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:

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

Oncogene volume 18, pages 7527–7534 (1999)Cite this article

Abstract

Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three `differentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allele-specific DNA methylation was identified spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-specific differential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other differential methylation was identified. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-specific methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately influence imprinting.

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
Figure 4

Similar content being viewed by others

Abbreviations

IGF2 :

insulin-like growth factor 2

kb:

kilobase

PCR:

polymerase chain reaction

dmr:

differentially methylated region

LOI:

loss of imprinting

LOH:

loss of heterozy-gosity

References

  • Church GM and Gilbert W. . 1984 Proc. Natl. Acad. Sci. USA 81: 1991–1995.

  • Cui HM, Horon IL, Ohlsson R, Hamilton SR and Feinberg AP. . 1998 Nat. Med. 4: 1276–1280.

  • Douc-Rasy S, Barrois M, Fogel S, Ahomadegbe JC, Stehelin D, Coll J and Riou G. . 1996 Oncogene 12: 423–430.

  • Efstratiadis A. . 1994 Curr. Opin. Genet. Dev. 4: 265–280.

  • Eversole-Cire P, Ferguson-Smith AC, Sasaki H, Brown KD, Cattanach BM, Gonzales FA, Surani AM and Jones PA. . 1993 Mol. Cell. Biol. 13: 4928–4938.

  • Feil R, Walter J, Allen ND and Reik W. . 1994 Development 120: 2933–2943.

  • Giannoukakis N, Deal C, Paquette J, Goodyer CG and Polychronakos C. . 1993 Nat. Genet. 4: 98–101.

  • Goshen R, Rachmilewitz J, Schneider T, De-Groot N, Ariel I, Palti Z and Hochberg AA. . 1993 Mol. Reprod. Devel. 34: 374–379.

  • Hashimoto K, Azuma C, Koyama M, Ohashi K, Kamiura S, Nobunaga T, Kimura T, Tokugawa Y, Kanai T and Saji F. . 1995 Nat. Genet. 9: 109–110.

  • Hashimoto K, Azuma C, Tokugawa Y, Nobunaga T, Aki TA, Matsui Y, Yanagida T, Izumi H, Saji F and Murata Y. . 1997 Hum. Pathol. 28: 862–865.

  • Hibi K, Nakamura H, Hirai A, Fujikake Y, Kasai Y, Akiyama S, Ito K and Takagi H. . 1996 Cancer Res. 56: 480–482.

  • Hu JF, Nguyen PH, Pham NV, Vu TH and Hoffman AR. . 1997a Mol. Endocrinol. 11: 1891–1898.

  • Hu JF, Vu TH and Hoffman AR. . 1997b J. Biol. Chem. 272: 20715–20720.

  • Issa JP, Vertino PM, Boehm CD, Newsham IF and Baylin SB. . 1996 Proc. Natl. Acad. Sci. USA 93: 11757–11762.

  • Joyce JA, Lam WK, Catchpoole DJ, Jenks P, Reik W, Maher ER and Schofield PN. . 1997 Hum. Mol. Genet. 6: 1543–1548.

  • Kim KS and Lee YI. . 1997 Cancer Lett. 119: 143–148.

  • Kirillov A, Kistler B, Mostoslavsky R, Cedar H, Wirth T and Bergman Y. . 1996 Nat. Genet. 13: 435–441.

  • Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A and Tilghman SM. . 1995a Nature 375: 34–39.

  • Leighton PA, Saam JR, Ingram RS, Stewart CL and Tilghman SM. . 1995b Genes Dev. 9: 2079–2089.

  • Li E, Beard C and Jaenisch R. . 1993 Nature 366: 362–365.

  • McCann AH, Miller N, O'Meara A, Pedersen I, Keogh K, Gorey T and Dervan PA. . 1996 Hum. Mol. Genet. 5: 1123–1127.

  • Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H and Reik W. . 1997 Proc. Natl. Acad. Sci. USA 94: 12509–12514.

  • Morison IM, Becroft DM, Taniguchi T, Woods CG and Reeve AE. . 1996 Nat. Med. 2: 311–316.

  • Moulton T, Crenshaw T, Hao Y, Moosikasuwan J, Lin N, Dembitzer F, Hensle T, Weiss L, McMorrow L, Loew T and et al. 1994 Nat. Genet. 7: 440–447.

  • Mummaneni P, Bishop PL and Turker MS. . 1993 J. Biol. Chem. 268: 552–558.

  • Mummaneni P, Walker KA, Bishop PL and Turker MS. . 1995 J. Biol. Chem. 270: 788–792.

  • Nonomura N, Miki T, Nishimura K, Kanno N, Kojima Y and Okuyama A. . 1997 J. Urol. 157: 1977–1979.

