GENOMED4ALL: Improving MDS Classification and Prognosis by AI

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Myelodysplastic syndromes (MDS) typically occur in elderly people. Patients present peripheral blood cytopenia, and with time a portion of these subjects evolve into acute myeloid leukaemia (AML). The natural history of MDS is heterogeneous ranging from conditions with a near-normal life expectancy ...

Myelodysplastic syndromes (MDS) typically occur in elderly people. Patients present peripheral blood cytopenia, and with time a portion of these subjects evolve into acute myeloid leukaemia (AML). The natural history of MDS is heterogeneous ranging from conditions with a near-normal life expectancy to forms close to AML, and therefore a risk-adapted treatment strategy is mandatory. Current prognostic scores (Revised International Prognostic Scoring System, IPSS-R) present limitations, and in most cases fail to capture reliable prognostic information at individual level. Study of MDS has been rapidly transformed by genome characterization. Somatic mutations occur in the genomes of hematopoietic stem cells at a low, but detectable frequency during normal DNA replication. Any genetic alteration that causes a selective advantage relative to other self-renewing cells will lead to clonal dominance (clonal haematopoiesis, CH). The consequence of CH is genomic instability leading to increased risk of acquiring additional mutations and to develop MDS, solid cancer and other illnesses. The time and place of individual mutations and their clonal emergence during the course of the disease are central issues for a better comprehension of MDS pathogenesis and phenotype and for the development of cancer preventive strategies. Important steps forward have been made in defining the molecular architecture of MDS. The MDS associated with 5q deletion derives from the haploinsufficiency of RPS14 gene. Genes encoding for spliceosome components were identified in a high proportion of subjects with MDS. There is a close relationship between ring sideroblasts and SF3B1 mutations, which is consistent with a causal relationship. In addition, an increasing number of genes have been found to carry recurrent mutations in MDS, involved in DNA methylation (DNMT3A, TET2, IDH1/2), chromatin modification (EZH2, ASXL1), transcriptional regulation (RUNX1), signal transduction (KRAS, CBL). Gene mutations have been reported to influence survival and risk of disease progression in MDS, and the evaluation of the mutation status may add significant information to currently used prognostic scores. For instance, we found that SF3B1 mutations were independent predictors of favorable prognosis, while driver mutations of ASXL1, SRSF2, RUNX1, TP53 and EZH2 genes were associated with a reduced probability of survival. MDS with ring sideroblasts provide the best evidence that the identification of the mutant gene responsible for the initial clone is relevant to clinical outcome. In fact, ring sideroblasts may be found not only in patients with a founding mutation in SF3B1, but also in those with an initiating oncogenic lesion in SRSF2. However, the median leukemia-free survival is >10 years in the former vs <2 years in the latter. Moreover, mutation screening may affect clinical decision making : a) in MDS with 5q-, subjects carrying TP53 mutations have a higher risk of leukemic progression and a lower probability of response to lenalidomide; b) in patients receiving HSCT, TP53 mutations predict high probability of relapse; c) SF3B1 mutations are associated with increased probability of erythroid response to TGFb inhibitors (luspatercept), and d) TET2 mutations might be associated with response to HMA. Despite these findings, caution is needed against immediately adopting such mutational testing in clinical practice. First, the presence of mutations in a given individual has only limited predictive power, as conversion to MDS is rare regardless of mutation status. In addition, in patients with overt MDS, genetic abnormalities explain only a proportion of the total hazard for survival associated with specific treatments, meaning that a large percentage is still associated with clinical and non-mutational factors. Comprehensive analyses of large patient population and new methods to study gene-gene interactions and genoptype-phenotype correlations are warranted to correctly estimate the independent effect of each genomic abnormality on clinical outcome and response to treatment. By combining an already available, large amount of sequenced genomic data and clinical information, the authors hypothesize that AI will allow to understand better MDS biology and classification, enhance prognostic/predictive capacity of currently available tools and apply treatments in a more targeted way, thus facilitating the implementation of personalized medicine program across EU.

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