Familial Cancer

, Volume 6, Issue 1, pp 97–102

A missense germline mutation in exon 7 of the MSH2 gene in a HNPCC family from center-Italy

  • Francesca Bianchi
  • Eva Galizia
  • Emilio Porfiri
  • Laura Belvederesi
  • Romina Catalani
  • Cristian Loretelli
  • Raffaella Bracci
  • Italo Bearzi
  • Chiara Turchi
  • Alessandra Viel
  • Riccardo Cellerino
Original Paper

Abstract

Introduction

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inherited disease predisposing to the development of colorectal cancers and several other malignancies (endometrium, ovaries, stomach, small bowel, hepatobiliary and urinary tract). HNPCC is caused by germline mutations in any of the MisMatch Repair (MMR) genes. Mutations in MLH1 and MSH2 account for almost 90% of all identified ones. About 15% of mutations identified in MSH2 are missense ones.

Patients and methods

We studied one family, fulfilling Amsterdam II criteria, referred to our Center for genetic counselling. The proband, and some of her relatives, have been investigated for microsatellite instability (MSI), immunohistochemical MMR protein staining and by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).

Results

All patients carried the same novel MSH2 germline missense mutation (R359S) in exon 7, which determines the substitution of an Arginine, which is a basic amino acid, with a polar Serine residue (R359S). The mutation was associated with lack of expression of MSH2 protein and high microsatellite instability in tumour tissues. The same mutation has been detected in one healthy relative.

Conclusions

The mutation here reported shows a high correlation with phenotype. The mutation is located in an evolutionary conserved domain. Taken together, our findings suggest evidence that the amino acid substitution can be interpreted as pathogenetic.

Keywords

Missense mutations MSH2 HNPCC Endometrial cancer Colon cancer 

Abbreviations

HNPCC

Hereditary Non-Polyposis Colorectal Cancer

MMR

MisMatch Repair

MSI

Microsatellite instability

IHC

Immunohistochemistry

InSiGHT

International Society for Gastrointestinal Hereditary Tumours

MLPA

Multiplex Ligation-dependent Probe Amplification

References

  1. 1.
    de la Chapelle A (2004) Genetic predisposition to colorectal cancer. Nat Rev Cancer 4:769–780CrossRefGoogle Scholar
  2. 2.
    Merg A, Lynch HT, Lynch JF et al (2005) Hereditary colorectal cancer-part II. Curr Probl Surg 42:267–333PubMedCrossRefGoogle Scholar
  3. 3.
    Vasen HF, Mecklin JP, Khan PM et al (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRefGoogle Scholar
  4. 4.
    Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A National Cancer Institute Workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762PubMedCrossRefGoogle Scholar
  5. 5.
    Umar A, Risinger JI, Hawk ET et al (2004) Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 4:153–158PubMedGoogle Scholar
  6. 6.
    Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary non-polyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRefGoogle Scholar
  7. 7.
    Pinol V, Castells A, Andreu M et al (2005) Accuracy of revised Bethesda guidelines, microsatellite instability and immunohistochemistry for the identification of patients with hereditary non-polyposis colorectal cancer. JAMA 293:1986–1994PubMedCrossRefGoogle Scholar
  8. 8.
    Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development on international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
  9. 9.
    Strate LL, Syngal S (2005) Hereditary colorectal cancer syndromes. Cancer Causes Control 16:201–213PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Peltomaki P, Vasen HF (1997) Mutations predisposing to hereditary non-polyposis coloretal cancer: database and results of a collaborative study. The International Collaborative Group on hereditary non-polyposis colorectal cancer. Gastroenterology 113:1146–1158PubMedCrossRefGoogle Scholar
  12. 12.
    Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedCrossRefGoogle Scholar
  13. 13.
    Syngal S, Fox EA, Li C et al (1999) Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer. JAMA 282:247–253PubMedCrossRefGoogle Scholar
  14. 14.
    Cravo M, Afonso AJ, Lage P et al (2002) Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing. Gut 50:405–412PubMedCrossRefGoogle Scholar
  15. 15.
    Scartozzi M, Bianchi F, Rosati S et al (2002) Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol 20:1203–1208PubMedCrossRefGoogle Scholar
  16. 16.
    Marcus VA, Madlensky L, Gryfe R et al (1999) Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors. Am J Surg Pathol 23:1248–1255PubMedCrossRefGoogle Scholar
  17. 17.
    Syngal S, Fox EA, Eng C et al (2000) Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 37:641–645PubMedCrossRefGoogle Scholar
  18. 18.
    Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer). N Engl J Med 352:1851–1860PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Francesca Bianchi
    • 1
    • 2
  • Eva Galizia
    • 1
    • 2
  • Emilio Porfiri
    • 3
  • Laura Belvederesi
    • 1
    • 2
  • Romina Catalani
    • 1
    • 2
  • Cristian Loretelli
    • 1
    • 2
  • Raffaella Bracci
    • 1
    • 2
    • 4
  • Italo Bearzi
    • 5
  • Chiara Turchi
    • 6
  • Alessandra Viel
    • 7
  • Riccardo Cellerino
    • 1
    • 2
  1. 1.Istituto di Medicina Clinica e Biotecnologie Applicate-Oncologia MedicaUniversità Politecnica delle MarcheAnconaItaly
  2. 2.Centro Regionale di Alta Specializzazione in Genetica Oncologica, Facoltà di Medicina e ChirurgiaUniversità Politecnica delle MarcheAnconaItaly
  3. 3.Cancer Research-UK Institute for Cancer StudiesUniversity of BirminghamBirminghamUK
  4. 4.Clinica di Oncologia MedicaUniversità Politecnica delle MarcheAnconaItaly
  5. 5.Anatomia ed Istologia PatologicaUniversità Politecnica delle MarcheAnconaItaly
  6. 6.Dipartimento di Neuroscienze-Medicina LegaleUniversità Politecnica delle MarcheAnconaItaly
  7. 7.Oncologia Sperimentale 1, Dipartimento di Ricerca Preclinica ed EpidemiologicaCentro Riferimento Oncologico, IRCCSAvianoItaly

Personalised recommendations