Advertisement

Pathology & Oncology Research

, Volume 9, Issue 4, pp 236–241 | Cite as

hMLHl and hMSH2 somatic inactivation mechanisms in sporadic colorectal cancer patients

  • Enikó Kámory
  • Orsolya Kolacsek
  • Szabolcs Ottó
  • Orsolya Csuka
Article

Abstract

Much is known about the role of germline inactivation in mismatch repair (MMR) genes in hereditary non-polyposis colorectal cancer (HNPCC), but the impact of somatic MMR gene changes on sporadic colorectal cancer remains to be elucidated. In hereditary cases the hMLHl and hMSH2 genes were shown to have a great importance, and in order to examine the somatic inactivation mechanisms of the two MMR genes hMLHl and hMSH2 we screened 37 Hungarian sporadic colorectal cancer patients for allelic imbalance (AI), microsatellite instability (MSI), hMLHl promoter hypermethylation and somatic mutations. Thirteen of the examined tumours (35%) were characterized by low-level MSI and none of the cases belonged to the high MSI group. Nine (24%) and seven (19%) cases had AI at the hMLHl and hMSH2 genes, respectively. Seven tumours (19%) showed dense promoter hypermethylation of hMLHl, but only two patients had somatic mutations, one for each MMR gene. According to our study on this limited set of cases the most prominent mismatch repair inactivation mechanism in sporadic colorectal cancer patients is the hMLHl promoter hypermethylation which may have a role in the carcinogenesis of sporadic colorectal cancer.

Keywords

sporadic colorectal cancer mismatch repair hMLHl hMSH2 microsatellite instability allelic imbalance promoter hypermethylation, and inactivation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Konishi M, Kikuchi-Yanoshita R, Tanaka K, et al: Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111: 307–317, 1996.PubMedCrossRefGoogle Scholar
  2. 2.
    Bevilacqua RAU, Simpson AJG: Methylation of the hMLHl promoter but no hMLHl mutations in sporadic gastric carcinomas with high-level microsatellite instability. Int J Cancer 87: 200–203, 2000.PubMedCrossRefGoogle Scholar
  3. 3.
    Kastan MB: Genetic Instability and Tumorigenesis. Springer-Verlag Berlin Heidelberg, 1997.Google Scholar
  4. 4.
    Fishel R, Lescoe MK, Rao MRS, et al: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038, 1993.PubMedCrossRefGoogle Scholar
  5. 5.
    Bronner CE, Baker SM, Morrison PT, et al: Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 368: 258–261, 1994.PubMedCrossRefGoogle Scholar
  6. 6.
    Hemminki A, Peltomaki P, Mecklin JP, et al: Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet 8: 405–410, 1994.PubMedCrossRefGoogle Scholar
  7. 7.
    Kolodner RD, Hall NR, Lipford J, et at Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlhl mutations. Cancer Res 55: 242–248, 1995.PubMedGoogle Scholar
  8. 8.
    Parsons R, Li GM, Longley M, et al: Mismatch repair deficiency in phenotipically normal human cells. Science 268: 738–740, 1995.PubMedCrossRefGoogle Scholar
  9. 9.
    Wong IHN: Methylation profiling of human cancers in blood: Molecular monitoring and prognostication. Int J Oncol 19: 1319–1324, 2001.PubMedGoogle Scholar
  10. 10.
    Kondo E, Furukawa T, Yoshinaga K, et al: Not hMSH2 but hMLHl is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with micro satellite instability. Int J Oncol 17: 535–541, 2000.PubMedGoogle Scholar
  11. 11.
    Esteller M, Levine R, Baylin SB, et al: hMLHl promoter hypermethylation is associated with microsatellite instability phenotype in sporadic endometrial carcinoma. Oncogene 16: 2413–2417, 1998.CrossRefGoogle Scholar
  12. 12.
    Cunningham JM, Christensen ER, Tester DJ, et al: Hypermethylation of the hMLHl promoter in colon cancer with microsatellite instability. Cancer Res 58: 3455–3460, 1998.PubMedGoogle Scholar
  13. 13.
    Maniatis T, Fritsch EF, Sambrook J: Molecular Cloning, A Laboratory Manual. Cold Spring Harbor Laboratory, New York, USA, 1982.Google Scholar
  14. 14.
    Tomlinson 1PM, Lambros MBK, Roylance RR: Loss of heterozygosity analysis: practically and conceptually flawed? Genes Chromosomes Cancer 34: 349–353, 2002.PubMedCrossRefGoogle Scholar
  15. 15.
    Boland CR, Thibodeau SN, Hamilton SR, et al: A National Cancer Institute workshop on micro satellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58: 5248–5257, 1998.PubMedGoogle Scholar
  16. 16.
    Kane MF, Loda M, Gaida GM, et al: Methylation of the hMLHl promoter correlates with lack of expression of hMLHl in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: 808–811, 1997.PubMedGoogle Scholar
  17. 17.
    Yanagisawa Y, Akiyama Y, Lida S, et al: Methylation of the hMLHl promoter in familial gastric cancer with microsatellite instability. Int J Cancer 85: 50–53, 2000.PubMedCrossRefGoogle Scholar
  18. 18.
    Beck NE, Tomlinson IPM, Homfray T, et al: Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria. Hum Genet 99: 219–224, 1997.PubMedCrossRefGoogle Scholar
  19. 19.
    Parc YR, Hailing KC, Wang L, et al: HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60: 2225–2231, 2000.PubMedGoogle Scholar
  20. 20.
    Kuismanen SA, Holmberg MT, Salovaara R, et al: Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 56: 1773–1779, 2000.Google Scholar
  21. 21.
    Furukawa T, Konishi F, Masubuchi S, et al: Densely methylated MLH1 promoter correlates with decreased mRNA expression in sporadic colorectal cancers. Genes Chromosomes Cancer 35: 1–10, 2002.PubMedCrossRefGoogle Scholar
  22. 22.
    Porfiri E, Scartozzi M, Piga A, et al: Missense mismatch repair gene alterations, microsatellite instability, and hereditary nonpolyposis colorectal cancer. J Clin Oncol 20: 3178–3179, 2002.Google Scholar
  23. 23.
    Brueckl WM, Limmert T, Brabletz T, et al: Mismatch repair deficiency in sporadic synchronous colorectal cancer. Anticancer Res 20: 4727–4732, 2000.PubMedGoogle Scholar
  24. 24.
    Toyota M, Ohe-Toyota M, Ahuja N, et al: Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. PNAS 97: 710–715, 2000.PubMedCrossRefGoogle Scholar
  25. 25.
    Han HJ, Maruyama M, Baba S, et al: Genomic structure of human mismatch repair gene, hMLHl, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC). Hum Mol Genet 14: 237–242, 1995.CrossRefGoogle Scholar
  26. 26.
    Maliaka YK, Chudina AP, Belev NF, et al: CpG dinucleotides in the hMSH2 and hMLHl genes are hotspots for HNPCC mutations. Hum Genet 97: 251–255, 1996.PubMedCrossRefGoogle Scholar
  27. 27.
    http://www.nfdht.nl/database/mdbchoice.htm)Google Scholar
  28. 28.
    Liu T, Wahlberg S, Rubio C, et al: DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLHl) in 34 Swedish families with colorectal cancer. Clin Genet 53: 131–135, 1998.PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2003

Authors and Affiliations

  • Enikó Kámory
    • 1
  • Orsolya Kolacsek
    • 1
  • Szabolcs Ottó
    • 1
  • Orsolya Csuka
    • 1
  1. 1.Department of PathogeneticsNational Institute of OncologyBudapestHungary

Personalised recommendations