title: Clinical and molecular detection of inherited colorectal cancers in northeast Italy: a first prospective study of incidence of Lynch syndrome and MUTYH-related colorectal cancer in Italy.
abstract: The reported incidence of hereditary colorectal cancers (CRCs) is widely variable. The principal aim of the study was to prospectively evaluate the incidence of familial CRCs in a region of northern Italy using a standardized method. Consecutive CRC patients were prospectively enrolled from October 2002 to December 2003. Patients underwent a structured family history, the microsatellite instability (MSI) test and a screen for MUTYH mutations. Following family history patients were classified as belonging to high, moderate and mild risk families. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins and investigation for MLH1/MSH2 mutations, for MLH1 promoter methylation and for the V600E hotspot BRAF mutation were performed in high MSI (MSI-H) cases. Of the 430 patients enrolled, 17 (4%) were high risk [4 hereditary non-polyposis colorectal cancer (HNPCC), 12 suspected HNPCC and 1 MUTYH-associated adenomatous polyposis coli (MAP)], 53 moderate risk and 360 mild risk cases. The MSI test was performed on 393 tumours, and 46 (12%) of them showed MSI-H. In these patients, one MLH1 pathogenetic mutations and two MSH2 pathogenetic mutations were found. Thirty-two (70%) MSI-H cases demonstrated MLH1 methylation and/or BRAF mutation: None of them showed MLH1/MSH2 mutation. Two biallelic germline MUTYH mutations were found, one with clinical features of MAP. A strong family history of CRC was present in 4% of the enrolled cases; incidence of MLH1/MSH2 or MUTHY mutations was 1.3% and of MSI-H phenotype was 12%. MLH1 methylation and BRAF mutation can exclude 70% of MSI-H cases from gene sequencing.
authors.affiliation: Clinica Chirurgica 2nd, Dipartimento Scienze Chirurgiche, Oncologiche e Gastroenterologiche, University of Padova, Padua, Italy. edl@unipd.it
authors.forename: E
authors.initials: E
authors.lastname: Urso
authors.forename: M
authors.initials: M
authors.lastname: Agostini
authors.forename: S
authors.initials: S
authors.lastname: Pucciarelli
authors.forename: M
authors.initials: M
authors.lastname: Rugge
authors.forename: R
authors.initials: R
authors.lastname: Bertorelle
authors.forename: I
authors.initials: I
authors.lastname: Maretto
authors.forename: C
authors.initials: C
authors.lastname: Bedin
authors.forename: E
authors.initials: E
authors.lastname: D'Angelo
authors.forename: C
authors.initials: C
authors.lastname: Mescoli
authors.forename: M
authors.initials: M
authors.lastname: Zorzi
authors.forename: A
authors.initials: A
authors.lastname: Viel
authors.forename: G
authors.initials: G
authors.lastname: Bruttocao
authors.forename: B
authors.initials: B
authors.lastname: Ferraro
authors.forename: F
authors.initials: F
authors.lastname: Erroi
authors.forename: P
authors.initials: P
authors.lastname: Contin
authors.forename: G L
authors.initials: GL
authors.lastname: De Salvo
authors.forename: D
authors.initials: D
authors.lastname: Nitti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; 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; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D048493:Proto-Oncogene Proteins B-raf; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein