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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P=0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, P<0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

Original publication

DOI

10.1038/sj.onc.1210236

Type

Journal article

Journal

Oncogene

Publication Date

07/2007

Volume

26

Pages

4541 - 4549

Addresses

Department of Medical Genetics, University of Helsinki, Helsinki, Finland. Miina.Ollikainen@Helsinki.fi

Keywords

Humans, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, Endometrial Neoplasms, Adaptor Proteins, Signal Transducing, Nuclear Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Cohort Studies, DNA Methylation, CpG Islands, Mutation, Loss of Heterozygosity, Female, DNA Mismatch Repair, Promoter Regions, Genetic, MutL Protein Homolog 1