A novel MLH1 mutation harbored as a germ line aberration by a young woman of an HNPCC-like family and exhibited by a CML patient when occurring prior to the initiation of the blast phase concomitant with a c-MYC amplification

Int J Mol Med. 2006 Jun;17(6):1023-6.


Germ line mutations in the MLH1 and MSH2 genes account for the majority of hereditary nonpolyposis colorectal cancer (HNPCC) families. Here, we describe a family that does not meet the international criteria for HNPCC, of which a young woman harbors a missense mutation (D132H). This novel germ line mutation has not previously been reported. Of the mismatch repair (MMR) genes, MLH1 has been shown to play an important role in hematologic malignancies. The novel mutation was also revealed to be a somatic aberration occurring prior to the initiation of the blast phase in a chronic myelogenous leukemia (CML) patient. Among the possible MLH1 partners involved in signaling MMR or apoptosis is the proto-oncogene c-MYC, which is closely related to cellular proliferation. We further revealed a concomitant c-MYC dramatic amplification in the CML-MLH1-mutation carrier patient, also occurring at the pre-blast phase. Our data contribute further to characterizing the mutational spectrum of the MLH1 gene. Furthermore, given the role of c-MYC and its interaction with MLH1, taken together with the mutational status of both genes revealed at the pre-blast phase in the CML patient, a plausible increased genetic instability might be expected to take place, possibly contributing to blast triggering. Our results may provide additional insight into the complex interplay between the MMR system and other cellular pathways.

Publication types

  • Case Reports

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins / genetics*
  • Chromosome Aberrations
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Female
  • Gene Amplification*
  • Genomic Instability
  • Germ-Line Mutation*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • MutL Protein Homolog 1
  • Mutation, Missense
  • Nuclear Proteins / genetics*
  • Pedigree
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc / genetics*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MAS1 protein, human
  • MLH1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc
  • MutL Protein Homolog 1