The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations

Abstract

Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16 and 119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analysis of 27 genes revealed ≥1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (P = 0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. © 2016 Wiley Periodicals, Inc.

Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report

“…Episomal reprogramming has identified del(5q) as an early cytogenetic lesion with the capacity to perturb genome stability and differentiation [ 6 ]. Larger del(5q) size has been correlated with higher mutation frequency [ 5 ], which in this case included the somatic driver mutations: TET2, TP53 , SF3B1 , and ASXL1 at high allele frequency (Table 1 ). We propose that this combination led to HSC injury and disease progression through sub-clone branching (Fig.…”

“…Transformation of MPN to acute lymphoblastic leukemia (ALL) is rare, with only seventeen cases reported in the literature [ 3 ]. Retrospective studies suggest that genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms play an important role in the observed conversion rate, as well as the varied clinical-pathologic entities that evolve [ 4 , 5 ].…”

Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders

“…Relatively slow rate of progression of the TP53 -mutated patients during AZA therapy may be still relatively well tolerated by the patients thus guaranteeing a survival benefit. It is also an important point that the mutations operate with other mutations in concert and thus higher occurrence of preceding 5q- aberration may have added to selection (during clonal evolution) of distinct TP53 mutations (observed in up to 31% of 5q- patients) [ 16 ] that are not as aggressive and still may provide certain cell-survival benefit for maturing blood elements to maintain residual hematopoiesis while preventing rapid progression to MDS/AML.…”

Assessing copy number aberrations and copy neutral loss of heterozygosity across the genome as best practice: An evidence based review of clinical utility from the cancer genomics consortium (CGC) working group for myelodysplastic syndrome, myelodysplastic/myeloproliferative and myeloproliferative neoplasms

“…Predictive markers remain scant even with the help of CMA. Specifically, response to lenalidomide among MDS patients with del(5q) and TKI resistance among CML patients did not correlate with CMA findings even though additional CNAs found by array and TP53 mutations/17p deletions are associated with disease progression and worse prognosis [60,62].…”

“…One study that assessed these patients for response to lenalidomide showed no significant difference in the response of patients with 5q deletions as the sole abnormality and those with additional abnormalities detected by CMA[60].Despite the lack of correlation with treatment response, one study identified significant differences in OS between patients with del(5q) as the sole abnormality by karyotype (median OS = 34 months) compared to 5q abnormalities (loss and CN-LOH) identified by CMA only (OS = 15 months)[14]. Furthermore, using CMA to refine 5q deletion breakpoints, Stengel et alhave shown in MDS, MPN and MDS/MPN cases that the size of 5q deletion correlated with the number of additional CNAs detected by array, and TP53 mutations were correlated with a larger del(5q) size and with disease progression and worse prognosis[62].…”