Human Cell

, Volume 19, Issue 1, pp 17–23 | Cite as

Large DNA palindromes as a common form of structural chromosome aberrations in human cancers

  • Hisashi Tanaka
  • Donald A. Bergstrom
  • Meng-Chao Yao
  • Stephen J. Tapscott
Feature: Gene Diagnosis — Treatment of Carcinoma


Breakage-fusion-bridge cycles contribute to chromosome aberrations and generate large DNA palindromes that facilitate oncogene amplification in cancer cells. At the molecular level, large DNA palindrome formation is initiated by chromosome breaks, and genomic architecture such as short inverted repeat sequences facilitates this process in mammalian cells. However, the prevalence of DNA palindromes in cancer cells is currently unknown. To determine the prevalence of DNA palindromes in human cancer cells, we have developed a new microarray-based approach called Genome-wide Analysis of Palindrome Formation (GAPF, Tanaka et al., Nat Genet 2005; 37: 320–7). This approach is based on a relatively simple and efficient method to purify “snap-back DNA” from large DNA palindromes by intramolecular base-pairing, followed by elimination of single-stranded DNA by nuclease S1. Comparison of Genome-wide Analysis of Palindrome Formation profiles between cancer and normal cells using microarray can identify genome-wide distributions of somatic palindromes. Using a human cDNA microarray, we have shown that DNA palindromes occur frequently in human cancer cell lines and primary medulloblastomas. Significant overlap of the loci containing DNA palindromes between Colo320DM and MCF7 cancer cell lines suggests regions in the genome susceptible to chromosome breaks and palindrome formation. A subset of loci containing palindromes is associated with gene amplification in Colo320DM, indicating that the location of palindromes in the cancer genome serves as a structural platform that supports subsequent gene amplification.

Key words

DNA palindrome GAPF gene amplification genome instability 


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  1. 1.
    Tlsty TD. Genomic instability and its role in neoplasia. Curr Top Microbiol Immunol 1997; 221: 37–46.PubMedGoogle Scholar
  2. 2.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396: 643–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Albertson DG, Collins C, McCormick F, Gray JW. Chromosome aberrations in solid tumors. Nat Genet 2003; 34: 369–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Tanaka H, Tapscott SJ, Trask BJ et al. Short inverted repeats initiate gene amplification through the formation of a large DNA palindrome in mammalian cells. Proc Natl Acad Sci USA 2002; 99: 8772–7.PubMedGoogle Scholar
  5. 5.
    Yasuda LF, Yao MC. Short inverted repeats at a free end signal large palindromic DNA formation in Tetrahymena. Cell 1991; 67: 505–16.CrossRefPubMedGoogle Scholar
  6. 6.
    Butler DK, Yasuda LE, Yao MC. Induction of large DNA palindrome formation in yeast: implications for gene amplification and genome stability in eukaryotes. Cell 1996; 87: 1115–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Toledo F, Le Roscouet D, Buttin G et al. Co-amplified markers alternate in megabase long chromosomal inverted repeats and cluster independently in interphase nuclei at early steps of mammalian gene amplification. EMBO J 1992; 11: 2665–73.PubMedGoogle Scholar
  8. 8.
    Smith KA, Stark MB, Gorman PA, Stark GR. Fusions near telomeres occur very early in the amplification of CAD genes in Syrian hamster cells. Proc Natl Acad Sci USA 1992; 89: 5427–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Ma C, Martin S, Trask B, Hamlin JL. Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes Dev 1993; 7: 605–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M. Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 1997; 89: 215–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Tanaka H, Bergstrom DA, Yao MC, Tapscott SJ. Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification. Nat Genet 2005; 37: 320–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Graf L, Iwata M, Torok-Storb B. Gene expression profiling of the functionally distinct human bone marrow stromal cell lines HS-5 and HS-27a. Blood 2002; 100: 1509–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Ford M, Fried M. Large inverted duplications are associated with gene amplification. Cell 1986; 45: 425–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Swisshelm K, Machl A, Planitzer S, Robertson R, Kubbies M, Hosier S. SEMP1, a senescence-associated cDNA isolated from human mammary epithelial cells, is a member of an epithelial membrane protein superfamily. Gene 1999; 226: 285–95.CrossRefPubMedGoogle Scholar
  16. 16.
    Ruiz JC, Wahl GM. Formation of an inverted duplication can be an initial step in gene amplification. Mol Cell Biol 1988; 8: 4302–13.PubMedGoogle Scholar
  17. 17.
    Shlomit R, Ayala AG, Michal D, et al. Gains and losses of DNA sequences in childhood brain tumors analyzed by comparative genomic hybridization. Cancer Genet Cytogenet 2000; 121: 67–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Michiels EM, Weiss MM, Hoovers JM et al. Genetic alterations in childhood medulloblastoma analyzed by comparative genomic hybridization. J Pediatr Hematol Oncol 2002; 24: 205–10.CrossRefPubMedGoogle Scholar

Copyright information

© Society and Springer Japan 2006

Authors and Affiliations

  • Hisashi Tanaka
    • 1
    • 2
  • Donald A. Bergstrom
    • 3
  • Meng-Chao Yao
    • 1
    • 4
  • Stephen J. Tapscott
    • 2
  1. 1.Division of Basic SciencesUniversity of WashingtonSeattleUSA
  2. 2.Division of Human Biology, Fred Hutchinson Cancer Research CenterUniversity of WashingtonSeattleUSA
  3. 3.Department of Laboratory MedicineUniversity of WashingtonSeattleUSA
  4. 4.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan

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