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:

Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice

Oncogene volume 24, pages 7924–7934 (2005)Cite this article

Abstract

Although radiation can directly induce DNA damage and is a known human and animal carcinogen, the number of genetic changes in radiation-induced tumors, and the pathways responsible for generating them, are unknown. We have used high-density BAC arrays covering >95% of the mouse genome for analysis of genomic patterns of aberrations in spontaneous and radiation-induced mouse lymphomas. The majority of radiation-induced tumors exhibit one of three ‘signatures’ based on gene copy number changes. Some exhibit extensive scrambling of the genome, with very high numbers of recurrent gains and losses. Two other signatures are characterized by excess gains but relatively few losses, or vice versa. Changes in spontaneous tumors often involve whole chromosomes, whereas radiation-induced tumors exhibit a high frequency of localized deletion/amplification events. The number of copy number abnormalities does not correlate with the latency or pathology of the tumors. We propose that specific early events following radiation exposure induce changes in ‘caretaker’ genes that control specific downstream pathways involved in DNA damage repair. The nature of these early events may determine the overall genomic signature observed in the resulting tumor.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  • Albertson DG . (2003). Breast Cancer Res. Treat., 78, 289–298.

  • Albertson DG, Collins C, McCormick F and Gray JW . (2003). Nat. Genet., 34, 369–376.

  • Alitalo K, Koskinen P, Makela TP, Saksela K, Sistonen L and Winqvist R . (1987). Biochim. Biophys. Acta, 907, 1–32.

  • Azzam EI, de Toledo SM and Little JB . (2003). Oncogene, 22, 7050–7057.

  • Bouffler SD, Kemp CJ, Balmain A and Cox R . (1995). Cancer Res., 55, 3883–3889.

  • Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, Lubin JH, Preston DL, Preston RJ, Puskin JS, Ron E, Sachs RK, Samet JM, Setlow RB and Zaider M . (2003). Proc. Natl. Acad. Sci. USA, 100, 13761–13766.

  • Cai WW, Mao JH, Chow CW, Damani S, Balmain A and Bradley A . (2002). Nat. Biotechnol., 20, 393–396.

  • Ferguson DO and Alt FW . (2001). Oncogene, 20, 5572–5579.

  • Fukasawa K, Choi T, Kuriyama R, Rulong S and Vande Woude GF . (1996). Science, 271, 1744–1747.

  • Gregory SG, Sekhon M, Schein J, Zhao S, Osoegawa K, Scott CE, Evans RS, Burridge PW, Cox TV, Fox CA, Hutton RD, Mullenger IR, Phillips KJ, Smith J, Stalker J, Threadgold GJ, Birney E, Wylie K, Chinwalla A, Wallis J, Hillier L, Carter J, Gaige T, Jaeger S, Kremitzki C, Layman D, Maas J, McGrane R, Mead K, Walker R, Jones S, Smith M, Asano J, Bosdet I, Chan S, Chittaranjan S, Chiu R, Fjell C, Fuhrmann D, Girn N, Gray C, Guin R, Hsiao L, Krzywinski M, Kutsche R, Lee SS, Mathewson C, McLeavy C, Messervier S, Ness S, Pandoh P, Prabhu AL, Saeedi P, Smailus D, Spence L, Stott J, Taylor S, Terpstra W, Tsai M, Vardy J, Wye N, Yang G, Shatsman S, Ayodeji B, Geer K, Tsegaye G, Shvartsbeyn A, Gebregeorgis E, Krol M, Russell D, Overton L, Malek JA, Holmes M, Heaney M, Shetty J, Feldblyum T, Nierman WC, Catanese JJ, Hubbard T, Waterson RH, Rogers J, de Jong PJ, Fraser CM, Marra M, McPherson JD and Bentley DR . (2002). Nature, 418, 743–750.

  • Hande MP, Azizova TV, Geard CR, Burak LE, Mitchell CR, Khokhryakov VF, Vasilenko EK and Brenner DJ . (2003). Am. J. Hum. Genet., 72, 1162–1170.

  • Hodgson G, Hager JH, Volik S, Hariono S, Wernick M, Moore D, Nowak N, Albertson DG, Pinkel D, Collins C, Hanahan D and Gray JW . (2001). Nat. Genet., 29, 459–464.

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M . (1993). Nature, 363, 558–561.

  • Jallepalli PV and Lengauer C . (2001). Nat. Rev. Cancer, 1, 109–117.

  • Jones PA and Baylin SB . (2002). Nat. Rev. Genet., 3, 415–428.

  • Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ and Wright EG . (1992). Nature, 355, 738–740.

  • Kemp CJ, Wheldon T and Balmain A . (1994). Nat. Genet., 8, 66–69.

