Gomez-Casares, M.T. (María T.)

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    Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project
    (2021) García-Boyero, R. (Raimundo); Serrano, J. (Josefina); Yébenes-Ramírez, M. (Manuel); Martínez-López, J. (Joaquín); Perez-Simon, J.A. (José Antonio); Amigo, M.L. (Mari Luz); Montesinos, P. (Pau); Martínez-Sánchez, P. (Pilar); García-Sanz, R. (Ramón); Florido-Ortega, Y. (Yanira); Sánchez-García, J. (Joaquín); Bergua, J. (Juan); Bernal, T. (Teresa); Ayala, R. (Rosa); Lavilla, E. (Esperanza); Tormo, M. (Mar); Costilla-Barriga, L. (Lisette); Llop, M. (Marta); Rapado, I. (Inmaculada); Janusz, K. (Kamila); Sanz, M.A. (Miguel A.); Herrera-Puente, P. (Pilar); Algarra, L. (Lorenzo); González-Díaz, M. (Marcos); Pérez-Santolalla, E. (Esther); Gomez-Casares, M.T. (María T.); Vazquez, I. (Iria); Barragán, E. (Eva); Noriega, V. (Víctor); Larrayoz, M.J. (María J.); Botella, C. (Carmen); Sargas, C. (Claudia); Soria, E. (Elena); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Cuadron, D. (David); Alonso-Domínguez, J.M. (Juan M.); Marchante, I. (Inmaculada); Bilbao, C. (Cristina); Sayas, M.J. (María J.); Carrillo-Cruz, E. (Estrella)
    Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group.
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    Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia
    (Ferrata Storti Foundation, 2011) Sierra, J. (Jorge); Cervera, J. (Jose); Marin-Bejar, O. (Oskar); Valencia, A. (Ana); Sanz, M.A. (Miguel A.); Lahortiga, I. (Idoya); Marcotegui, N. (Nerea); Gomez-Casares, M.T. (María T.); Gomez-Benito, M. (María); Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Lumbreras, E. (Eva); Brunet, S. (Salut); Carranza, C. (Claudia); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Maicas, M. (Miren); Aguirre-Ena, X. (Xabier); Vicente, C. (Carmen)
    BACKGROUND: The EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia. DESIGN AND METHODS: We analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene. RESULTS: Our data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter. CONCLUSIONS: Our results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level.