title: Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes.
abstract: OBJECTIVE
  Colorectal cancer (CRC) occurs rarely in young individuals (<45 yr) and represents one of the criteria for suspecting hereditary cancer families. In this study we evaluated clinical features and molecular pathways (chromosomal instability [CIN] and microsatellite instability [MSI]) in early-onset CRC of 71 patients.
  
  
  METHODS
  Detailed family and personal history were obtained for each patient. Expression of APC, beta-catenin, p53, MLH1, MSH2, and MSH6 genes was evaluated by immunohistochemistry. MSI analysis was performed and constitutional main mutations of the mismatch repair (MMR) genes were searched by gene sequencing.
  
  
  RESULTS
  Fourteen (19.7%) out of the 71 cases showed both MSI and altered expression of MMR proteins. In the 57 MSI-negative (MSI-) lesions altered expression of APC, beta-catenin, and p53 genes were found more frequently than in MSI-positive(MSI+) tumors. Seven (50%) out of the 14 patients with MSI+ tumors presented clinical features of Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) and in all but one, constitutional mutations in MLH1 or MSH2 genes could be detected. The same mutations were also found in other family members.
  
  
  CONCLUSIONS
  Our study demonstrates the involvement of CIN in a majority of early-onset colorectal tumors. Furthermore, we identified Lynch syndromes in seven cases (50%) of early-onset colorectal carcinomas with impairment of the MMR system. These results suggest that patients with early-onset CRC should be screened for hereditary cancer syndrome through clinical and molecular characterizations.
authors.affiliation: Department of Pathology, University of Modena and Reggio, Emilia, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Losi
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Gregorio
authors.forename: Monica
authors.initials: M
authors.lastname: Pedroni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ponti
authors.forename: Luca
authors.initials: L
authors.lastname: Roncucci
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scarselli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Silvana
authors.initials: S
authors.lastname: Baglioni
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Marino
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rossi
authors.forename: Piero
authors.initials: P
authors.lastname: Benatti
authors.forename: Stefania
authors.initials: S
authors.lastname: Maffei
authors.forename: Mirco
authors.initials: M
authors.lastname: Menigatti
authors.forename: Barbara
authors.initials: B
authors.lastname: Roncari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ponz de Leon
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D017668:Age of Onset; D020137:Base Pair Mismatch / Q000502:physiology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin