Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes

• Published in: PloS one Vol. 11; no. 10; p. e0164370
• Main Authors: Abáigar, María, Robledo, Cristina, Benito, Rocío, Ramos, Fernando, Díez-Campelo, María, Hermosín, Lourdes, Sánchez-Del-Real, Javier, Alonso, Jose M, Cuello, Rebeca, Megido, Marta, Rodríguez, Juan N, Martín-Núñez, Guillermo, Aguilar, Carlos, Vargas, Manuel, Martín, Ana A, García, Juan L, Kohlmann, Alexander, Del Cañizo, M Consuelo, Hernández-Rivas, Jesús M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-10-2016; Public Library of Science (PLoS)
• Subjects: Abnormalities; Adolescent; Adult; Aged; Aged, 80 and over; Biology and Life Sciences; BRCA2 protein; Breast cancer; Cancer; Child; Chromosome 13; Chromosome Aberrations; Chromosomes; Chromosomes, Human, Pair 13; Comparative analysis; Comparative Genomic Hybridization; Copy number; Core Binding Factor Alpha 2 Subunit - genetics; Cytogenetics; Deoxyribonucleic acid; Disorders; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA - chemistry; DNA - isolation & purification; DNA - metabolism; DNA Copy Number Variations; DNA Mutational Analysis; DNA repair; DNA-Binding Proteins - genetics; Female; Gene deletion; Genes; Genetic abnormalities; Genetic engineering; Genomes; Genomics; Health aspects; High-Throughput Nucleotide Sequencing; Humans; Hybridization; Karyotype; Leukemia; Male; Medical research; Methyltransferases; Middle Aged; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - diagnosis; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Neoplasms; p53 Protein; Patients; Proto-Oncogene Proteins - genetics; Recurrence; Research and analysis methods; Risk; Runx1 protein; Sequences; Studies; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; Young Adult; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164370

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.