title: Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation.
abstract: Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC-) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients.
authors.affiliation: UOC Genetica Medica-Dipartimento di Biomedicina dell'Età Evolutiva-Università di Bari Aldo Moro Azienda, Ospedaliero-Universitaria Policlinico P.zza G. Cesare 11, 70124 Bari, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lastella
authors.forename: Margherita
authors.initials: M
authors.lastname: Patruno
authors.forename: Giovanna
authors.initials: G
authors.lastname: Forte
authors.forename: Alba
authors.initials: A
authors.lastname: Montanaro
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Gregorio
authors.forename: Carlo
authors.initials: C
authors.lastname: Sabbà
authors.forename: Patrizia
authors.initials: P
authors.lastname: Suppressa
authors.forename: Adalgisa
authors.initials: A
authors.lastname: Piepoli
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007558:Italy; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics
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