  • Kennedy AR, Cairns J and Little JB . (1984). Nature, 307, 85–86.

  • Kennedy AR and Little JB . (1984). Radiat. Res., 99, 228–248.

  • Khanna KK and Jackson SP . (2001). Nat. Genet., 27, 247–254.

  • Kinzler KW and Vogelstein B . (1997). Nature, 386, 761–763.

  • Liyanage M, Weaver Z, Barlow C, Coleman A, Pankratz DG, Anderson S, Wynshaw-Boris A and Ried T . (2000). Blood, 96, 1940–1946.

  • Loeb LA, Springgate CF and Battula N . (1974). Cancer Res., 34, 2311–2321.

  • Mao JH, Wu D, Perez-Losada J, Nagase H, DelRosario R and Balmain A . (2003). Oncogene, 22, 8379–8385.

  • Mao JH, Perez-Losada J, Wu D, Delrosario R, Tsunematsu R, Nakayama KI, Brown K, Bryson S and Balmain A . (2004). Nature, 432, 775–779.

  • Marx J . (2002). Science, 297, 544–546.

  • Mills KD, Ferguson DO and Alt FW . (2003). Immunol. Rev., 194, 77–95.

  • Mitelman Database of Chromosome Aberrations in Cancer. (2005). Mitelman F, Johansson B and Mertens F (eds), http://cgap.nci.nih.gov/Chromosomes/Mitelman.

  • Okano H, Saito Y, Miyazawa T, Shinbo T, Chou D, Kosugi S, Takahashi Y, Odani S, Niwa O and Kominami R . (1999). Oncogene, 18, 6677–6683.

  • Peterson LE . (2002). Comput. Meth. Prog. Biomed., 69, 179–188.

  • Rajagopalan H, Nowak MA, Vogelstein B and Lengauer C . (2003). Nat. Rev. Cancer, 3, 695–701.

  • Saito Y, Ochiai Y, Kodama Y, Tamura Y, Togashi T, Kosugi-Okano H, Miyazawa T, Wakabayashi Y, Hatakeyama K, Wakana S, Niwa O and Kominami R . (2001). Oncogene, 20, 5243–5247.

  • Sieber OM, Heinimann K and Tomlinson IP . (2003). Nat. Rev. Cancer, 3, 701–708.

  • Sigurdson AJ and Jones IM . (2003). Oncogene, 22, 7018–7027.

  • Thibodeau SN, Bren G and Schaid D . (1993). Science, 260, 816–819.

  • Uno M, Wirschubsky Z, Babonits M, Wiener F, Sumegi J and Klein G . (1987). Int. J. Cancer, 40, 540–549.

  • Volik S, Zhao S, Chin K, Brebner JH, Herndon DR, Tao Q, Kowbel D, Huang G, Lapuk A, Kuo WL, Magrane G, De Jong P, Gray JW and Collins C . (2003). Proc. Natl. Acad. Sci. USA, 100, 7696–7701.

  • Watson GE, Lorimore SA, Clutton SM, Kadhim MA and Wright EG . (1997). Int. J. Radiat. Biol., 71, 497–503.

Download references

Acknowledgements

These studies were initially supported by the Commission of the European Communities and the Cancer Research Campaign (UK), and subsequently by NCI Grant U01 CA84244 and a Grant DE-FG02-03ER63630 from the DOE to AB. Special thanks to the CRC Beatson Institute animal house staff for help with animal husbandry. Dr Jian-Hua Mao is the recipient of a Leukemia & Lymphoma Society Fellowship. Dr Jesus Perez-Losada has a Fellowship from the ‘Ministerio de Educacion y Ciencia of Spain’.

Author information

Author notes

  1. Jiang-Hua Mao and Jiangzhen Li: These two authors contributed equally to this work

Authors and Affiliations

  1. Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, 94143, CA, USA

    Jiang-Hua Mao, Di Wu, Jesus Perez-Losada, Reyno DelRosario & Allan Balmain

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm T936, Houston, 77030, TX

    Jiangzhen Li, Tao Jiang, Qian Li & Wei-Wen Cai

  3. USA,

    Jiangzhen Li, Tao Jiang, Qian Li & Wei-Wen Cai

  4. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Rm T936, Houston, 77030, TX, USA

    Leif Peterson

Authors
  1. Jiang-Hua Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiangzhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Di Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jesus Perez-Losada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reyno DelRosario
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leif Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Allan Balmain
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei-Wen Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Allan Balmain or Wei-Wen Cai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mao, JH., Li, J., Jiang, T. et al. Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice. Oncogene 24, 7924–7934 (2005). https://doi.org/10.1038/sj.onc.1208926

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208926

Keywords

This article is cited by

Search

Advanced search

Quick links