CHROMOTHRIPSIS IN BONE MARROW CELLS OF ADULT PATIENTS WITH NEWLY DIAGNOSED MYELODYSPLASTIC SYNDROMES (MDS) WITH COMPLEX KARYOTYPES

ABSSUB-4925

Background: Approximately 20% of patients with newly diagnosed MDS have complex chromosomal aberrations (CCAs) which are associated with a poor prognosis and high risk of transformation to AML. The mechanisms leading to formation of CCAs in MDS remain poorly understood. It is not clear whether the complex karyotypes arise by a gradual acquisition of genetic changes during the clonal evolution or by extensive chromosome fragmentation and reorganization through a unique cellular crisis (chromothripsis).

Aims: The aim of the study was to perform detailed genome wide analyses of bone marrow cells of newly diagnosed MDS patients with CCAs in order to assess the frequency and clinical significance of chromothripsis in the high risk MDS.

Methods: A comprehensive retrospective molecular cytogenetic analysis was performed of fixed bone-marrow cells from 170 patients with CCAs (³3 aberrations) identified with conventional G-banding technique at the time of diagnosis of MDS (85 men, 85 women; median age 67 years). The CCAs and breakpoints on the affected chromosomes were studied by FISH with Vysis DNA probes (Abbott, Des Plaines, IL) and mFISH/mBAND methods, using the 24XCyte and the XCyte color kits (MetaSystems, Altlussheim, Germany). Genomic imbalances were identified with CytoChip Cancer SNP 180K (BlueGnome, Cambridge, UK) or with Illumina Human CytoSNP-12 arrays (Illumina, San Diego, CA).

Results: The molecular cytogenetic findings in 83 patients of this cohort corresponded to the gradual accumulation of random chromosomal changes during the clonal evolution. In the rest of the patients (87pts ; 51 %), mFISH/mBAND and microarray assays showed breaks with a large number of chromatin losses and gains, probably as a results  of chromothripsis. The fragmentation or shattering of chromosomes into many small pieces was observed as well. Parts of the fragmented chromosomes were often translocated or inserted elsewhere in the genome, leading to the chaotically reassembled chromosomes with the most frequently shattered nos. 5, 7, 17, and 12. Surprisingly, the OS of patients with shattered chromosomes did not significantly differ from that of patients with no evidence of fragmentation (p = 0.224; median OS in both groups, four months).

Summary/Conclusion: Signs of chromothripsis were observed in 51% of MDS patients with CCAs. Although initial studies have suggested that patients displaying the chromothripsis have more aggressive tumors and poor outcomes, in this cohort no significant difference in the OS of patients with and without chromothripsis was found. It can be assumed that in MDS, CCAs can occur by either mechanism, i.e., as the result of chromothripsis or with gradual clonal evolution. However, under both circumstances the prognosis  is very poor.

Supported by grants RVO-VFN64165/2012, GACR P302/12/G157/1, PRVOUK-P27/LF1/1 and MHCR 00023736.

Keywords: Chromosomal instability, Complex aberrant karyotype, MDS

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