Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia

Maung, Kyaw Ze Ya; Leo, Paul; Bassal, Mahmoud A.; Casolari, Débora A.; Gray, Jennifer; Bray, Sarah C; Pederson, Stephen; Singhal, Deepak; Samaraweera, Saumya E.; Nguyen, Tran; Cildir, Gökhan; Marshall, Mhairi; Ewing, Adam D.; Duncan, Emma L.; Brown, Matthew A.; Saal, Russell; Tergaonkar, Vinay; To, Luen Bik; Marlton, Paula; Gill, Devinder; Lewis, Ian D.; Deans, Andrew J.; Brown, Anna L.; D’Andrea, Richard J.; Gonda, Thomas J.

doi:10.1038/s41408-018-0090-7

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…The FA pathway is known to be an essential DNA repair pathway, and deficiency of FA genes result in Fanconi anemia, and hence increase the chance of having myeloid malignancies. In line with our finding, Maung et al also show that there is an enrichment of deleterious germline rare variants on FA genes in AML patients (Maung, 2018).…”

Section: Discussionsupporting

confidence: 93%

Rare germline variant contributions to myeloid malignancy susceptibility

Wang

Wei

et al. 2020

Leukemia

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Section: Discussionsupporting

confidence: 93%

Rare germline variant contributions to myeloid malignancy susceptibility

Wang

Wei

et al. 2020

Leukemia

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“…76 Biallelic germline pathogenic variants in the 22 FANC genes (except FANCB and FANCR) are associated with AML. 77 Inherited bone marrow-failure syndromes grouped by gene variants affecting telomere structure and function, also known as short telomere syndrome (STS), display a wide spectrum of phenotypic diversity (premature graying of hair, idiopathic pulmonary fibrosis, immune dysregulation, and/or cryptogenic cirrhosis) and are characterized by increased predisposition toward MDS/AML. 40,41,[78][79][80] Specifically among STS genes, thus far only TERT, TERC, and RTEL1 have been associated with myeloid neoplasms.…”

Section: Nonsyndromic Familial Myeloid Predisposition Syndromesmentioning

confidence: 99%

Hereditary Predisposition to Hematopoietic Neoplasms

Mangaonkar

Patnaik

2020

Mayo Clinic Proceedings

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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.

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“…Fanconi anemia is an autosomal recessive or X-linked recessive IBMFS caused by mutations in almost 22 genes [110]. FA patients show variable hematological and non-hematological manifestations.…”

Section: Fanconi Anemiamentioning

confidence: 99%

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Bezzerri

Api

Allegri

et al. 2020

IJMS

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Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.

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Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia

Cited by 18 publications

References 15 publications

Rare germline variant contributions to myeloid malignancy susceptibility

Rare germline variant contributions to myeloid malignancy susceptibility

Hereditary Predisposition to Hematopoietic Neoplasms

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

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