title: Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome.
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.
authors.affiliation: Department of Oncology, Biology and Genetics, University of Genoa, 16132 Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gargiulo
authors.forename: M
authors.initials: M
authors.lastname: Torrini
authors.forename: S
authors.initials: S
authors.lastname: Ollila
authors.forename: S
authors.initials: S
authors.lastname: Nasti
authors.forename: L
authors.initials: L
authors.lastname: Pastorino
authors.forename: R
authors.initials: R
authors.lastname: Cusano
authors.forename: L
authors.initials: L
authors.lastname: Bonelli
authors.forename: L
authors.initials: L
authors.lastname: Battistuzzi
authors.forename: L
authors.initials: L
authors.lastname: Mastracci
authors.forename: W
authors.initials: W
authors.lastname: Bruno
authors.forename: V
authors.initials: V
authors.lastname: Savarino
authors.forename: S
authors.initials: S
authors.lastname: Sciallero
authors.forename: G
authors.initials: G
authors.lastname: Borgonovo
authors.forename: M
authors.initials: M
authors.lastname: Nyström
authors.forename: G
authors.initials: G
authors.lastname: Bianchi-Scarrà
authors.forename: C
authors.initials: C
authors.lastname: Mareni
authors.forename: P
authors.initials: P
authors.lastname: Ghiorzo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein