwok PY. Single nucleotide polymorphism hunting in cyberspace. Hum Mutat. 1998. 12:221–225.

4. Shastry BS. SNP alleles in human disease and evolution. J Hum Genet. 2002. 47:561–566.

5. Stephens JC. Single-nucleotide polymorphisms, haplotypes, and their relevance to pharmacogenetics. Mol Diagn. 1999. 4:309–317.

6. Gilliland DG. Molecular genetics of human leukemia. Leukemia. 1998. 12:1. S7–12.

7. Ronen A, Glickman BW. Human DNA repair genes. Environ Mol Mutagen. 2001. 37:241–283.

8. Rotman G, Shiloh Y. ATM: from gene to function. Hum Mol Genet. 1998. 7:1555–1563.

9. Yu Z, Chen J, Ford BN, Brackley ME, Glickman BW. Human DNA repair systems: an overview. Environ Mol Mutagenesis. 1999. 33:3–20.

10. Ma X, Jin Q, Försti A, Hemminki K, Kumar R. Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes. Int J Cancer. 2000. 88:938–942.

11. Fink D, Aebi S, Howell SB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res. 1998. 4:1–6.

12. Thomas DC, Umar A, Kunkel TA. Microsatellite instability and mismatch repair defects in cancer. Mutat Res. 1996. 350:201–205.

13. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993. 260:816–819.

14. Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994. 368:258–261.

15. Annese V, Piepoli A, Andriulli A, Latiano A, Napolitano G, Li HH, et al. Association of Crohn's disease and ulcerative colitis with haplotypes of the MLH1 gene in Italian inflammatory bowel disease patients. J Med Genet. 2002. 39:332–334.

16. Pokorny RM, Hofmeister A, Galandiuk S, Dietz AB, Cohen ND, Neibergs HL. Crohn's disease and ulcerative colitis are associated with the DNA repair gene MLH1. Ann Surg. 1997. 225:718–723. discussion 723-5.

17. Lenz G, Hutter G, Hiddemann W, Dreyling M. Promoter methylation and expression of DNA repair genes hMLH1 and MGMT in acute myeloid leukemia. Ann Hematol. 2004. 83:628–633.

18. Seedhouse CH, Das-Gupta EP, Russell NH. Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia. 2003. 17:83–88.

19. Wang Y, Friedl W, Propping P, Li J, Li Z, Wang J. Val384Asp in hMLH1 gene in Chinese, Japanese and German and its etiological role in colorectal cancer. Zhonghua yi xue yi chuan xue za zhi. 1998. 15:263–266.

20. Wang Y, Zhou J, Li Z, Wang J, Li J, Gao C, et al. 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. 2000. 17:82–86.

21. Zhang XM, Li JT, Zhu M, Wu XL, Gao P, Zhou P, et al. 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. 2004. 25:978–981.

22. Kim JC, Roh SA, Koo KH, Ka IH, Kim HC, Yu CS, et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004. 3:129–137.

23. Wang Y, Friedl W, Lamberti C, Nothen MM, Kruse R, Propping P. A novel missense mutation in the DNA mismatch repair gene hMLH1 present among East Asians but not among Europeans. Hum Hered. 1998. 48:87–91.

24. Kondo E, Suzuki H, Horii A, Fukushige S. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003. 63:3302–3308.

25. Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, et al. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology. 2002. 122:211–219.

26. Modrich P. DNA mismatch correction. Ann Rev Biochem. 1987. 56:435–466.

27. Okuda T, Fujioka Y, Kamide K, Kawano Y, Goto Y, Yoshimasa Y, et al. Verification of 525 coding SNPs in 179 hypertension candidate genes in the Japanese population: identification of 159 SNPs in 93 genes. J Hum Genet. 2002. 47:387–394.

28. Lee JK, Kim HT, Cho SM, Kim KH, Jin HJ, Ryu GM, et al. Characterization of 458 single nucleotide polymorphisms of disease candidate genes in the Korean population. J Hum Genet. 2003. 48:213–216.