Clinical and Translational Oncology

, Volume 20, Issue 7, pp 827–836 | Cite as

Clinical implications of the deregulated TP73 isoforms expression in cancer

  • N. Rodríguez
  • A. Peláez
  • R. Barderas
  • G. Domínguez
Review Article
  • 87 Downloads

Abstract

TP73 is a member of the TP53 family whose expression has been observed altered in most human cancers and associated with the prognosis. TP73 translates into a complex number of isoforms with both oncogenic and tumour-suppressor functions and presents a complex cross-talk with other members of the family (TP53 and TP63). In this revision, we focus on the evidence that may support TP73 variants as prognostic markers in cancer. Nowadays, most publications in this topic highlight the association between overexpression of the oncogenic variants and failure to respond to chemotherapy and/or shorter survival. In addition, we comment on the putative possibilities that the detection through a liquid biopsy of TP73 variants may provide, and finally, the significance of determining the value of the combined alteration of the TP53 family members in the clinical setting.

Keywords

TP73 isoforms Cancer Human patients Prognosis Clinical translation 

Notes

Acknowledgements

We acknowledge ISCIII, FIS, FEDER and Cátedra de Patrocinio UAM-Roche for funding our current research through the PI15/00246 Grant and the Grant from the MINECO (SAF2014-53209-R) and CIBERONC.

Compliance with ethical standards

Conflict of interest

We declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Not applicable.