  • Oda H, Kume H, Shimizu Y, Inoue T and Ishikawa T. . 1998 Int. J. Cancer. 75: 343–346.

  • Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ and Reeve AE. . 1993 Nature 362: 749–751.

  • Ohlsson R, Nystrom A, Pfeifer-Ohlsson S, Tohonen V, Hedborg F, Schofield P, Flam F and Ekstrom TJ. . 1993 Nat. Genet. 4: 94–97.

  • Okamoto K, Morison IM, Taniguchi T and Reeve AE. . 1997 Proc. Natl. Acad. Sci. USA 94: 5367–5371.

  • Pedone PV, Tirabosco R, Cavazzana AO, Ungaro P, Basso G, Luksch R, Carli M, Bruni CB, Frunzio R and Riccio A. . 1994 Hum. Mol. Genet. 3: 1117–1121.

  • Rainier S, Dobry CJ and Feinberg AP. . 1995 Cancer Res. 55: 1836–1838.

  • Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE and Feinberg AP. . 1993 Nature 362: 747–749.

  • Randhawa GS, Cui H, Barletta JA, Strichman-Almashanu LZ, Talpaz M, Kantarjian H, Deisseroth AB, Champlin RC and Feinberg AP. . 1998 Blood 91: 3144–3147.

  • Reeve AE, Eccles MR, Wilkins RJ, Bell GI and Millow LJ. . 1985 Nature 317: 258–260.

  • Reik W, Brown KW, Schneid H, Le Bouc Y, Bickmore W and Maher ER. . 1995 Hum. Mol. Genet. 4: 2379–2385.

  • Reik W, Brown KW, Slatter RE, Sartori P, Elliott M and Maher ER. . 1994 Hum. Mol. Genet. 3: 1297–1301.

  • Sasaki H, Jones PA, Chaillet JR, Ferguson-Smith AC, Barton SC, Reik W and Surani MA. . 1992 Genes Dev. 6: 1843–1856.

  • Schneid H, Seurin D, Vazquez M-P, Gourmelen M, Cabrol S, Le Bouc Y. . 1993 J. Med. Genet. 30: 353–362.

  • Steenman MJ, Rainier S, Dobry CJ, Grundy P, Horon IL and Feinberg AP. . 1994 Nat. Genet. 7: 433–439.

  • Suzuki H, Veda R and Takahashi T. . 1994 Nat. Genet. 6: 332–333.

  • Taniguchi T, Schofield AE, Scarlett JL, Morison IM, Sullivan MJ and Reeve AE. . 1995a Oncogene 11: 751–756.

  • Taniguchi T, Sullivan MJ, Ogawa O and Reeve AE. . 1995b Proc. Natl. Acad. Sci. USA 92: 2159–2163.

  • van Gurp RJ, Oosterhuis JW, Kalscheuer V, Mariman EC and Looijenga LH. . 1994 J. Natl. Cancer Inst. 86: 1070–1075.

  • Vu TH and Hoffman A. . 1996 J. Biol. Chem. 271: 9014–9023.

  • Weksberg R, Teshima I, Williams BR, Greenberg CR, Pueschel SM, Chernos JE, Fowlow SB, Hoyme E, Anderson IJ, Whiteman DA, et al. 1993 Hum. Mol. Genet. 2: 549–556.

  • Wu HK, Weksberg R, Minden MD and Squire JA. . 1997 Biochem. Biophys. Res. Commun. 231: 466–472.

  • Zhan S, Shapiro DN and Helman LJ. . 1994 J. Clin. Invest. 94: 445–448.

  • Zhang Y, Shields T, Crenshaw T, Hao Y, Moulton T and Tycko B. . 1993 Am. J. Hum. Genet. 53: 113–124.

Download references

Acknowledgements

We thank Michael Eccles, Mathias Frevel, Ian Morison, Parry Guilford and Keisei Okamoto for valuable comments. Dr E Holthuizen kindly provided the IGF2 cosmid. MJ Sullivan was a recipient of the Air New Zealand Cancer Research Repatriation Fellowship. This work was supported by the Health Research Council of New Zealand, New Zealand Lottery Grants Board, and the Cancer Society of New Zealand. Accession numbers GENBANK U80849, U80850, U80851.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Cancer Genetics Laboratory, University of Otago, PO Box 56, Dunedin, New Zealand

    Michael J Sullivan, Takanobu Taniguchi, Agnes Jhee, Natalie Kerr & Anthony E Reeve

Authors
  1. Michael J Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takanobu Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Agnes Jhee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalie Kerr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony E Reeve
    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

Sullivan, M., Taniguchi, T., Jhee, A. et al. Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 18, 7527–7534 (1999). https://doi.org/10.1038/sj.onc.1203096

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203096

Keywords

This article is cited by

Search

Advanced search

Quick links