Putative Monosomy 5 In Myelodysplastic Syndromes (MDS) Is Probably Resulting From Chromothripsis

Aberrations of chromosome 5 are common cytogenetic findings in bone marrow cells of patients with myelodysplastic syndromes (MDS). The most frequent is the interstitial deletion of the long arm of chromosome 5 [del(5q)] - occurring as sole abnormality or in combination with additional aberrations in ∼30% of primary and up to 50% of secondary MDS. Extent and breakpoints of deleted segment differs among patients. A critical area deleted in all cases (the common deleted region, CDR) has been localized between bands 5q31.1 and 5q32. Loss of the whole chromosome 5 was described in about 3-8% MDS cases. However, in recent studies it has been shown that many suspected monosomies 5 are in fact cryptic translocations or insertions, undetectable by conventional G-banding. The aim of the study was to perform detailed genome wide analyses of bone marrow cells of MDS patients with suspected monosomy 5 detected by conventional G-banding at diagnosis, to verify the loss of genetic material of chromosome 5, to compare the breakpoints and extent of chromosome 5 deletions in individual patients, and to assess real existence and clinical significance of monosomy 5 in MDS.

In the period 2002–2012, bone-marrow samples from 870 adults with newly diagnosed MDS were examined and 80 patients (9.2%) with suspected monosomy 5 were identified (50 males, 30 females; median age 67 years). Karyotypes were analyzed by conventional G-banding, FISH with Vysis DNA probes (Abbott, Des Plaines, IL), and mFISH/mBAND (MetaSystems, Altlussheim, Germany). Genomic imbalances were identified with oligonucleotide CGH-SNP arrays (BlueGnome, Cambridge, UK) or with SNP arrays (Illumina, San Diego, CA).

All 80 patients presented a complex karyotype with confirmed del(5)(q31). The most frequent breakpoints on chromosome 5 involved bands 5q14.3, 5q34, 5q33.3, 5q11.2, and 5q13.2. On 5p, breaks occurred sporadically (recurrent breakpoints at 5p12, 5p14.1, and 5p15.3). The extent of del(5q) ranged from 23.55 Mb to 131.4 Mb (whole arm). The most proximal and most distal breakpoints were located at 5q11.1 and 5q35.3, respectively. The CDR occurred between bands 5q31.1 and 5q32 (15.1 Mb). No patient with pure monosomy 5 was found. In all cases, parts of the deleted chromosome 5 were fragmented and inserted elsewhere in the genome. A commonly retained region conserved in all patients was established at 5p11.1–p14.2 (22.31 Mb). The most recurrent partners of deleted chromosome 5 in cryptic unbalanced rearrangements were chromosomes 17, 3, 7, and 18. Patients with deleted chromosome 5 involved in complex aberrations have an extremely poor prognosis (in the present cohort, a median OS of only two months).

Based on these results, we believe that pure monosomy 5, quoted in the literature, in MDS does not actually exist. It seems that the primary interstitial deletion of 5q is likely the cause of increased genomic instability, which may, under certain circumstances, lead to fragmentation and disintegration of the whole chromosome 5 and to the emergence of additional complex rearrangements. Mechanism responsible for fragmentation of deleted chromosome 5 remains unclear. One of possible explanations might be the phenomenon called chromothripsis, whereby one or more chromosomes or chromosomal regions shatter into pieces in a single catastrophic event. Some of these pieces are then stitched haphazardly together by DNA repair machinery, whereas some of them are lost. This process is resulting in severe genomic damage and fast disease progression. MDS patients with deleted chromosome 5 involved in complex rearrangements should be considered as a unique entity with extremely poor prognosis.

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

No relevant conflicts of interest to declare.