title: Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes.
abstract: To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases. 285 abnormalities were identified in 71 patients (23.6%). Three high-risk MDS cases (1.2%) displayed chromothripsis involving exclusively chromosome 13 and affecting some cancer genes: FLT3, BRCA2 and RB1. All three cases carried TP53 mutations as revealed by NGS. Moreover, in the whole series, the integrative analysis of aCGH and NGS enabled the identification of cryptic recurrent deletions in 2p23.3 (DNMT3A; n = 2.8%), 4q24 (TET2; n = 10%) 17p13 (TP53; n = 8.5%), 21q22 (RUNX1; n = 7%), and Xp11.4 (BCOR; n = 2.8%), while mutations in the non-deleted allele where found only in DNMT3A (n = 1), TET2 (n = 3), and TP53 (n = 4). These cryptic abnormalities were detected mainly in patients with normal (45%) or non-informative (15%) karyotype by conventional cytogenetics, except for those with TP53 deletion and mutation (15%), which had a complex karyotype. In addition to well-known copy number defects, the presence of chromothripsis involving chromosome 13 was a novel recurrent change in high-risk MDS patients. Array CGH analysis revealed the presence of cryptic abnormalities in genomic regions where MDS-related genes, such as TET2, DNMT3A, RUNX1 and BCOR, are located.
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Abáigar
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Robledo
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Benito
authors.affiliation: IBIOMED, Instituto de Biomedicina, Universidad de León, León, Spain.|Servicio de Hematología, Hospital Universitario de León, León, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Díez-Campelo
authors.affiliation: Servicio de Hematología, Hospital Jerez de la Frontera, Cádiz, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Hermosín
authors.affiliation: Servicio de Hematología, Hospital Universitario de León, León, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sánchez-Del-Real
authors.affiliation: Servicio de Hematología, Hospital Río Carrión, Palencia, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Alonso
authors.affiliation: Servicio de Hematología, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Cuello
authors.affiliation: Servicio de Hematología, Hospital del Bierzo, Ponferrada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Megido
authors.affiliation: Servicio de Hematología, Hospital Juan Ramón Jiménez, Huelva, Spain.
authors.forename: Juan N
authors.initials: JN
authors.lastname: Rodríguez
authors.affiliation: Servicio de Hematología, Hospital Virgen del Puerto, Plasencia, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Martín-Núñez
authors.affiliation: Servicio de Hematología, Hospital General de Soria, Soria, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Aguilar
authors.affiliation: Servicio de Hematología, Hospital Comarcal de Jarrio, Jarrio-Coaña, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Martín
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: Juan L
authors.initials: JL
authors.lastname: García
authors.affiliation: AstraZeneca, Personalized Healthcare and Biomarkers, Innovative Medicines and Early Development, Cambridge, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.
authors.forename: M Consuelo
authors.initials: MC
authors.lastname: Del Cañizo
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.|Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Rivas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002869:Chromosome Aberrations; D002882:Chromosomes, Human, Pair 13; D055028:Comparative Genomic Hybridization; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D056915:DNA Copy Number Variations; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059785:Karyotype; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012008:Recurrence; D012306:Risk; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A