Rapado, I. (Inmaculada)
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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.
- Spanish guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia(2019) Cedena, M.T. (María Teresa); Zamora, L. (Lurdes); Cervera, J. (Jose); Cigudosa, J.C. (Juan Cruz); Fernandez-Mercado, M. (Marta); Palomo, L. (Laura); Alvarez, S. (Sara); Sole, F. (Francesc); Hernandez, J.M. (J. M.); Ibáñez, M. (Mariam); Acha, P. (Pamela); Such, E. (Esperanza); Tazón-Vega, Bárbara; Valcarcel, D. (David); Benito, R. (Rocío); Rapado, I. (Inmaculada); Cabezón, Marta; Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Larrayoz, M.J. (María J.); Fuster-Tormo, F. (Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Sanz, G. (Guillermo); Abaigar, M. (María)The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
- Differentiation stage of myeloma plasma cells: biological and clinical significance(Nature Publishing Group, 2017) Cedena, M.T. (María Teresa); Martínez-López, J. (Joaquín); Bladé, J. (Joan); Barlogie, B. (Bart); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Jong, B.G. (Britt G.) de; Gonzalez, Y. (Yolanda); Pascual, M. (Marien); Mateos, M.V. (María Victoria); Epstein, J. (Joshua); Hernandez, M.T. (Miguel Teodoro); Delgado, J.A. (Jose Antonio); Puig, N. (Noemí); Ruiz-Paz, Y; Morgan, G.J. (Gareth J.); Cordón, L. (Lourdes); Alignani, D. (Diego); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Rapado, I. (Inmaculada); Dongen, J.J.M. (Jacques J. M.) van; Paiva, B. (Bruno); Oriol, A. (Albert); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion); Martin-Subero, J.I. (Jose Ignacio); Van Zelm, M.C. (Menno C.)The notion that plasma cells (PCs) are terminally-differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly-diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully-differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+), and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR:1.7;P=.005) and overall survival (HR:2.1;P=.006). Longitudinal comparison of diagnostic vs. minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (e.g.:PAX5), and show distinct mutation profile vs. fully-differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.