References

  1. 1.
    Amelio I, Inoue S, Markert EK, Levine AJ, Knight RA, Mak TW, et al. TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. Proc Natl Acad Sci USA. 2015;112:226–31.CrossRefPubMedGoogle Scholar
  2. 2.
    Bahnassy AA, Zekri AR, Salem SE, Abou-Bakr AA, Sakr MA, Abdel-Samiaa AG, et al. Differential expression of p53 family proteins in colorectal adenomas and carcinomas: prognostic and predictive values. Histol Histopathol. 2014;29:207–16.PubMedGoogle Scholar
  3. 3.
    Becker K, Pancoska P, Concin N, Vanden Heuvel K, Slade N, Fischer M, et al. Patterns of p73 N-terminal isoform expression and p53 status have prognostic value in gynecological cancers. Int J Oncol. 2006;29:889–902.PubMedGoogle Scholar
  4. 4.
    Casciano I, Mazzocco K, Boni L, Pagnan G, Banelli B, Allemanni G, et al. Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ. 2002;9:246–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Castellino RC, De Bortoli M, Lin LL, Skapura DG, Rajan JA, Adesina AM, et al. Overexpressed TP73 induces apoptosis in medulloblastoma. BMC Cancer. 2007;7:127.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen YK, Huse SS, Lin LM. Differential expression of p53, p63 and p73 proteins in human buccal squamous-cell carcinomas. Clin Otolaryngol Allied Sci. 2003;28:451–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Chen Y, Wang X, Li F, Zhang L, Ma L, Liu Y. Relationship between expression of P27, Fragile Histidine Triad (FHT), phosphatase and tensin homolog deleted on chromosome ten (PTEN), P73, and prognosis in esophageal squamous cell carcinoma. Ann Diagn Pathol. 2015;19:33–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Choi HR, Batsakis JG, Zhan F, Sturgis E, Luna MA, El-Naggar AK. Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis. Hum Pathol. 2002;33:158–64.CrossRefPubMedGoogle Scholar
  9. 9.
    Concin N, Becker K, Slade N, Erster S, Mueller-Holzner E, Ulmer H, et al. Transdominant DeltaTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Res. 2004;64:2449–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Concin N, Hofstetter G, Berger A, Gehmacher A, Reimer D, Watrowski R, et al. Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53–p73 cross-talk in vivo. Clin Cancer Res. 2005;11:8372–83.CrossRefPubMedGoogle Scholar
  11. 11.
    De la Fuente M, Jones M-C, Santander-Ortega MJ, Mirenska A, Marimuthu P, Uchegbu I, et al. A nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer. Nanomedicine. 2015;11:369–77.CrossRefPubMedGoogle Scholar
  12. 12.
    Domínguez G, García JM, Peña C, Silva J, García V, Martínez L, et al. DeltaTAp73 upregulation correlates with poor prognosis in human tumors: putative in vivo network involving p73 isoforms, p53, and E2F-1. J Clin Oncol. 2006;24:805–15.CrossRefPubMedGoogle Scholar
  13. 13.
    Dulloo I, Hooi PB, Sabapathy K. Hypoxia-induced DNp73 stabilization regulates Vegf-A expression and tumor angiogenesis similar to TAp73. Cell Cycle. 2015;14:3533–9.Google Scholar
  14. 14.
    Faridoni-Laurens L, Bosq J, Janot F, Vayssade M, Le Bihan ML, Kaghad M, et al. P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63? Oncogene. 2001;20:5302–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Faridoni-Laurens L, Tourpin S, Alsafadi S, Barrois M, Temam S, Janot F, et al. Involvement of N-terminally truncated variants of p73, deltaTAp73, in head and neck squamous cell cancer: a comparison with p53 mutations. Cell Cycle. 2008;7:1587–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Fatt MP, Cancino GI, Miller FD, Kaplan DR. p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells. Cell Death Differ. 2014;21:1546–59.Google Scholar
  17. 17.
    Fernandez-Alonso R, Martin-Lopez M, Gonzalez-Cano L, Garcia S, Castrillo F, Diez-Prieto I, et al. p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling. Cell Death Differ. 2015;22:1287–99.Google Scholar
  18. 18.
