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Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer

  • Mahdi Montazer HaghighiEmail author
  • Ramin RadpourEmail author
  • Katayoun Aghajani
  • Narges Zali
  • Mahsa Molaei
  • Mohammad Reza Zali
Original Article

Abstract

Background

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found.

Materials and methods

The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing.

Results

We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient.

Conclusion

In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.

Keywords

HNPCC Mismatch repair MMR Microsatellite instability MLH1 PMS2 

Notes

Acknowledgments

We thank Regan Geissmann for proofreading the text, and we are indebted to the patients for their cooperation. This research was supported by grants from the Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University.

References

  1. 1.
    Stephenson BM, Finan PJ, Gascoyne J et al (1991) Frequency of familial colorectal cancer. Br J Surg 78:1162–1166PubMedCrossRefGoogle Scholar
  2. 2.
    Wagner A, Tops C, Wijnen JT et al (2002) Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation. J Med Genet 39:833–837PubMedCrossRefGoogle Scholar
  3. 3.
    Robinson KL, Liu T, Vandrovcova J et al (2007) Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. JNCI J Natl Cancer Inst 99:291–299CrossRefGoogle Scholar
  4. 4.
    Liu S-R, Zhao Bo, Wang Z-J et al (2004) Clinical features and mismatch repair gene mutation screening in Chinese patients with hereditary nonpolyposis colorectal carcinoma. World J Gastroenterol 10:2647–2651PubMedGoogle Scholar
  5. 5.
    Park J-G, Kim D-W, Hong CW et al (2006) Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer. Clin Cancer Res 12:3389–3393PubMedCrossRefGoogle Scholar
  6. 6.
    Peltomaki P, Vasen HF (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 113:1146–1158PubMedCrossRefGoogle Scholar
  7. 7.
    Liu B, Parsons R, Papadopoulos N et al (1996) Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 2:169–174PubMedCrossRefGoogle Scholar
  8. 8.
    Peltomaki P, Gao X, Mecklin JP et al (2001) Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs shared predisposing mutations. Fam Cancer 1:9–15PubMedCrossRefGoogle Scholar
  9. 9.
    Mead LJ, Jenkins MA, Young J et al (2007) Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. Clin Cancer Res 13:2865–2869PubMedCrossRefGoogle Scholar
  10. 10.
    Hatch SB, Lightfoot HM Jr, Garwacki CP et al (2005) Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors. Clin Cancer Res 11:2180–2187PubMedCrossRefGoogle Scholar
  11. 11.
    Mori Y, Selaru FM, Sato F et al (2003) The impact of microsatellite instability on the molecular phenotype of colorectal tumors. Cancer Res 63:4577–4582PubMedGoogle Scholar
  12. 12.
    Ponz de Leon M, Sant M, Micheli A et al (1992) Clinical and pathological prognostic indicators in colorectal cancer. A population-based study. Cancer 69:626–635PubMedCrossRefGoogle Scholar
  13. 13.
    Morson BC, Sobin LH et al (1977) International histological classification of tumours. Dis Colon Rectum 8:697–699Google Scholar
  14. 14.
    Jover R, Payá A, Alenda C et al (2004) Defective mismatch-repair colorectal cancer. Am J Clin Pathol 122:389–394PubMedCrossRefGoogle Scholar
  15. 15.
    Buhard O, Suraweera N, Lectard A et al (2004) Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis. Dis Markers 20:l251–1257Google Scholar
  16. 16.
    Burgart LJ et al (2005) Testing for defective DNA mismatch repair in colorectal carcinoma: a practical guide. Arch Pathol Lab Med 129:1385–1389PubMedGoogle Scholar
  17. 17.
    Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
  18. 18.
    Jin H-Y, Liu X, Li Vicky Ka Ming et al (2008) Detection of mismatch repair gene germline mutation carrier among Chinese population with colorectal cancer. BMC Cancer 8:44–48PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Mahdi Montazer Haghighi
    • 1
    Email author
  • Ramin Radpour
    • 2
    Email author
  • Katayoun Aghajani
    • 1
  • Narges Zali
    • 1
  • Mahsa Molaei
    • 1
  • Mohammad Reza Zali
    • 1
  1. 1.Research Center for Gastroenterology and Liver DiseasesTaleghani Hospital, Shaheed Beheshti Medical UniversityTehranIran
  2. 2.Laboratory for Prenatal Medicine and Gynecologic Oncology, Women’s Hospital/Department of BiomedicineUniversity of BaselBaselSwitzerland

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