Abstract
DNA mismatch repair deficiency is observed in about 15% of human colorectal, gastric, and endometrial tumors and in lower frequencies in a minority of other tumors thereby causing insertion/deletion mutations at short repetitive sequences, recognized as microsatellite instability (MSI). Evolution of tumors, including those with MSI, is a continuous process of mutation and selection favoring neoplastic growth. Mutations in microsatellite-bearing genes that promote tumor cell growth in general (Real Common Target genes) are assumed to be the driving force during MSI carcinogenesis. Thus, microsatellite mutations in these genes should occur more frequently than mutations in microsatellite genes without contribution to malignancy (ByStander genes). So far, only a few Real Common Target genes have been identified by functional studies. Thus, comprehensive analysis of microsatellite mutations will provide important clues to the understanding of MSI-driven carcinogenesis. Here, we evaluated published mutation frequencies on 194 repeat tracts in 137 genes in MSI-H colorectal, endometrial, and gastric carcinomas and propose a statistical model that aims to identify Real Common Target genes. According to our model nine genes including BAX and TGFβRII were identified as Real Common Targets in colorectal cancer, one gene in gastric cancer, and three genes in endometrial cancer. Microsatellite mutations in five additional genes seem to be counterselected in gastrointestinal tumors. Overall, the general applicability, the capacity to unlimited data analysis, the inclusion of mutation data generated by different groups on different sets of tumors make this model a useful tool for predicting Real Common Target genes with specificity for MSI-H tumors of different organs, guiding subsequent functional studies to the most likely targets among numerous microsatellite harboring genes.
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Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J and Hamilton SR . (1993). Science, 260, 812–816.
Bicknell DC, Kaklamanis L, Hampson R, Bodmer WF and Karran P . (1996). Curr. Biol., 6, 1695–1697.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava S . (1998). Cancer Res., 58, 5248–5257.
Chadwick RB, Jiang GL, Bennington GA, Yuan B, Johnson CK, Stevens MW, Niemann TH, Peltomaki P, Huang S and de la Chapelle A . (2000). Proc. Natl. Acad. Sci. USA, 97, 2662–2667.
Duval A, Gayet J, Zhou XP, Iacopetta B, Thomas G and Hamelin R . (1999). Cancer Res., 59, 4213–4215.
Duval A, Rolland S, Compoint A, Tubacher E, Iacopetta B, Thomas G and Hamelin R . (2001). Hum. Mol. Genet., 10, 513–518.
Duval A and Hamelin R . (2002). Cancer Res., 62, 2447–2454.
Duval A, Reperant M, Compoint A, Seruca R, Ranzani GN, Iacopetta B and Hamelin R . (2002). Cancer Res., 62, 1609–1612.
Hediger MA . (2002). Nat. Med., 8, 445–446.
Huet S, Bouvier A, Gruet M and Jolivet E . (1996). Statistical tools for nonlinear regression. A Practical Guide with δ-Plus Examples. Springer, New York.
Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M . (1993). Nature, 363, 558–561.
Ionov Y, Yamamoto H, Krajewski S, Reed JC and Perucho M . (2000). Proc. Natl. Acad. Sci. USA, 97, 10872–10877.
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 and Miyaki M . (1996). Gastroenterology, 111, 307–317.
Kunkel TA and Bebenek K . (2000). Annu. Rev. Biochem., 69, 497–529.
Lengauer C, Kinzler KW and Vogelstein B . (1997). Nature, 386, 623–627.
Lengauer C, Kinzler KW and Vogelstein B . (1998). Nature, 396, 643–649.
Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI and Thibodeau SN . (2000). Nat. Genet., 26, 146–147.
Loeb LA . (2001). Cancer Res., 61, 3230–3239.
Malkhosyan S, Rampino N, Yamamoto H and Perucho M . (1996). Nature, 382, 499–500.
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW and Vogelstein B . (1995). Science, 268, 1336–1338.
Mignone F, Gissi C, Liuni, S and Pesole G . (2002). Genome Biol., 3, REVIEWS0004, 1–10.
Mori Y, Yin J, Rashid A, Leggett BA, Young J, Simms L, Kuehl PM, Langenberg P, Meltzer SJ and Stine OC . (2001). Cancer Res., 61, 6046–6049.
Myeroff LL, Parsons R, Kim SJ, Hedrick L, Cho KR, Orth K, Mathis M, Kinzler KW, Lutterbaugh J and Park K . (1995). Cancer Res., 55, 5545–5547.
O'Donnell M, Jeruzalmi D and Kuriyan J . (2001). Curr. Biol., 11, R935–R946.
Perucho M, Peinado MA, Ionov Y, Casares S, Malkhosyan S and Stanbridge E . (1994). Cold Spring Harb. Symp. Quant. Biol., 59, 339–348.
Perucho M . (1999). Cancer Res., 59, 249–256.
Piao Z, Fang W, Malkhosyan S, Kim H, Horii A, Perucho M and Huang S . (2000). Cancer Res., 60, 4701–4704.
Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC and Perucho M . (1997). Science, 275, 967–969.
Sagher D, Hsu A and Strauss B . (1999). Mutat. Res., 423, 73–77.
Sakurada K, Furukawa T, Kato Y, Kayama T, Huang S and, Horii A . (2001). Genes Chromosomes Cancer, 30, 207–211.
Schwartz Jr S, Yamamoto H, Navarro M, Maestro M, Reventos J and Perucho M . (1999). Cancer Res., 59, 2995–3002.
Sia EA, Kokoska RJ, Dominska M, Greenwell P and Petes TD . (1997). Mol. Cell. Biol., 17, 2851–2858.
Sotiriou S, Gispert S, Cheng J, Wang Y, Chen A, Hoogstraten-Miller S, Miller GF, Kwon O, Levine M, Guttentag SH and Nussbaum RL . (2002). Nat. Med., 8, 514–517.
Souza RF, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, Zou TT, Shi YQ, Lei J, Cottrell J, Cymes K, Biden K, Simms L, Leggett B, Lynch PM, Frazier M, Powell SM, Harpaz N, Sugimura H, Young J and Meltzer SJ . (1996). Nat. Genet., 14, 255–257.
Souza RF, Wang S, Thakar M, Smolinski KN, Yin J, Zou TT, Kong D, Abraham JM, Toretsky JA and Meltzer SJ . (1999). Oncogene, 18, 4063–4068.
Thibodeau SN, Bren G and Schaid D . (1993). Science, 260, 816–819.
Woerner SM, Gebert J, Yuan YP, Sutter C, Ridder R, Bork P and von Knebel Doeberitz M . (2001). Int. J. Cancer, 93, 12–19.
Zhang L, Yu J, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B . (2001). Cancer Res., 61, 3801–3805. References of Supplemental Tables (available at http://www.med.uni-heidelberg.de/patho/pathomol/woerner/model_real_targets/)
Acknowledgements
We thank J Lacroix for helpful discussion and critical reading of the manuscript, and G Dallenbach-Hellweg for kindly providing endometrium carcinoma tissues. Technical assistance is acknowledged to G Russel, S Bielau, and B Kuchenbuch. Financial support was obtained from the Deutsche Krebshilfe and from the Verein zur Foerderung der Krebsforschung in Deutschland e.V. This article is dedicated to Harald zur Hausen on the occasion of his retirement as head of the German Cancer Research Center.
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Woerner, S., Benner, A., Sutter, C. et al. Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene 22, 2226–2235 (2003). https://doi.org/10.1038/sj.onc.1206421
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DOI: https://doi.org/10.1038/sj.onc.1206421
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