J.B. and G.M. represent the CAPP consortium, several of whose members submitted samples for mutation detection as part of the search for carriers of HNPCC eligible to take part in a long-term chemoprevention study [www.capp2.com].
Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)
Article first published online: 7 JUN 2005
Copyright © 2005 Wiley-Liss, Inc.
Genes, Chromosomes and Cancer
Volume 44, Issue 2, pages 123–138, October 2005
How to Cite
van der Klift, H., Wijnen, J., Wagner, A., Verkuilen, P., Tops, C., Otway, R., Kohonen-Corish, M., Vasen, H., Oliani, C., Barana, D., Moller, P., DeLozier-Blanchet, C., Hutter, P., Foulkes, W., Lynch, H., Burn, J., Möslein, G. and Fodde, R. (2005), Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosom. Cancer, 44: 123–138. doi: 10.1002/gcc.20219
- Issue published online: 2 AUG 2005
- Article first published online: 7 JUN 2005
- Manuscript Accepted: 19 APR 2005
- Manuscript Received: 25 FEB 2005
- Dutch Cancer Society (KWF/NKB)
- Netherlands Organisation for Scientific Research (NWO)
- Deutsche Krebshilfe, Verbundprojekt familiarer Darmkrebs
- Center of Medical System Biology (CMSB), established by the Netherlands Genomics Initiative (NGI) and NWO
A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories. © 2005 Wiley-Liss, Inc.