Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists

Abstract

Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve telomere maintenance, DNA repair, biogenesis of ribosomes, control of proliferation and others. The increased knowledge on the genes involved in MDS pathogenesis and the wider availability of molecular diagnostic assessment have led to an improvement in the detection of IBMFS genetic predisposition in MDS patients. A punctual recognition of these disorders implies a strict surveillance of the patient in order to detect early signs of progression and promptly offer allogeneic hematopoietic stem cell transplantation, which is the only curative treatment. Moreover, identifying an inherited mutation allows the screening and counseling of family members and directs the choice of donors in case of need for transplantation. Here we provide an overview of the most recent data on MDS with genetic predisposition highlighting the main steps of the diagnostic and therapeutic management. In order to highlight the pitfalls of detecting IBMFS in adults, we report the case of a 27-year-old man affected by MDS with an underlying telomeropathy.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Interestingly, the aetiology of the inherited MDS is associated with germline predisposition in genes involved in telomere maintenance, DNA repair, biogenesis of ribosomes and cell proliferation. Further detailed reviews on the genetics and clinical implications of various gene mutations in these disorders have been extensively covered elsewhere [7][8][9][10]. Recent studies have suggested that the addition of molecular data to the prognostic scoring systems can improve its predictive applicability in the clinical settings [6,[11][12][13], that will not only help in the clinical diagnosis but can also be used for the monitoring of disease progression.…”

Increased clonal hematopoiesis involving DNA damage response genes in patients undergoing lung transplantation

“…There is evidence that certain germline variants predispose to the development of CH. Genetic carriers of telomere biology disorders have an increased risk of developing both interstitial lung disease and CH carrying DDR gene variants (29). To test the hypothesis that germline variants in genes predisposing in telomere maintenance genes are enriched in lung transplant patients with DDR CH, we performed whole exome sequencing on a subset of 52 patients, including all patients with ILD or DDR CH.…”