What lies beyond del(5q) in myelodysplastic syndrome?

Abstract

M yelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by ineffective differentiation of one or more bone marrow cell lineages. Much of the phenotypic variability is likely explained by the diverse set of genetic abnormalities responsible for the development and progression of these disorders. However, current clinical decision-making for MDS is based on diagnostic and prognostic criteria that do not include any molecular genetic information. In fact, the only subtype of MDS to be defined by a genetic abnormality is the group with isolated deletion of chromosome 5q [del(5q)].1 Just under 50% of patients with de novo MDS will be found to have cytogenetic abnormalities, of which del(5q) is the most common. In the 10% of cases with the del(5q) as a sole abnormality, this lesion is associated with a more favorable prognosis.2 In another 5-10% of cases, del(5q) is found as part of a complex karyotype (3 or more cytogenetic abnormalities): the prognosis in these cases is poorer.Substantial effort has gone into understanding how the del(5q) abnormality contributes to the pathogenesis of MDS.3 Early studies tried and failed to find recurrently mutated genes in the remaining intact genes that mapped to the commonly deleted region of chromosome 5. Instead, it was discovered that haploinsufficiency of several genes located in this region were capable of generating the clinical phenotype seen in patients with MDS. Loss of one RPS14 allele for example, can recapitulate the dyserythropoiesis seen in MDS patients with del(5q). Loss of one copy of the microRNA miR-145 and miR146 may confer a clonal advantage and contribute to preserved or increased platelet counts observed in patients with the 5q-minus syndrome. 4 Haploinsufficiency of several other genes of the commonly deleted region, including HSPA9, CTNNA1, and EGR1, may also cooperate to promote the development of disease. Finally, loss of the more proximal APC gene and the more distal NPM1 gene may play a role in higher risk MDS cases with more adverse outcomes since this group tends to have larger 5q deletions that extend well beyond the commonly deleted region. 3Identification of these disease-related haploinsufficient genes has informed our biological understanding of del(5q) MDS. Loss of ribosomal protein genes, such as RPS14, has been shown to increase levels of p53, primarily in erythroblasts, and promote their apoptosis -both elements observed in patients with isolated del(5q) MDS. If p53 activity checks the growth of more primitive del(5q) disease cells, there may be a selective pressure for them to mutate or lose the TP53 gene. In fact, the del(5q) abnormality and TP53 mutations have been found to co-exist more often than their base occurrence rates alone would predict, indicating a likely synergy between these lesions. 5 More importantly, this is not restricted to those patients with complex karyotypes in whom TP53 mutations are most common. Even patients with isolated del(5q) and presumed lower ri...

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

“…We observed a distinct pattern of mutated genes in the respective entities with del(5q) that is in line with previous studies analyzing molecular mutations in complete cohorts of MDS, MPN and MDS/MPN (Bacher et al, 2009;Adema and Bejar 2013;Fernandez-Mercado et al, 2013;Haferlach et al, 2014) (Table 1). Thus, the spectrum of mutations found in MDS and MPN cases with del(5q) does not differ considerably from MDS or MPN patients without del(5q).…”

“…Deletions of chromosome 5q are somatically acquired, heterozygous and encompass many genes (Ebert 2009). They can occur either as the sole abnormality or accompanied by additional chromosome aberrations, in the latter context most frequently leading to a complex karyotype (Adema and Bejar 2013;Boultwood et al, 2010). In contrast to MDS, chromosomal aberrations are less frequent in MPN and MDS/MPN overlap cases (5-35% in MPN, 25% in MDS/MPN) and del(5q) are quite rare (Bacher et al, 2009;Bench 2001).…”

The evolving role of next generation sequencing in myelodysplastic syndromes

“…Cytogenetics have been very informative in the diagnosis and prognosis of MDS (Haase et al , ; Adema & Bejar, ; Horny, ), and evolving data suggest that more granular somatic and germline mutations are also key markers of clonality. At least one genetic mutation has been identified in 70 to 90% of MDS patients (Bejar et al , ; Papaemmanuil et al , ; Haferlach et al , ).…”

Mutational profiling in patients with MDS: Ready for every-day use in the clinic?

“…In more advanced MDS cases, the proportions of mutation carriers were higher as compared to early MDS cases. This suggested a role of the respective mutations for disease progression in MDS with 5q deletion [39,40]. Additionally, gene alterations were recently identified within the Cohesin complex in patients with MDS and other myeloid malignancies such as AML or chronic myelomonocytic leukemia (CMML).…”