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Gene Conversion Is a Frequent Mechanism of Inactivation of the Wild-Type Allele in Cancers from MLH1/MSH2 Deletion Carriers

¹ Research Group Human Genetics, Division of Medical Genetics UKBB, Center of Biomedicine DKBW, University of Basel, Basel; ² Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; and ³ Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

Requests for reprints: Karl Heinimann, Research Group Human Genetics, Center of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Phone: 41-61-267-0777; Fax: 41-61-267-0778; E-mail: karl.heinimann{at}unibas.ch.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation–dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation–dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNPCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus. (Cancer Res 2006; (66)2: 659-64)

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