Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations

Fam Cancer. 2001;1(1):9-15. doi: 10.1023/a:1011564720772.


Hereditary nonpolyposis colorectal cancer (HNPCC) is a multi-organ cancer syndrome associated with heritable mutations in DNA mismatch repair genes, particularly MLH1 (MutL Homologue 1) and MSH2 (MutS Homologue 2). We took advantage of the unique characteristics of the Finnish HNPCC families to assess genotype- phenotype correlations in this disorder. We studied 295 mutation carriers (10 mutations in MLH1 and 3 in MSH2) segregating in 55 families. In addition to the comparison of families with different mutations, the enrichment of two MLH1 mutations, one affecting exon 16 (29 families, 186 individuals) and another one affecting exon 6 (10 families, 45 individuals) allowed the comparison of kindreds with identical predisposing mutations. Extracolonic cancers were more common in MSH2 than MLH1 mutation carriers, with the ratios of 0.48 and 0.64, respectively, of colorectal cancer to all cancers (P = 0.076). Within MLH1, two mutations affecting only the amino terminal portion showed a significant association with late onset of cancer as compared to the remaining mutations. Importantly, families with the MLH1 exon 16 mutation displayed significant variation (P = 0.012) in the age at onset of colon cancer, despite shared predisposition. We conclude that even though characteristics of the inherited mutations may explain part of the observed clinical variation, other factors have a significant impact on HNPCC phenotype determination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Base Pair Mismatch
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Repair
  • DNA-Binding Proteins*
  • Female
  • Finland
  • Genetic Predisposition to Disease
  • Genotype*
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Mutation / genetics*
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Phenotype*
  • Proto-Oncogene Proteins / genetics*


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