Abstract
Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is an autosomal, dominantly inherited disease accounting for about 1%–5% of all colorectal cancer cases. HNPCC predisposition is caused by germline mutations in at least five genes coding for DNA mismatch repair (MMR) proteins. More than 400 MMR gene mutations have been identified in HNPCC patients. About 90% of mutations affect the MLH1 and MSH2 genes. The mutational spectrum mainly includes point mutations and small deletions or insertions. Here, we report a large 184 base-pair Alu insertion mutation in exon 6 of the MSH2 gene in a German HNPCC family. The inserted sequence contains repetitive Alu sequence elements that present the highest homology with the old Alu J subfamily. The Alu J insertion was most likely derived from Alu-mediated recombination, since Alu J elements have been found close to the insertion site in adjacent introns, and since elements pivotal for Alu retrotransposition are missing. Our results suggest that the recombination event occurred at least one generation ago. This is the first report of an Alu insertion in the coding sequence of a MMR gene as the cause of HNPCC. Our data thus further extend the spectrum of MMR gene mutations causative for HNPCC.
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References
Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colon cancer. Cancer Res 58:5248–5257
Claverie-Martin F, Gonzalez-Acosta H, Flores C, Anton-Gamero M, Garcia-Nieto V (2003) De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent’s disease. Hum Genet 113:480–485
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038
Grady WM, Rajput A, Myeroff L, Liu DF, Kwon K, Willis J, Markowitz S (1998) Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res 58:3101–3104
Hempen PM, Zhang L, Bansal RK, Iacobuzio-Donahue CA, Murphy KM, Maitra A, Vogelstein B, Whitehead RH, Markowitz SD, Willson JK, Yeo CJ, Hruban RH, Kern SE (2003) Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers. Cancer Res 635:994–999
Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M (2000) Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 97:10872–10877
Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MR, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P (1994) Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for MSH2 mutations. Genomics 24:516–526
Kolomietz E, Meyn MS, Pandita A, Squire JA (2002) The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosom Cancer 35:97–112
Kutty RK, Kutty G, Rodriguez IR, Chader GJ, Wiggert B (1994) Chromosomal localization of the human oxygenase genes: heme oxygenase-1 (HMOX1) maps to chromosome 22q12 and heme oxygenase-2 (HMOX2) maps to chromosome 16p13.3. Genomics 20:513–516
Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, Chapelle A de la, Hamilton SR, Vogelstein B, Kinzler KW (1996) Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 2:169–174
Marshall B, Isidro G, Boavida MG (1996) Insertion of a short Alu sequence into the hMSH2 gene following a double cross over next to sequences with chi homology. Gene 174:175–179
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H (2002) Mismatch repair genes MLH1 and MSH2 and colorectal cancer: a HuGE review. Am J Epidemiol 156:885–902
Muller A, Fishel R (2002) Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest 20:102–109
Nystrom-Lahti M, Kristo P, Nicolaides NC, Chang SY, Aaltonen LA, Moisio AL, Jarvinen HJ, Mecklin JP, Kinzler KW, Vogelstein B, et al (1995) Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med 1:1203–1206
Peltomaki P (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10:735–740
Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179
Peltomaki P, Vasen HF (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113:1146–1158
Peltomaki P, Aaltonen LA, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Green JS, Jass JR, Weber JL, Leach FS, et al (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812
Ricci V, Regis S, Di Duca M, Filocamo M (2003) An Alu-mediated rearrangement as cause of exon skipping in Hunter disease. Hum Genet 112:419–425
Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59:290–293
Sutter C, Gebert J, Bischoff P, Herfarth C, Knebel Doeberitz M von (1999) Molecular screening of potential HNPCC patients using a multiplex microsatellite PCR system. Mol Cell Probes 13:157–165
Taylor CF, Charlton RS, Burn J, Sheridan E, Taylor GR (2003) Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. Hum Mutat 22:428–433
Umar A, Risinger JI, Hawk ET, Barrett JC (2004) Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 4:153–158
Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The international collaborative group on hereditary non polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425
Vilkki S, Tsao JL, Loukola A, Poyhonen M, Vierimaa O, Herva R, Aaltonen LA, Shibata D (2001) Extensive somatic microsatellite mutations in normal human tissue. Cancer Res 61:4541–4544
Wagner A, Barrows A, Wijnen JT, Klift H van der, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, Puijenbroek M van, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, Chapelle A de la, Lynch HT, Fodde R (2003) Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72:1088–1100
Wang Y, Friedl W, Lamberti C, Jungck M, Mathiak M, Pagenstecher C, Propping P, Mangold E (2003) Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer 103:636–641
Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE (2002) A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res 62:359–362
Wijnen J, Leeuw W de, Vasen H, Klift H van der, Moller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Moslein G, Tops C, Brocker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R (1999) Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23:142–144
Woerner SM, Benner A, Sutter C, Schiller M, Yuan YP, Keller G, Bork P, Knebel Doeberitz M von, Gebert JF (2003) Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative real common target genes. Oncogene 22:2226–2235
Acknowledgements
We thank Irina Voehringer, Beate Kuchenbuch, and Gabriele Russell for their excellent technical assistance. This work was supported in part by a grant from the German Cancer Aid (Deutsche Krebshilfe, grant no. 70-3026-Kn 5).
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M. Kloor and C. Sutter contributed equally to this work
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Kloor, M., Sutter, C., Wentzensen, N. et al. A large MSH2 Alu insertion mutation causes HNPCC in a German kindred. Hum Genet 115, 432–438 (2004). https://doi.org/10.1007/s00439-004-1176-9
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DOI: https://doi.org/10.1007/s00439-004-1176-9