title: Genotype-phenotype correlations in individuals with a founder mutation in the MLH1 gene and hereditary non-polyposis colorectal cancer.
abstract: OBJECTIVE
  A unique mutation of the MLH1 gene was recently reported in six families living in a small area of Northern Italy. The mutation consists in the insertion of a T base between nucleotides 2269 and 2270 (2269-2270insT), causing the synthesis of an unstable polypeptide. The mutation was not reported by other investigators or outside this small geographic area, thus suggesting a possible founder effect. The main purpose of this investigation was to investigate whether patients (and families) with the 2260-2270insT mutation show relevant clinical differences when compared with individuals with other MLH1 or MSH2 gene alterations.
  
  
  METHODS
  We identified hereditary non-polyposis colorectal cancer (HNPCC) families through the specialized colorectal cancer registry following a previously described multistep approach. In all, 58 HNPCC families were identified; of these, 38 were detected through the registry, and 20 were referred from other areas in Italy.
  
  
  RESULTS
  Small differences were found in the main clinical and pathologic features; however, tumour burden per family tended to be higher in kindred sharing the founder mutation; in addition, multiple primaries (four or five different tumours in some subjects) were significantly more frequent in patients with the 2269-2270insT than in individuals with MSH2, MLH1 gene mutations or sporadic colorectal neoplasms. No significant difference in prognosis was found between patients with the founder mutation and those with other MLH1 or MSH2 mutations. Regardless of the type of mutation, neoplasms of the colon-rectum, stomach and endometrium represented nearly 80% of the tumour burden in families with HNPCC.
  
  
  CONCLUSIONS
  A proclivity to multiple tumours arising in the same subject and a higher tumour burden per family were the most relevant findings observed in affected patients with the founder mutation compared with other MLH1 or MSH2 mutations. In general, the results of the study underline the difficulty in discriminating between Lynch I and Lynch II syndromes on the basis of specific molecular changes.
authors.affiliation: Dipartimento di Medicina Interna, Università di Modena e Reggio Emilia, Modena, Italy. deleon@unimore.it
authors.forename: Maurizio Ponz
authors.initials: MP
authors.lastname: de Leon
authors.forename: Piero
authors.initials: P
authors.lastname: Benatti
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Gregorio
authors.forename: Lorena
authors.initials: L
authors.lastname: Losi
authors.forename: Monica
authors.initials: M
authors.lastname: Pedroni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ponti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Emanuela
authors.initials: E
authors.lastname: Lucci-Cordisco
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rossi
authors.forename: Luca
authors.initials: L
authors.lastname: Roncucci
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000704:Analysis of Variance; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012042:Registries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1