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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.
Highlights
The progressive accumulation of genetic aberrations such as copy number abnormalities, in the form of gains or losses of genetic material affecting certain regions of the genome, and particular gene mutations, provide the basis for cancer development [1,2]
Our results demonstrated the presence of chromothripsis, inferred from array-based comparative genomic hybridization (aCGH) profiles, as an infrequent but recurrent genomic abnormality in high-risk myelodysplastic syndromes (MDS)
Our results showed that the combination of these conventional and genomewide scanning approaches enables a better characterization of MDS and related neoplasms, and provides new information that could improve the current diagnostic and treatment of these patients
Summary
The progressive accumulation of genetic aberrations such as copy number abnormalities, in the form of gains or losses of genetic material affecting certain regions of the genome, and particular gene mutations, provide the basis for cancer development [1,2]. A key feature of chromothripsis is the occurrence of tens to hundreds of clustered genomic rearrangements usually in one or, in some instances, several chromosomes. This complex abnormality can affect an entire chromosome, a chromosome arm, or be confined to a single region of a chromosome [2,3,4,5,6,7,8,9]. Some congenital disorders show chromothripsis [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]
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