Genomic patterns associated with hypoplastic compared to hyperplastic myelodysplastic syndromes

Abstract

While the bone marrow in most patients with myelodysplastic syndromes (MDS) has normal or increased cellularity (hyper-MDS), approximately 10%-15% of MDS patients will present with a hypocellular bone marrow (hypo-MDS).1 Since the diagnosis of MDS relies mainly on the presence of dyplastic morphology of myeloid precursors and/or the presence of recurrent chromosomal abnormalities, low cellularity aspirates in patients with hypo-MDS may compromise morphologic evaluation and karyotypic analyses, and ultimately contribute to difficulties in distinguishing hypo-MDS from other bone marrow failure syndromes. Further, approximately 50% of MDS patients, including those with hypo-MDS, have normal karyotype by metaphase cytogenetics (MC), which makes the distinction even more difficult. 2We previously reported that single nucleotide polymorphism (SNP) array karyotyping can improve the detection of chromosomal lesions that can distinguish hypo-MDS patients from those with aplastic anemia (AA).3 This finding suggests that clonal abnormalities can be detected in haematologica 2015; 100:e434 LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o nhypo-MDS and AA by using higher sensitivity methods other than MC. Recently, next generation sequencing (NGS) technologies of the human genome identified several genes that are frequently affected by somatic mutations and play an important role in both the prognosis and the pathogenesis of MDS.4-6 Some of these mutations have a significant impact on disease phenotype, the progression of MDS to acute myeloid leukemia (AML), and on overall survival (OS).4-6 Somatic mutations in genes such as ASXL1, TET2, and DNMT3A are present in healthy individuals, and their incidence increases with age.7 More importantly, the presence of these mutations predisposes these individuals to develop hematologic malignancies.7 Furthermore, somatic mutations in genes such as ASXL1, TET2, DNMT3A and BCOR, were found in 19% of patients with AA, and their presence was associated with an increased risk of transformation to MDS and AML. 8These findings suggest that somatic mutations in certain genes have the potential to contribute to both disease initiation and progression.Using NGS technologies, we hypothesized that identification of somatic mutations and their combinations may help to define the clonal architecture that can lead to the development of hypo-MDS, and that these somatic mutations can possibly be used to aid in establishing the diagnosis.Bone marrow and peripheral blood samples were collected from 237 patients diagnosed with MDS (according to the 2008 WHO criteria) 9 at our institution between January 2000 and December 2013. Informed consent for sample collection was obtained according to protocols approved by the institutional review boards of Cleveland Clinic and in accordance with the Declaration of Helsinki. Hypo-MDS was defined using a standard definition of bone marrow cellularity </= 25%, regardless of age. When indicated based on clinical suspicion, immunohistochemical staini...

MDS overlap disorders and diagnostic boundaries

“…These cases have differences in genetic profiles that include a lower rate of mutations and a lower frequency of splicing factor gene mutations compared with hyperplastic patients. 68 This pattern is more similar to that observed in SAA. is difficult to evaluate when considering hMDS vs SAA or nonsevere AA.…”

Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome

“…[28][29][30][31] So far, few genetic studies have focused on h-MDS, without firm conclusion. [32][33][34][35] In a recent study on patients with unexplained cytopenia, including MDS and AA, we found that mutation profiling has a high predictive value for identifying individuals with a myeloid neoplasm. [36] In particular, selected mutation patterns were proven highly specific for myeloid neoplasms with myelodysplasia, which may possibly identify bona fide MDS even in the absence of definitive morphological features, as previously acknowledged for selected cytogenetic abnormalities.…”

Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS)

“…Gene mutations have started to be taken into account for risk stratification of myeloid malignancies recently, and cumulating data are suggesting that certain gene mutations have prognostic significance in MDS [ 22 , 23 ]. Of particular interest, Nazha et al recently reported the genomic analysis of 237 MDS patients, in which h-MDS patients comprised 14% [ 10 ]. In their study, there was no difference in the distribution of cytogenetic abnormalities between their NH-MDS and h-MDS subgroups.…”

“…Recently, age-adjusted criteria of marrow hypocellularity have also been proposed to define h-MDS, for instance, <30% cellularity in patients younger than 70 years and <20% cellularity in patients older than 70 years, to account for the physiologically deceasing marrow cellularity with increasing age [ 6 – 8 ]. Although h-MDS share a number of similar clinical features with NH-MDS, and both have a propensity to leukemic transformation during clinical follow-up, h-MDS appear to be a distinct clinico-pathological entity [ 9 , 10 ], suggesting an unique underlying pathogenesis of this disease. Recently, a number of somatic mutations, such as mutations in ASXL1, EZH2, TET2, IDH1/2, DMNT3A, RUNX1, NRAS, KRAS, TP53 , and splicing complex genes, which may play important roles in the pathogenesis of MDS, have been described [ 11 ].…”