Strategy for identification of a potential inherited leukemia predisposition in a 299 patient’s cohort with tumor-only sequencing data

Aguilera-Diaz, Almudena; Larráyoz, María José; Palomino‐Echeverría, Sara; Vázquez, Iria; Ariceta, Beñat; Mañú, Amagoia; Blasco-Iturri, Zuriñe; Bernal, Teresa; Salaverri, Matxalen Olivares; Rubio, María Teresa Olave; Rifon-Roca, Jose; Prósper, Felipe; Fernández-Mercado, Marta; Calasanz, Marı́a José

doi:10.1016/j.leukres.2020.106386

Cited by 3 publications

(1 citation statement)

References 26 publications

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“…Important to also recognize is that the somatic hotspot variant p.R525H is found in more than half of the patients with germline DDX41 variants [ 44 ]. In myeloid malignancies, patients with a ‘double-hit’ in a gene such as CEBPA , RUNX1 , or DDX41 often have one variant in the germline with a VAF between 40 and 60%, and a second variant of somatic origin with variable VAF [ 52 ].…”

Section: Germline Predisposition To Mdsmentioning

confidence: 99%

Genetics of Myelodysplastic Syndromes

Saygin

Godley

2021

Cancers

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Myelodysplastic syndrome (MDS) describes a heterogeneous group of bone marrow diseases, now understood to reflect numerous germline and somatic drivers, characterized by recurrent cytogenetic abnormalities and gene mutations. Precursor conditions including clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance confer risk for MDS as well as other hematopoietic malignancies and cardiovascular complications. The future is likely to bring an understanding of those individuals who are at the highest risk of progression to MDS and preventive strategies to prevent malignant transformation.

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Section: Germline Predisposition To Mdsmentioning

confidence: 99%

Genetics of Myelodysplastic Syndromes

Saygin

Godley

2021

Cancers

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Germline predisposition to hematopoietic malignancies

Feurstein

Drazer

Godley

2021

Human Molecular Genetics

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Once thought to be exceedingly rare, the advent of next-generation sequencing has revealed a plethora of germline predisposition disorders that confer risk for haematopoietic malignancies (HMs). These syndromes are now recognized to be much more common than previously thought. The recognition of a germline susceptibility risk allele in an individual impacts the clinical management and health surveillance strategies in the index patient and relatives who share the causative DNA variant. Challenges to accurate clinical testing include a lack of familiarity in many health care providers, the requirement for DNA samples that reasonably approximate the germline state, and a lack of standardization among diagnostic platforms as to which genes are sequenced and their capabilities in detecting the full range of variant types that confer risk. Current knowledge gaps include a comprehensive understanding of all predisposition genes; whether scenarios exist in which an allogeneic stem cell transplant using donor haematopoietic stem cells with deleterious variants is permissive; and effective means of delivering genetic counseling and results disclosure for these conditions. We are hopeful that comprehensive germline genetic testing, universal germline testing for all patients with an HM, universal germline testing for allogeneic haematopoietic stem cell donors, and the development of preventive strategies to delay or even prevent malignancies will be available in the near future. These factors will likely contribute to improved health outcomes for at-risk individuals and their family members.

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Germline and somatic drivers in inherited hematologic malignancies

Zoller,

Trajanova,

Feurstein

2023

Front. Oncol.

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Inherited hematologic malignancies are linked to a heterogenous group of genes, knowledge of which is rapidly expanding using panel-based next-generation sequencing (NGS) or whole-exome/whole-genome sequencing. Importantly, the penetrance for these syndromes is incomplete, and disease development, progression or transformation has critical clinical implications. With the earlier detection of healthy carriers and sequential monitoring of these patients, clonal hematopoiesis and somatic driver variants become significant factors in determining disease transformation/progression and timing of (preemptive) hematopoietic stem cell transplant in these patients. In this review, we shed light on the detection of probable germline predisposition alleles based on diagnostic/prognostic ‘somatic’ NGS panels. A multi-tier approach including variant allele frequency, bi-allelic inactivation, persistence of a variant upon clinical remission and mutational burden can indicate variants with high pre-test probability. We also discuss the shared underlying biology and frequency of germline and somatic variants affecting the same gene, specifically focusing on variants in DDX41, ETV6, GATA2 and RUNX1. Germline variants in these genes are associated with a (specific) pattern or over-/underrepresentation of somatic molecular or cytogenetic alterations that may help identify the underlying germline syndrome and predict the course of disease in these individuals. This review is based on the current knowledge about somatic drivers in these four syndromes by integrating data from all published patients, thereby providing clinicians with valuable and concise information.

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Strategy for identification of a potential inherited leukemia predisposition in a 299 patient’s cohort with tumor-only sequencing data

Cited by 3 publications

References 26 publications

Genetics of Myelodysplastic Syndromes

Genetics of Myelodysplastic Syndromes

Germline predisposition to hematopoietic malignancies

Germline and somatic drivers in inherited hematologic malignancies

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