Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency

Oncogene volume 19, pages 5755–5763 (2000)Cite this article

Abstract

Apc1638N mice, which are heterozygous for a germline mutation in Apc, typically develop three to five spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc1638N with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1−/−Apc1638N animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 deficiency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927–929, 1209–1211 and 1461–1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid β-catenin binding domain and the first Axin-binding SAMP repeat, yielding Apc proteins that are predicted to be deficient in destabilizing β-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 deficiency. This demonstrates a direct effect of Mlh1 deficiency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D and Birchmeier W. . 1998 Science 280: 596–599.

  • Bhattacharyya NP, Skandalis A, Ganesh A, Groden J and Meuth M. . 1994 Proc. Natl. Acad. Sci. USA 91: 6319–6323.

  • Branch P, Hampson R and Karran P. . 1995 Cancer Res. 55: 2304–2309.

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P and Matrisian LM. . 1999 Oncogene 18: 2883–2891.

  • de Wind N, Dekker M, Berns A, Radman M and te Riele H. . 1995 Cell 82: 321–330.

  • Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, Umar A, Kunkel T, Cattoretti G, Chaganti R, Pollard JW, Kolodner RD and Kucherlapati R. . 1996 Cell 85: 1125–1134.

  • Edelmann W, Yang K, Kuraguchi M, Heyer J, Lia M, Kneitz B, Fan K, Brown AM, Lipkin M and Kucherlapati R. . 1999 Cancer Res. 59: 1301–1307.

  • Fishel R and Kolodner RD. . 1995 Curr. Opin. Genet. Dev. 5: 382–395.

  • Fodde R, Edelmann W, Yang K, van LC, Carlson C, Renault B, Breukel C, Alt E, Lipkin M, Khan PM and Kucherlapati R. . 1994 Proc. Natl. Acad. Sci. USA 91: 8969–8973.

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M and White R. . 1991 Cell 66: 589–600.

  • Habraken Y, Sung P, Prakash L and Prakash S. . 1997 Curr. Biol. 7: 790–793.

  • Habraken Y, Sung P, Prakash L and Prakash S. . 1998 J. Biol. Chem. 273: 9837–9841.

  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B and Polakis P. . 1998 Curr. Biol. 8: 573–581.

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW. . 1998 Science 281: 1509–1512.

  • Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ, Wyllie AH, Zheng S, Willson JK, Markowitz SD, Morin P, Kinzler KW, Vogelstein B and Dunlop MG. . 1996 Proc. Natl. Acad. Sci. USA 93: 9049–9054.

  • Joslyn G, Carlson M, Thliveris A, Albertsen H, Gelbert L, Samowitz W, Groden J, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M and White R. . 1991 Cell 66: 601–613.

  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D and et al. 1991 Science 253: 661–665.

  • Kinzler KW and Vogelstein B. . 1996 Cell 87: 159–170.

  • Kitaeva MN, Grogan L, Williams JP, Dimond E, Nakahara K, Hausner P, DeNoble JW, Soballe PW and Kirsch IR. . 1997 Cancer Res. 57: 4478–4481.

  • Kolodner R. . 1996 Genes Dev. 10: 1433–1442.

  • 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.

  • Korinek V, Barker N, Morin PJ, van WD, de WR, Kinzler KW, Vogelstein B and Clevers H. . 1997 Science 275: 1784–1787.

  • Levy DB, Smith KJ, Beazer BY, Hamilton SR, Vogelstein B and Kinzler KW. . 1994 Cancer Res. 54: 5953–5958.

  • Li GM and Modrich P. . 1995 Proc. Natl. Acad. Sci. USA 92: 1950–1954.

  • Marra G and Boland CR. . 1995 J. Natl. Cancer Inst. 87: 1114–1125.

  • Marsischky GT, Filosi N, Kane MF and Kolodner R. . 1996 Genes Dev. 10: 407–420.

  • Matsumine A, Ogai A, Senda T, Okumura N, Satoh K, Baeg G-H, Kawahara T, Kobayashi S, Okada M, Toyoshima K and Akiyama T. . 1996 Science 272: 1020–1023.

  • Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y, Koike M, Shitara N, Iwama T and Kuroki T. . 1999 Cancer Res. 59: 4506–4509.

  • Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Maeda Y, Iwama T, Mishima Y, Mori T and Koike M. . 1994 Cancer Res. 54: 3011–3020.

  • Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T and Nakamura Y. . 1992 Hum. Mol. Genet. 1: 229–233.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW. . 1997 Science 275: 1787–1790.

  • Moser AR, Pitot HC and Dove WF. . 1990 Science 247: 322–324.

  • Munemitsu S, Albert I, Souza B, Rubinfeld B and Polakis P. . 1995 Proc. Natl. Acad. Sci. USA 92: 3046–3050.

