1. ¹Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
2. ²The Second Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
3. ³The Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland

Correspondence: Professor LA Aaltonen, Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Room B520a, PO Box 63, Haartmaninkatu 8, Helsinki 00014, Finland. E-mail: lauri.aaltonen@helsinki.fi

Received 15 June 2006; Revised 4 August 2006; Accepted 25 August 2006; Published online 9 October 2006.

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.