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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)547-553
Number of pages7
JournalFamilial Cancer
Issue number4
Publication statusPublished - Dec 2009


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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Oncology
  • Genetics(clinical)


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