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High expression of DNA repair pathways is associated with metastasis in melanoma patients

Oncogene volume 27, pages 565–573 (2008)Cite this article

Abstract

We have identified a gene-profile signature for human primary malignant melanoma associated with metastasis to distant sites and poor prognosis. We analyse the differential gene expression by looking at whole biological pathways rather than individual genes. Among the most significant pathways associated with progression to metastasis, we found the DNA replication (P=10−14) and the DNA repair pathways (P=10−16). We concentrated our analysis on DNA repair and found that 48 genes of this category, among a list of 234 genes, are associated with metastatic progression. These genes belong essentially to the pathways allowing recovery of stalled replication forks due to spontaneous blockage or induced DNA lesions. Because almost all these differentially expressed repair genes were overexpressed in primary tumors with bad prognosis, we speculate that primary melanoma cells that will metastasize try to replicate in a fast and error-free mode. In contrast to the progression from melanocytes to primary melanoma, genetic stability appears to be necessary for a melanoma cell to give rise to distant metastasis. This overexpression of repair genes explains nicely the extraordinary resistance of metastatic melanoma to chemo- and radio-therapy. Our results may open a new avenue for the discovery of drugs active on human metastatic melanoma.

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References

  • Armstrong BK, Kricker A . (2001). The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63: 8–18.

    Article  CAS  Google Scholar 

  • Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. (2000). Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25: 25–29.

    Article  CAS  PubMed  Google Scholar 

  • Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N et al. (2001). Prognostic factors analysis of 17 600 melanoma patients: validation of the American joint committee on cancer melanoma staging system. J Clin Oncol 19: 3622–3634.

    Article  CAS  PubMed  Google Scholar 

  • Bastian BC, Olshen AB, LeBoit PE, Pinkel D . (2003). Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 163: 1765–1770.

    Article  CAS  PubMed  Google Scholar 

  • Bernal JA, Luna R, Espina A, Lazaro I, Ramos-Morales F, Romero F et al. (2002). Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet 32: 306–311.

    Article  CAS  PubMed  Google Scholar 

  • Bradshaw PS, Stavropoulos DJ, Meyn MS . (2005). Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat Genet 37: 193–197.

    Article  CAS  PubMed  Google Scholar 

  • Burden DA, Osheroff N . (1998). Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1400: 139–154.

    Article  CAS  PubMed  Google Scholar 

  • Chin L, Garraway LA, Fisher DE . (2006). Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev 20: 2149–2182.

    Article  CAS  PubMed  Google Scholar 

  • Costa RH . (2005). FoxM1 dances with mitosis. Nat Cell Biol 7: 108–110.

    Article  CAS  PubMed  Google Scholar 

  • Dyrskjot L, Thykjaer T, Kruhoffer M, Jensen JL, Marcussen N, Hamilton-Dutoit S et al. (2003). Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 33: 90–96.

    Article  CAS  PubMed  Google Scholar 

  • Eder JP, Chan VT, Ng SW, Rizvi NA, Zacharoulis S, Teicher BA et al. (1995). DNA topoisomerase II alpha expression is associated with alkylating agent resistance. Cancer Res 55: 6109–6116.

    CAS  PubMed  Google Scholar 

  • Gronostajski RM . (2000). Roles of the NFI/CTF gene family in transcription and development. Gene 249: 31–45.

    Article  CAS  PubMed  Google Scholar 

  • Halazonetis TD . (2004). Constitutively active DNA damage checkpoint pathways as the driving force for the high frequency of p53 mutations in human cancer. DNA Repair (Amst) 3: 1057–1062.

    Article  CAS  Google Scholar 

  • Hamid T, Malik MT, Kakar SS . (2005). Ectopic expression of PTTG1/securin promotes tumorigenesis in human embryonic kidney cells. Mol Cancer 4: 1–13.

    Article  Google Scholar 

  • Hoeijmakers JH . (2001). Genome maintenance mechanisms for preventing cancer. Nature 411: 366–374.

    Article  CAS  PubMed  Google Scholar 

  • Howe HL, Wingo PA, Thun MJ, Ries LA, Rosenberg HM, Feigal EG et al. (2001). Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93: 824–842.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Devesa SS, Hartge P, Tucker MA . (2001). Recent trends in cutaneous melanoma incidence among whites in the United States. J Natl Cancer Inst 93: 678–683.

