The genetic basis of myelodysplasia and its clinical relevance

Abstract

Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient’s genome are now needed.

The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms

“…Overall, these mutation frequencies are in line with published data, except for a slightly higher frequency of CBL mutations in CMML and the absence of NRAS mutations in MDS/MPN, U. [2][3][4][5]10,[12][13][14] In previous studies the frequency of the CBL mutation was found to be ~10% in CMML instead of the 24% in our study and RAS mutations were detected in 14% of MDS/MPN, U, contrasting with the 0% in the present study.…”

Clonal hematopoiesis in acquired aplastic anemia

“…The clones are thought to be neoplastic, in that their growth is no longer compatible with normal hematopoiesis, causing ineffective production of mature blood cells, enhanced apoptosis, and even progression to AML, although the clinical presentation is highly variable. 41,42 Thus, at least conceptually, clonality is an essential requisite for the pathophysiology of MDS, but for the sake of clinical/pathological diagnosis, clinicians and pathologists usually diagnose the involvement of a neoplastic process primarily relying on cell morphology, in which the presence of excess blasts ($5%) (propensity to leukemia) and/or dysplasia (in $10% of myeloid cells) with or without increased ($15%) ring sideroblasts (deregulated myelopoiesis) empirically, but consistently, indicates that the defective hematopoiesis is caused by malignant clones, although morphologic examination may not necessarily be consistent between observers ( Figure 2). 41 Alternatively, direct demonstration of a malignant clonal process by cytogenetics can establish the diagnosis of MDS, even in the absence of dysplasia or increased blast counts, but the borderline between malignant and benign lesions is obscured: a set of abnormalities, including 27/del(7q), 25/del(5q),…”

“…16,18,63 Somatic mutations in AA Somatic mutations are more reliable and sensitive markers for detecting clonal populations than NRXI or cytogenetics. The revolutionized technologies of next-generation DNA sequencing (NGS), together with the accumulated knowledge about the major driver mutations in MDS/AML, 42,64 have prompted investigations on somatic mutations in AA in relation to clonal evolution to MDS/AML. Thus, since the first report by Lane et al, 13 there have been several NGS-based mutation studies on AA during the past 2 years reporting varying mutation frequencies ranging from 5.3% to 72% [13][14][15][16][17][18] (Table 1).…”

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

“…Clonal analysis based on the variant allele frequency of SF3B1 and other co-existing mutations revealed that mutations in SF3B1 are present in the dominant clone in most cases. Interestingly, the percentage of BM RS is highly correlated with SF3B1 mutant allele burden [4,[6][7][8], which strongly suggests that mutant SF3B1 directly or indirectly contributes to the formation of RS. In fact, SF3B1 mutations have a high positive predictive value for disease phenotype with RS of 97.7%, whereas the absence of these mutations has an equivalent negative prediction value [7].…”