Hereditary Predisposition to Hematopoietic Neoplasms

Abstract

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasmsd collectively known as hereditary predisposition syndromes (HPS)dare being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma-cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromesdsuch as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopeniasdalso have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.

Germline risk of clonal haematopoiesis

“…Family-based studies of inherited risk of MDS and AML have noted a high prevalence of non-disease CHIP in carriers of rare inherited variants affecting RUNX1 , a member of the core binding factor family of transcription factors and a key regulator of definitive haematopoiesis 100 , 101 . Aside from RUNX1 , there are several other germline variants recognized to predispose to myeloid, lymphoid or plasma-cell neoplasms that could presumably also predispose to asymptomatic CHIP 102 . Genetic association studies of CHIP-only cohorts (that is, only individuals without haematological disease; discussed in detail in the ‘Results from genetic association studies’ section below) have seen a significant signal with just one of these genes: TERT 27 .…”

Donor Cell-Derived Acute Myeloid Leukaemia with 3q26.2 Involvement/MECOM Rearrangement ‐ A Case Report and Literature Review

“…The age of her sibling donor remains unknown to us. Some germline variants, particularly those involving ANKRD26, CEBPA, DDX41, ETV6, GATA2, and RUNX1, have been reported as hereditary predispositions to developing myeloid malignancies [28][29][30], including donorcell derived malignancies [31]. All these six genes are included in our clinical NGS-based 81-gene leukaemia mutation panel, and none of them had variant alleles.…”

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

“…For the purpose of this manuscript, the above major categories have been reviewed in relation to novel findings concerning germline predispositions in haematological malignancies. In addition, hereditary predispositions also include lymphoid and plasma-cell cancers, with recent discoveries of pathogenic variants in the KDM1A/LSD1 and DIS3 genes, respectively [ 17 ].…”