Open AccessChromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes
Author(s) -
María Abáigar,
Cristina Robledo,
Rocío Benito,
Fernando Ramos,
María Díez-Campelo,
Lourdes Hermosín,
Javier Sánchez-del-Real,
José M. Alonso,
Rebeca Cuello,
Marta Megido,
Juan Nicolás Rodríguez,
Guillermo Martín–Núñez,
Carlos Aguilar,
Manuel Vargas,
Ana A. Martín,
Juan Luis Garcı́a,
Alexander Kohlmann,
M.C. del Cañizo,
Jesús M. Hernández-Rivas
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0164370
Subject(s) - chromothripsis , biology , comparative genomic hybridization , myelodysplastic syndromes , karyotype , genetics , copy number variation , runx1 , chromosome , cancer research , gene , genome , dna , genome instability , bone marrow , dna damage , transcription factor , immunology
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.