Larrayoz, M.J. (María J.)

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    Determinación de enfermedad mínima residual molecular en sangre periférica mediante NGS como nueva herramienta en el seguimiento posttrasplante alogénico de progenitores hematopoyéticos
    (2019) Fernandez-Mercado, M. (Marta); Aguilera-Díaz, A. (Almudena); Arnedo, P. (P.); Bandres, E. (Eva); Viguria, M.C. (María C.); Aguirre-Ruiz, P. (P.); Zudaire, M.T. (Maria Teresa); Redondo, M. (M.); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Jauregui, A. (A.); Prosper-Cardoso, F. (Felipe); Mateos, M.C. (María C.); Blasco-Iturri, Z. (Zuriñe); Calasanz-Abinzano, M.J. (Maria Jose)
    La determinación de la EMR en médula ósea y del quimerismo hematopoyético (QH) en sangre periférica (SP), son herramientas imprescindibles para detectar recaídas en el seguimiento post-alo-TPH. La combinación de tecnologías más sensibles, que identifiquen cambios en el QH, y más específicos que detecten recaídas en sangre periférica, pueden complementar los estudios de EMR realizados en médula ósea (MO) y permitir tomar decisiones clínicas más precoces y específicas. El objetivo de este estudio fue valorar la aplicabilidad clínica de determinar la EMR molecular mediante Next Generation Sequencing (NGS) en SP en aquellos momentos en los que se observa un cambio del QH.
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    Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics
    (2012) Kondo, T. (Toshinori); McDonald, E.J. (Emma Jane); Perez, C. (Cristina); Fernandez-Mercado, M. (Marta); Wainscoat, J.S. (James S.); Pellagatti, A. (Andrea); Davies, C. (Carwyn); Boultwood, J. (Jacqueline); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Yip, B.H. (Bon Ham); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier); Killick, S. (Sally)
    Abstract Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML
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    Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design
    (2020) Ariceta, B. (Beñat); Fernandez-Mercado, M. (Marta); Aguilera-Díaz, A. (Almudena); Prieto-Conde, M.I. (María Isabel); García-Sanz, R. (Ramón); Palomino-Echeverría, S. (Sara); Mañú, A. (Amagoia); Alfonso-Piérola, A. (Ana); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Chillón, M.C. (María del Carmen); Blasco-Iturri, Z. (Zuriñe); Calasanz-Abinzano, M.J. (Maria Jose)
    The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel¿s depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now.
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    Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells
    (Nature Publishing Group, 2004) Pelicci, P.G. (Pier G.); Lo-Coco, F. (Francesco); Lahortiga, I. (Idoya); Gasparini, P. (P.); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Belloni, E. (E.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier)
    Patients with myeloid malignancies and either the 3q21q26 syndrome or t(1;3)(p36;q21) have been reported to share similar clinicopathological features and a common molecular mechanism for leukemogenesis. Overexpression of MDS1/EVI1 (3q26) or MEL1/PRDM16 (1p36), both members of the PR-domain family, has been directly implicated in the malignant transformation of this subset of neoplasias. The breakpoints in both entities are outside the genes, and the 3q21 region, where RPN1 is located, seems to act as an enhancer. MEL1 has been reported to be expressed in leukemia cells with t(1;3) and in the normal uterus and fetal kidney, but neither in bone marrow (BM) nor in other tissues, suggesting that this gene is specific to t(1;3)-positive MDS/AML. We report the molecular characterization of a t(1;3)(p36;q21) in a patient with MDS (RAEB-2). In contrast to previous studies, we demonstrate that MEL1, the PR-containing form, and MEL1S, the PR-lacking form, are widely expressed in normal tissues, including BM. The clinicopathological features and the breakpoint on 1p36 are different from cases previously described, and MEL1 is not overexpressed, suggesting a heterogeneity in myeloid neoplasias with t(1;3).