    Ferru A, Denis S, Guilhot J, Gibelin H, Tourani JM, Kraimps JL, et al. Expression of TAp73 and DeltaNp73 isoform transcripts in thyroid tumours. Eur J Surg Oncol. 2006;32:228–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Fillippovich I, Sorokina N, Gatei M, Haupt Y, Hobson K, Moallem E, et al. Transactivation-deficient p73alpha (p73Deltaexon2) inhibits apoptosis and competes with p53. Oncogene. 2001;20:514–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Ganzetti G, Rubini C, Campanati A, Zizzi A, Molinelli E, Rosa L, et al. IL-17, IL-23, and p73 expression in cutaneous melanoma: a pilot study. Melanoma Res. 2015;25:232–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Gonzalez-Cano L, Fuertes-Alvarez S, Robledinos-Anton N, Bizy A, Villena-Cortes A, Fariñas I, et al. p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture. Dev Neurobiol. 2016;76:730–47.Google Scholar
  22. 22.
    Grob TJ, Novak U, Maisse C, Barcaroli D, Lüthi AU, Pirnia F, et al. Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ. 2001;8:1213–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Guan M, Chen Y. Aberrant expression of DeltaNp73 in benign and malignant tumours of the prostate: correlation with Gleason score. J Clin Pathol. 2005;58:1175–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hamdy MS, El-Saadany ZA, Makhlouf MM, Salama AI, Ibrahim NS, Gad AA. TAp73 and ΔNp73 relative expression in Egyptian patients with lymphoid neoplasms. Tumori. 2016;.  https://doi.org/10.5301/tj.5000506.PubMedGoogle Scholar
  25. 25.
    Hong SM, Cho H, Moskaluk CA, Yu E, Zaika AI. p63 and p73 expression in extrahepatic bile duct carcinoma and their clinical significance. J Mol Histol. 2007;38:167–75.CrossRefPubMedGoogle Scholar
  26. 26.
    Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, et al. TBCRC009: a multicenter Phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 2015;33:1902–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T, Ikawa S. Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73. Cancer Res. 2002;62:636–41.PubMedGoogle Scholar
  28. 28.
    Ito Y, Takeda T, Wakasa K, Tsujimoto M, Sakon M, Matsuura N. Expression of p73 and p63 proteins in pancreatic adenocarcinoma: p73 overexpression is inversely correlated with biological aggressiveness. Int J Mol Med. 2001;8:67–71.PubMedGoogle Scholar
  29. 29.
    Ito Y, Uramoto H, Funa K, Yoshida H, Jikuzono T, Asahi S, et al. Delta Np73 expression in thyroid neoplasms originating from follicular cells. Pathology. 2006;38:205–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  31. 31.
    Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997;389:191–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997;90:809–19.Google Scholar
  33. 33.
    Kilic E, Brüggenwirth HT, Meier M, Naus NC, Beverloo HB, Meijerink JP, et al. Increased expression of p73Deltaex2 transcript in uveal melanoma with loss of chromosome 1p. Melanoma Res. 2008;18:208–13.CrossRefPubMedGoogle Scholar
  34. 34.
    Killick R, Niklison-Chirou M, Tomasini R, Bano D, Rufini A, Grespi F, et al. p73: a multifunctional protein in neurobiology. Mol Neurobiol. 2011;43:139–46.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Landré V, Antonov A, Knight R, Melino G. p73 promotes glioblastoma cell invasion by directly activating POSTN (periostin) expression. Oncotarget. 2016;7:11785–802.Google Scholar
  36. 36.
    Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest. 2007;117:1370–80.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Leupin N, Lüthi A, Novak U, Grob TJ, Hügli B, Graber H, et al. P73 status in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma. 2004;45:1205–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Lin YL, Sengupta S, Gurdziel K, Bell GW, Jacks T, Flores ER. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genet. 2009;5:e1000680.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu SS, Chan KYK, Cheung ANY, Liao XY, Leung TW, Ngan HYS. Expression of deltaNp73 and TAp73alpha independently associated with radiosensitivities and prognoses in cervical squamous cell carcinoma. Clin Cancer Res. 2006;12:3922–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Lo Iacono M, Monica V, Saviozzi S, Ceppi P, Bracco E, Papotti M, et al. p63 and p73 isoform expression in non-small cell lung cancer and corresponding morphological normal lung tissue. J Thorac Oncol. 2011;6:473–81.CrossRefPubMedGoogle Scholar
  41. 41.
