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A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

  1. Beatriz Sánchez-Espiridión1,*,
  2. Carlos Montalbán2,*,
  3. Ángel López1,
  4. Javier Menárguez3,
  5. Pilar Sabín3,
  6. Carmen Ruiz-Marcellán4,
  7. Andrés Lopez4,
  8. Rafael Ramos5,
  9. Jose Rodríguez5,
  10. Araceli Cánovas6,
  11. Carmen Camarero6,
  12. Miguel Canales7,
  13. Javier Alves7,
  14. Reyes Arranz8,
  15. Agustín Acevedo8,
  16. Antonio Salar9,
  17. Sergio Serrano9,
  18. Águeda Bas10,
  19. Jose M. Moraleda10,
  20. Pedro Sánchez-Godoy11,
  21. Fernando Burgos11,
  22. Concepción Rayón12,
  23. Manuel F. Fresno12,
  24. José García Laraña10,
  25. Mónica García-Cosío2,
  26. Carlos Santonja13,
  27. Jose L. López13,
  28. Marta Llanos14,
  29. Manuela Mollejo15,
  30. Joaquín González-Carrero16,
  31. Ana Marín17,
  32. Jerónimo Forteza18,
  33. Ramón García-Sanz19,
  34. Jose F. Tomás20,
  35. Manuel M. Morente1,
  36. Miguel A. Piris1,
  37. Juan F. García1,20, and
  38. on behalf of the Spanish Hodgkin Lymphoma Study Group
  1. 1Molecular Pathology Programme, the Genetic and Molecular Epidemiology Group, and the Tumour Bank, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid;
  2. 2Hospital Ramón y Cajal, Madrid;
  3. 3Hospital Gregorio Marañón, Madrid;
  4. 4Hospital Vall d′Hebron, Barcelona;
  5. 5Hospital Son Dureta, Palma de Mallorca;
  6. 6Hospital de Cruces, Baracaldo;
  7. 7Hospital La Paz, Madrid;
  8. 8Hospital La Princesa, Madrid;
  9. 9Hospital del Mar, Barcelona;
  10. 10Hospital Universitario Virgen de la Arrixaca, Murcia;
  11. 11Hospital Severo Ochoa, Madrid;
  12. 12Hospital Central de Asturias, Oviedo;
  13. 13Fundación Jiménez Díaz, Madrid;
  14. 14Hospital Universitario de Canarias, Tenerife;
  15. 15Hospital Virgen de la Salud, Toledo;
  16. 16Hospital Xeral-Cíes, Vigo;
  17. 17Hospital Virgen del Rocío, Sevilla;
  18. 18Hospital Clínico Universitario, Santiago Compostela;
  19. 19Hospital Universitario de Salamanca, Salamanca; and
  20. 20M. D. Anderson España, Madrid, Spain

Abstract

Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

  • Submitted February 12, 2010.
  • Accepted April 10, 2010.
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