Abstract
One of the characteristics of tumors from patients with germline mutations of DNA mismatch repair genes is instability at microsatellite regions (MSI). We analysed alterations at repeated sequences of coding regions, as well as those of 5′ upstream regions, in 29 MSI-High colorectal tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot syndrome. We found that repeated sequences in 5′ upstream regions were altered in these tumors, at considerable frequencies. The (A)10 repeat in the promoter region (position −178∼−169) of the GAPDH gene was altered in 17% of the tumors. The (A)10(TA)9 in the 5′ upstream region (position −318∼−291) of the mitochondrial isoleucyl tRNA synthetase gene (IleRS-A), coded in nuclear DNA, was altered in 59% of the tumors, whereas (A)9 in the 5′ upstream region (position −859∼−851) of cytoplasmic isoleucyl tRNA synthetase gene (IleRS-B) was not altered. Alteration at repeated sequences in the coding regions were 72% at TGFβRII(A)10, 24% at IGFIIR(G)8, 45% at BAX(G)8, 55% at E2F4(CAG)13, 66% at caspase-5 (A)10, 31% at MBD4(A)10, 55% at hMSH3(A)8 and 34% at hMSH6(C)8. The number of altered genes increased with the advancement of carcinoma according to Dukes categories: mean numbers of altered genes within these 10 genes were 2.6 for Dukes A, 4.7 for Dukes B and 7.8 for Dukes C. The mean number for adenomas was 2.0. These results suggest that the MSI phenotype also causes alteration of 5′ upstream regions which may affect apoptosis and some mitochondrial functions in HNPCC and Turcot tumors, and that accumulation of altered genes with repeated sequences is associated with the progression of HNPCC and Turcot colorectal tumors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aaltonen LA, Petromäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin J-P, Järvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A . 1993 Science 260: 812–816
Aki T, Yanagisawa S, Akanuma H . 1997 J. Biochem. 122: 271–278
Ercolani L, Florence B, Denaro M, Alexander M . 1988 J. Biol. Chem. 263: 15335–15341
Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner G . 1993 Cell 75: 1027–1038
Ionov Y, Peinado MA, Malkosyan S, Shibata D, Perucho M . 1993 Nature 363: 558–561
Kamada S, Funahashi Y, Tsujimoto Y . 1997 Cell Death Differ. 4: 473–478
Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Konishi F, Utsunomiya J, Miyaki M . 1996 Gastroenterology 111: 307–317
Leach FS, Nicolaidis NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M, Guan XY, Zang Z, Meltzer PS, Yu JW, Kao FT, Chen DJ, Cerosalitti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin JP, Jarvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B . 1993 Cell 75: 1215–1225
Lynch HT, Smyrk T . 1996 Cancer 78: 1149–1167
Malkhosyan S, Rampino N, Yamamoto H, Perucho M . 1996 Nature 382: 499–500
Markovitz S, Wang J, Myeroff L, Parsons R, Sun L-Z, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, Brattain M, Willson JKV . 1995 Science 268: 1336–1338
Miyaki M, Konishi M, Muraoka M, Kikuchi-Yanoshita R, Tanaka K, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Utsunomiya J . 1995 J. Mol. Med. 73: 515–520
Miyaki M, Nishio J, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Nagato M, Chong J-M, Koike M, Terada T, Kawahara Y, Fukutome A, Tomiyama J, Chuganji Y, Momoi M, Utsunomiya J . 1997a Oncogene 15: 2877–2881
Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T . 1997b Nat. Genet. 17: 271–272
Miyashita T, Reed JC . 1995 Cell 80: 293–299
Rampino N, Yamamoto H, Ionov Y, Li Y, Wawai H, Reed JC, Perucho M . 1997 Science 275: 967–969
Riccio A, Aaltonen LA, Godwin AK, Loukola A, Peresepe A, Salovaara R, Masciullo V, Genuardi M, Paravatou-Petsotas M, Bassi DE, Ruggeri BA, Klein-Szanto AJP, Testa JR, Neri G, Ballacosa A . 1999 Nature Genetics 23: 266–268
Sawa A, Khan AA, Hester LD, Synder SH . 1997 Proc. Natl. Acad. Sci. USA 94: 11669–11674
Schwartz Jr S, Yamamoto H, Navarro M, Maestro M, Reventos J, Perucho M . 1999 Cancer Res. 59: 2995–3002
Shiba K, Suzuki N, Shigesada K, Namba Y, Shimmel P, Noda T . 1994 Proc. Natl. Acad. Sci. USA 91: 7435–7439
Souza RF, Apple R, Yin J, Wang S, Smolinski KN, Abraham JM, Zou T-T, Shi Y-Q, Lei J, Cottrell J, Cymes K, Biden K, Simms L, Leggett B, Lynch PM, Frazier M, Powell SM, Harpaz N, Sugimura H, Young J, Meltzer SJ . 1996 Nat. Genet. 14: 255–257
Thibodeau SN, Bren G, Schaid D . 1993 Science 260: 816–819
Yoshitaka T, Matsubara N, Ikeda M, Tanino M, Hanafusa H, Tanaka N, Shimizu K . 1996 Biochem. Biophys. Res. Commun. 227: 553–557
Acknowledgements
This work was supported in part by the Project ‘High-Technology Research Center' from Ministry of Education, Science, Sport and Culture of Japan, and Smoking Research Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Miyaki, M., Iijima, T., Shiba, K. et al. Alterations of repeated sequences in 5′ upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome. Oncogene 20, 5215–5218 (2001). https://doi.org/10.1038/sj.onc.1204578
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204578
Keywords
This article is cited by
-
Functional and pathologic association of aminoacyl-tRNA synthetases with cancer
Experimental & Molecular Medicine (2022)
-
Knockdown of IARS2 suppressed growth of gastric cancer cells by regulating the phosphorylation of cell cycle-related proteins
Molecular and Cellular Biochemistry (2018)
-
Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation
British Journal of Cancer (2015)
-
Predicting sub-cellular localization of tRNA synthetases from their primary structures
Amino Acids (2012)