    Article  CAS  PubMed  Google Scholar 

  • Laoukili J, Kooistra MR, Bras A, Kauw J, Kerkhoven RM, Morrison A et al. (2005). FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 7: 126–136.

    Article  CAS  PubMed  Google Scholar 

  • Munoz P, Blanco R, Flores JM, Blasco MA . (2005). XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat Genet 37: 1063–1071.

    Article  CAS  PubMed  Google Scholar 

  • Niida H, Nakanishi M . (2006). DNA damage checkpoints in mammals. Mutagenesis 21: 3–9.

    Article  CAS  PubMed  Google Scholar 

  • O’Donnell RK, Kupferman M, Wei SJ, Singhal S, Weber R, O’Malley B et al. (2005). Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity. Oncogene 24: 1244–1251.

    Article  PubMed  Google Scholar 

  • Rosenquist TA, Zaika E, Fernandes AS, Zharkov DO, Miller H, Grollman AP . (2003). New insights for understanding the transcription-coupled repair pathway. DNA Repair (Amst) 2: 581–591.

    Article  CAS  Google Scholar 

  • Schuur ER, Kruse U, Iacovoni JS, Vogt PK . (1995). Nuclear factor I interferes with transformation induced by nuclear oncogenes. Cell Growth Differ 6: 219–227.

    CAS  PubMed  Google Scholar 

  • Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G et al. (2000). Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20: 1659–1668.

    Article  CAS  PubMed  Google Scholar 

  • Spatz A, Giglia-Mari G, Benhamou S, Sarasin A . (2001). Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum. Cancer Res 61: 2480–2486.

    CAS  PubMed  Google Scholar 

  • Stary A, Sarasin A . (2002). The genetics of the hereditary xeroderma pigmentosum syndrome. Biochimie 84: 49–60.

    Article  CAS  PubMed  Google Scholar 

  • Thompson JF, Scolyer RA, Kefford RF . (2005). Cutaneous melanoma. Lancet 365: 687–701.

    Article  CAS  PubMed  Google Scholar 

  • van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. Nature 415: 530–536.

    Article  Google Scholar 

  • Wang L, Eastmond DA . (2002). Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Environ Mol Mutagen 39: 348–356.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F et al. (2005). Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365: 671–679.

    Article  CAS  PubMed  Google Scholar 

  • Warters RL, Adamson PJ, Pond CD, Leachman SA . (2005). Melanoma cells express elevated levels of phosphorylated histone H2AX foci. J Invest Dermatol 124: 807–817.

    Article  CAS  PubMed  Google Scholar 

  • Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR et al. (2006). Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 98: 472–482.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Institut Gustave Roussy, and particularly Professors Gilbert Lenoir and Thomas Tursz for their constant interest in this work and their financial support. Grants were obtained from the ‘Cancéropole Ile-de–France’ and the INCa (Paris, France). AK got a fellowship from the French Ministry of National Education and Research (University Paris VII Denis Diderot, France). We thank Stefan Michiels and Dr Leela Daya-Grosjean for their critical reading of the manuscript.

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Authors and Affiliations

  1. Laboratory of Genomes and Cancer, FRE2939 CNRS, Gustave-Roussy Institute, Villejuif and University Paris-Sud, Orsay, France

    A Kauffmann, F Rosselli, P Dessen & A Sarasin

  2. Unit of Functional Genomics, Gustave-Roussy Institute, Villejuif, France

    V Lazar

  3. Department of Pathology, University Hospitals of Maastricht, P. Debyelaan 25, Maastricht, HX, The Netherlands

    V Winnepenninckx

  4. Department of Bio-Pathology, Gustave-Roussy Institute, Villejuif, France

    A Mansuet-Lupo & A Spatz

  5. Department of Morphology and Molecular Pathology, University Hospitals, Katholieke Universiteit Leuven (KUL), Leuven, Belgium

    J J van den Oord

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  1. A Kauffmann
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  2. F Rosselli
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  9. A Sarasin
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Corresponding author

Correspondence to A Sarasin.

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Availability: http://www.ebi.ac.uk/arrayexpressE-TABM-1 IGR_ MELANOMA_STUDYE-TABM-2 IGR_MELANOMA_VALID

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Kauffmann, A., Rosselli, F., Lazar, V. et al. High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene 27, 565–573 (2008). https://doi.org/10.1038/sj.onc.1210700

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  • DOI: https://doi.org/10.1038/sj.onc.1210700

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