Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer

Genes Chromosomes Cancer. 1997 Jan;18(1):8-18. doi: 10.1002/(sici)1098-2264(199701)18:1<8::aid-gcc2>;2-7.


Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the "Amsterdam criteria." A combination of different techniques, including reverse transcription-polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Base Sequence
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA / analysis
  • DNA Mutational Analysis
  • DNA Repair / genetics*
  • DNA-Binding Proteins*
  • Gene Rearrangement
  • Germ-Line Mutation*
  • Humans
  • Italy / epidemiology
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins / genetics*
  • RNA-Directed DNA Polymerase


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • DNA
  • RNA-Directed DNA Polymerase
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein