Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-01, Vol.66 (2), p.659-664
• Main Authors: JIAN ZHANG, LINDROOS, Annette, OLLILA, Saara, RUSSELL, Anna, MARRA, Giancarlo, MUELLER, Hansjakob, PELTOMAKI, Paivi, PLASILOVA, Martina, HEINIMANN, Karl
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Aged; Biological and medical sciences; Carrier Proteins - genetics; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Mutational Analysis; Female; Finland; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Conversion; Gene Deletion; Gene Dosage; Gene Expression Profiling; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Loss of Heterozygosity; Male; Medical sciences; Microsatellite Repeats; Middle Aged; Molecular and cellular biology; MutL Protein Homolog 1; MutS Homolog 2 Protein - genetics; Nuclear Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Switzerland; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4043

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).