    Lucena-Araujo AR, Kim HT, Thomé C, Jacomo RH, Melo RA, Bittencourt R, et al. High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia. Blood. 2015;126:2302–6.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Meier M, den Boer ML, Meijerink JPP, Broekhuis MJC, Passier MMCJ, van Wering ER, et al. Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia. Leukemia. 2006;20:1377–84.CrossRefPubMedGoogle Scholar
  43. 43.
    Melino G, De Laurenzi V, Vousden KH. p73: friend or foe in tumorigenesis. Nat Rev Cancer. 2002;2:605–15.CrossRefPubMedGoogle Scholar
  44. 44.
    Niklison-Chirou MV, Steinert JR, Agostini M, Knight RA, Dinsdale D, Cattaneo A, et al. TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor. Proc Natl Acad Sci USA. 2013;110:18952–7.Google Scholar
  45. 45.
    O’Nions J, Brooks LA, Sullivan A, Bell A, Dunne B, Rozycka M, et al. p73 is over-expressed in vulval cancer principally as the Delta 2 isoform. Br J Cancer. 2001;85:1551–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Olivier M, Petitjean A, Marcel V, Pétré A, Mounawar M, Plymoth A, et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther. 2009;16:1–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Park HR, Kim YW, Park JH, Maeng YH, Nojima T, Hashimoto H, Park YK. Low expression of p63 and p73 in osteosarcoma. Tumori. 2004;90:239–43.CrossRefPubMedGoogle Scholar
  48. 48.
    Pozniak CD, Radinovic S, Yang A,  McKeon F, Kaplan DR, Miller FD. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science. 2000;289:304–6.Google Scholar
  49. 49.
    Puig P, Capodieci P, Drobnjak M, Verbel D, Prives C, Cordon-Cardo C, et al. p73 expression in human normal and tumor tissues: loss of p73alpha expression is associated with tumor progression in bladder cancer. Clin Cancer Res. 2003;9:5642–51.PubMedGoogle Scholar
  50. 50.
    Rizzo MG, Giombini E, Diverio D, Vignetti M, Sacchi A, Testa U, et al. Analysis of p73 expression pattern in acute myeloid leukemias: lack of DeltaN-p73 expression is a frequent feature of acute promyelocytic leukemia. Leukemia. 2004;18:1804–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Romani M, Scaruffi P, Casciano I, Mazzocco K, Lo Cunsolo C, Cavazzana A, et al. Stage-independent expression and genetic analysis of tp73 in neuroblastoma. Int J Cancer. 1999;84:365–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Scian MJ, Carchman EH, Mohanraj L, Stagliano KER, Anderson MAE, Deb D, et al. Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene. 2008;27:2583–93.CrossRefPubMedGoogle Scholar
  53. 53.
    Schuster A, Schilling T, De Laurenzi V, Koch AF, Seitz S, Staib F, Teufel A, et al. ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. Cell Cycle. 2010;9:2629–39.CrossRefPubMedGoogle Scholar
  54. 54.
    Sherr CJ, Weber JD. The ARF/p53 pathway. Curr Opin Genet Dev. 2000;10:94–9.Google Scholar
  55. 55.
    Soldevilla B, Díaz R, Silva J, Campos-Martín Y, Muñoz C, García V, et al. Prognostic impact of ΔTAp73 isoform levels and their target genes in colon cancer patients. Clin Cancer Res. 2011;17:6029–39.CrossRefPubMedGoogle Scholar
  56. 56.
    Soldevilla B, Rodríguez M, San Millán C, García V, Fernández-Periañez R, Gil-Calderón B, et al. Tumor-derived exosomes are enriched in ΔNp73, which promotes oncogenic potential in acceptor cells and correlates with patient survival. Hum Mol Genet. 2014;23:467–78.CrossRefPubMedGoogle Scholar
  57. 57.
    Song D, Yue L, Wu G, Ma S, Yang H, Liu Q, et al. Evaluation of promoter hypomethylation and expression of p73 as a diagnostic and prognostic biomarker in Wilms’ tumour. J Clin Pathol. 2016;69:12–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Steder M, Alla V, Meier C, Spitschak A, Pahnke J, Fürst K, et al. DNp73 exerts function in metastasis initiation by disconnecting the inhibitory role of EPLIN on IGF1R-AKT/STAT3 signaling. Cancer Cell. 2013;24:512–27.Google Scholar
  59. 59.
    Stiewe T, Theseling CC, Pützer BM. Transactivation-deficient Delta TA-p73 inhibits p53 by direct competition for DNA binding: implications for tumorigenesis. J Biol Chem. 2002;277:14177–85.CrossRefPubMedGoogle Scholar
  60. 60.
    Sun XF. p73 overexpression is a prognostic factor in patients with colorectal adenocarcinoma. Clin Cancer Res. 2002;8:165–70.PubMedGoogle Scholar
  61. 61.