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    Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
    (2022) Reinhardt, H.C. (Hans Christian); Vilas, A. (Amaia); Sanchez-Garcia, I. (Isidro); Perez, C. (Cristina); Paiva, A. (Artur); López-de-Arancibia, A. (Aitziber); Sacco, A. (Antonio); Santos, S. (S.); Celay, J. (Jon); Sarvide, S. (Sarai); García-Sanz, R. (Ramón); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gárate-Luzuriaga, S. (Sonia); Carrasco, Y.R. (Yolanda R.); Panizo, C. (Carlos); Larrayoz, M. (Marta); Vitoria, H. (Helena); Puig, N. (Noemí); Botta, C. (Cirino); Rodríguez-Díaz, S. (Saray); Garcés-Latre, J.J. (Juan José); Motta, M. (Marina); Geraldes, C. (Catarina); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Duarte, S. (Sara); Paiva, B. (Bruno); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Roccaro, A.M. (Aldo M.); Fuerte, G. (Gema); Tucci, A. (Alessandra); San-Miguel, J.F. (Jesús F.); Gentile, M. (Massimo); Jiménez, C. (Cristina)
    Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
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    Citogenética y biología molecular en la leucemia aguda linfoblástica
    (Doyma, 2002) Novo-Villaverde, F. J. (Francisco Javier); Vizmanos-Pérez, J.L. (José Luis); Larrayoz, M.J. (María J.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores)
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    Remission of acute monocytic leukemia, secondary to treatment with epipodophyllotoxins, in a patient with t(8;16)(p11;p13) and MYST3-CREBBP fusion
    (Elsevier, 2004) Novo-Villaverde, F. J. (Francisco Javier); Lahortiga, I. (Idoya); Vizmanos-Pérez, J.L. (José Luis); Hernandez, R. (Roberto); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Ardanaz, M.T. (M.T.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores)
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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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    Insertion (22;9)(q11;q34q21) in a patient with chronic myeloid leukemia characterized by fluorescence in situ hybridization
    (Elsevier, 2001) Gomez, E. (Emilio); Ferreira, C. (C.); Giraldo, P. (P.); Novo-Villaverde, F. J. (Francisco Javier); Lahortiga, I. (Idoya); García-Delgado, M. (Marina); Larrayoz, M.J. (María J.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Martin-Subero, J.I. (Jose Ignacio)
    An unusual cytogenetic rearrangement, described as ins(22;9)(q11;q34q21), was detected in a 49-year-old male patient diagnosed with chronic myeloid leukemia (CML). Reverse transcriptase polymerase chain reaction (RT-PCR) revealed a b3a2 fusion transcript. In order to confirm the cytogenetic findings and fully characterize the inverted insertion, we performed fluorescence in situ hybridization (FISH) assays using locus-specific and whole chromosome painting probes. Our FISH analysis showed the presence of the BCR/ABL fusion gene, verified the insertion and determined that the breakpoint on chromosome 22 where the insertion took place was located proximal to the BCR gene and distal to the TUPLE1 gene on 22q11.
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    TP53 abnormalities are underlying the poor outcome associated with chromothripsis in chronic lymphocytic leukemia patients with complex karyotype
    (2022) Cuneo, A. (Antonio); Kamaso, J. (Joanna); Ramos-Campoy, S. (Silvia); Espinet, B. (Blanca); Oscier, D. (David); Blanco, M.L. (María Laura); Bea, S. (Silvia); Bougeon, S. (Sandrine); Baumann, T. (Tycho); Moreno, C. (Carolina); Salgado, R. (Rocío); Puiggros, A. (Anna); Gimeno, E. (Eva); Nguyen-Khac, F. (Florence); Costa, D. (Dolors); Collado, R. (Rosa); Haferlach, C. (Claudia); Rigolin, G.M. (Gian Matteo); Calvo, X. (Xavier); Parker, H. (Helen); Larrayoz, M.J. (María J.); Ancín, I. (Idoya); Schoumans, J. (Jacqueline); Strefford, J.C. (Jonathan C.); Calasanz-Abinzano, M.J. (Maria Jose); Salido, M. (Marta); Moro-García, M.A. (Marco A.)
    Simple Summary Chromothripsis, a genomic event that generates massive chromosomal rearrangements, has been described in 1-3% of CLL patients and is associated with poor prognostic factors (e.g., TP53 abnormalities and genomic complexity). However, previous studies have not assessed its role in CLL patients with complex karyotypes. Herein, we aimed to describe the genetic characteristics of 33 CLL patients with high genomic complexity and chromothripsis. Moreover, we analyzed the clinical impact of chromothripsis, comparing these patients against a cohort of 129 patients with complex karyotypes not presenting this catastrophic event. Nine cases were also assessed via the novel cytogenomic methodology known as optical genome mapping. We confirmed that this phenomenon is heterogeneous and associated with a shorter time to first treatment. Nonetheless, our findings suggested that TP53 abnormalities, rather than chromothripsis itself, underlie the dismal outcome. Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic ...