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Familial Cancer

, Volume 8, Issue 4, pp 547–553 | Cite as

Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome

  • S. Gargiulo
  • M. Torrini
  • S. Ollila
  • S. Nasti
  • L. Pastorino
  • R. Cusano
  • L. Bonelli
  • L. Battistuzzi
  • L. Mastracci
  • W. Bruno
  • V. Savarino
  • S. Sciallero
  • G. Borgonovo
  • M. Nyström
  • G. Bianchi-Scarrà
  • C. Mareni
  • P. Ghiorzo
Article

Abstract

Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

Keywords

Lynch syndrome Hereditary non-polyposis colorectal cancer MLH1 Mismatch repair genes MSH2 MSH6 Pancreatic cancer 

Abbreviations

PC

Pancreatic cancer (pancreatic adenocarcinoma)

s-LS

Suspected-Lynch syndrome

Notes

Acknowledgments

This work was supported by the 2007 Italian Ministry of Health DGRST.4/4235-P1.9.A.B. We wish to thank the Galliera Genetic Bank—Network of Telethon Genetic Biobanks (project GTB07001) for providing lymphoblastoid cell lines.

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • S. Gargiulo
    • 1
  • M. Torrini
    • 2
  • S. Ollila
    • 3
  • S. Nasti
    • 1
  • L. Pastorino
    • 1
  • R. Cusano
    • 1
  • L. Bonelli
    • 4
  • L. Battistuzzi
    • 1
  • L. Mastracci
    • 5
  • W. Bruno
    • 1
  • V. Savarino
    • 6
  • S. Sciallero
    • 7
  • G. Borgonovo
    • 8
  • M. Nyström
    • 3
  • G. Bianchi-Scarrà
    • 1
  • C. Mareni
    • 2
  • P. Ghiorzo
    • 1
  1. 1.Department of Oncology, Biology and GeneticsUniversity of GenoaGenoaItaly
  2. 2.Department of Internal MedicineUniversity of GenoaGenoaItaly
  3. 3.Department of Biological and Environmental Sciences, GeneticsUniversity of HelsinkiHelsinkiFinland
  4. 4.Secondary Prevention and Screening, National Cancer InstituteGenoaItaly
  5. 5.Department of Anatomic PathologyUniversity of GenoaGenoaItaly
  6. 6.Division of Gastroenterology, Department of Internal MedicineUniversity of GenoaGenoaItaly
  7. 7.Medical Oncology UnitSan Martino HospitalGenoaItaly
  8. 8.Department of Surgical and Morphological Disciplines and Integrated MethodologiesUniversity of GenoaGenoaItaly

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