    Takahashi H, Ichimiya S, Nimura Y, Watanabe M, Furusato M, Wakui S, et al. Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Res. 1998;58:2076–7.PubMedGoogle Scholar
  62. 62.
    Thakur AK, Nigri J, Lac S, Leca J, Bressy C, Berthezene P, et al. TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma. Cell Death Differ. 2016;23:1358–70.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Tomasini R, Tsuchihara K, Wilhelm M, Fujitani M, Rufini A, Cheung CC, et al. TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes Dev. 2008;22:2677–91.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Toumi AA, El Hadj OEA, Ben Mahmoud LK, Ben Hmida AEM, Chaar I, Gharbi L, et al. The prognostic value of p73 overexpression in colorectal carcinoma: a clinicopathologic, immunohistochemical, and statistical study of 204 patients. Appl Immunohistochem Mol Morphol. 2010;18:128–36.CrossRefPubMedGoogle Scholar
  65. 65.
    Tuve S, Wagner SN, Schittek B, Pützer BM. Alterations of DeltaTA-p 73 splice transcripts during melanoma development and progression. Int J Cancer. 2004;108:162–6.CrossRefPubMedGoogle Scholar
  66. 66.
    Uramoto H, Sugio K, Oyama T, Nakata S, Ono K, Morita M, et al. Expression of deltaNp73 predicts poor prognosis in lung cancer. Clin Cancer Res. 2004;10:6905–11.CrossRefPubMedGoogle Scholar
  67. 67.
    Vilgelm A, Wei JX, Piazuelo MB, Washington MK, Prassolov V, El-Rifai W, et al. DeltaNp73alpha regulates MDR1 expression by inhibiting p53 function. Oncogene. 2008;27:2170–6.CrossRefPubMedGoogle Scholar
  68. 68.
    Vilgelm AE, Hong SM, Washington MK, Wei J, Chen H, El-Rifai W, et al. Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors. Oncogene. 2010;29:5861–8.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Wager M, Guilhot J, Blanc JL, Ferrand S, Milin S, Bataille B, et al. Prognostic value of increase in transcript levels of Tp73 DeltaEx2-3 isoforms in low-grade glioma patients. Br J Cancer. 2006;95:1062–9.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Weber A, Bellmann U, Bootz F, Wittekind C, Tannapfel A. Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck. Int J Cancer. 2002;99:22–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Wilhelm MT, Rufini A, Wetzel MK, Tsuchihara K, Inoue S, Tomasini R, et al. Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. Genes Dev. 2010;24:549–60.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Yokomizo A, Mai M, Bostwick DG, Tindall DJ, Qian J, Cheng L, et al. Mutation and expression analysis of the p73 gene in prostate cancer. Prostate. 1999;39:94–100.CrossRefPubMedGoogle Scholar
  73. 73.
    Yong M, Yang L, Suyila Q, Han W, Yuan H, Zhao C, et al. Expression and clinical implications of P53, P63, and P73 protein in malignant tumor of the parotid gland. Turk J Med Sci. 2014;44:875–82.CrossRefPubMedGoogle Scholar
  74. 74.
    Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, et al. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med. 2002;196:765–80.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zitterbart K, Zavrelova I, Kadlecova J, Spesna R, Kratochvilova A, Pavelka Z, et al. p73 expression in medulloblastoma: TAp73/DeltaNp73 transcript detection and possible association of p73alpha/DeltaNp73 immunoreactivity with survival. Acta Neuropathol. 2007;114:641–50.CrossRefPubMedGoogle Scholar
  76. 76.
    Zhao W, Zhang B, Guo X, Zhang X, Hu J, Hu X, et al. Expression of Ki-67, Bax and p73 in patients with hilar cholangiocarcinoma. Cancer Biomark. 2014;14:197–202.CrossRefPubMedGoogle Scholar
  77. 77.
    Zhu X, Pan X, Yang Z, Xing P, Zhang Y, Li F, et al. Expression and prognostic significance of TAp73 and ΔNp73 in FIGO stage I–II cervical squamous cell carcinoma. Oncol Lett. 2015;9:2090–4.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Servicio de Oncología MédicaHospital Universitario La Paz, CIBERONCMadridSpain
  2. 2.Servicio de Anatomía Patológica and Molecular Pathology and Therapeutic Targets GroupHospital Universitario La Paz, IdiPAZMadridSpain
  3. 3.UFIEC, ISCIIIMadridSpain
  4. 4.Departamento de Medicina, Facultad de MedicinaInstituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-Universidad Autónoma de Madrid, CIBERONCMadridSpain

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