  • Munemitsu S, Souza B, Muller O, Albert I, Rubinfeld B and Polakis P. . 1994 Cancer Res. 54: 3676–3681.

  • Nusse R. . 1997 Cell 89: 321–323.

  • Ohzeki S, Tachibana A, Tastumi K and Kato T. . 1997 Carcinogenesis 18: 1127–1133.

  • Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C and Taketo M. . 1995 Proc. Natl. Acad. Sci. USA 92: 4482–4486.

  • Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B and Modrich P. . 1993 Cell 75: 1227–1236.

  • Peifer M, Berg S and Reynolds AB. . 1994 Cell 76: 789–791.

  • Peltomaki P and de la Chapelle A. . 1997 Adv. Cancer Res. 71: 93–119.

  • Polakis P. . 1997 Biochim. Biophys. Acta 1332: F127–F147.

  • Prolla TA, Christie DM and Liskay RM. . 1994a Mol. Cell. Biol. 14: 407–415.

  • Prolla TA, Pang Q, Alani E, Kolodner RD and Liskay RM. . 1994b Science 265: 1091–1093.

  • Rosin-Arbesfeld R, Townsley F and Bienz M. . 2000 Nature 406: 1009–1012.

  • Rubinfeld B, Albert I, Porfiri E, Munemitsu S and Polakis P. . 1997 Cancer Res. 57: 4624–4630.

  • Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S and Polakis P. . 1993 Science 262: 1731–1734.

  • Saparbaev M, Prakash L and Prakash S. . 1996 Genetics 142: 727–736.

  • Shoemaker AR, Haigis KM, Baker SM, Dudley S, Liskay RM and Dove WF. . 2000 Oncogene 19: 2774–2779.

  • Shoemaker AR, Luongo C, Moser AR, Marton LJ and Dove WF. . 1997 Cancer Res. 57: 1999–2006.

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R and Ben-Ze'ev A. . 1999 Proc. Natl. Acad. Sci. USA 96: 5522–5527.

  • Smith KJ, Levy DB, Maupin P, Pollard TD, Vogelstein B and Kinzler KW. . 1994 Cancer Res. 54: 3672–3675.

  • Smits R, Kartheuser A, Jagmohan CS, Leblanc V, Breukel C, de Vries A, van Kranen H, van Krieken J, Williamson S, Edelmann W, Kucherlapati R, Khan P and Fodde R. . 1997 Carcinogenesis 18: 321–327.

  • Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S, Hofland N, van Dijk J, White R, Edelmann W, Kucherlapati R, Khan PM and Fodde R. . 1999 Genes Dev. 13: 1309–1321.

  • Sparks AB, Morin PJ, Vogelstein B and Kinzler KW. . 1998 Cancer Res. 58: 1130–1134.

  • Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C, Gould KA and Dove WF. . 1992 Science 256: 668–670.

  • Su LK, Vogelstein B and Kinzler KW. . 1993 Science 262: 1734–1737.

  • Tetsu O and McCormick F. . 1999 Nature 398: 422–426.

  • Umar A, Risinger JI, Glaab WE, Tindall KR, Barrett JC and Kunkel TA. . 1998 Genetics 148: 1637–1646.

  • Willert K and Nusse R. . 1998 Curr. Opin. Genet. Dev. 8: 95–102.

  • Yang K, Edelmann W, Fan K, Lau K, Kolli VR, Fodde R, Khan PM, Kucherlapati R and Lipkin M. . 1997 J. Exp. Zool. 277: 245–254.

Download references

Acknowledgements

We thank Louise Howe and Keith Brennan for comments on the manuscript. This work was supported by a postdoctoral fellowship from the Cancer Research Foundation of America (to M Karaguchi); an Irma T Hirschl Career Scientist Award (to A Brown); and by funding from NIH grants CA76329 (to W Edelmann), CA67944 and N01-CN-65031 (to M Lipkin and R Karaguchi), CA13330 to Albert Einstein College of Medicine, and CA29502 and CA47207 (to A Brown).

Author information

Authors and Affiliations

  1. Strang Cancer Research Laboratory at The Rockefeller University, 1230 York Avenue, New York, 10021, NY, USA

    Mari Kuraguchi, Kan Yang, Martin Lipkin & Anthony MC Brown

  2. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

    Winfried Edelmann

  3. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

    Raju Kucherlapati

  4. Department of Cell Biology and Anatomy, Weill Medical College of Cornell University, 1300 York Avenue, New York, 10021, NY, USA

    Anthony MC Brown

Authors
  1. Mari Kuraguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Winfried Edelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Lipkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raju Kucherlapati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anthony MC Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuraguchi, M., Edelmann, W., Yang, K. et al. Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency. Oncogene 19, 5755–5763 (2000). https://doi.org/10.1038/sj.onc.1203962

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203962

Keywords

This article is cited by

Search

Advanced search

Quick links