Inherited bone marrow failure (BMF) syndromes are genetically diverse - more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic ...counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in
,
,
and
. This will provide important data that may help to individualize and improve care for these patients.
Abstract
Once thought to be exceedingly rare, the advent of next-generation sequencing has revealed a plethora of germline predisposition disorders that confer risk for hematopoietic 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 hematopoietic 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 hematopoietic 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.
Patients with thrombocytopenia 5 have an autosomal dominant disorder of decreased platelet number with tendency to bleed, usually presenting in childhood, and have been found to have germline ...mutations in
ETV6
, which encodes a master hematopoietic transcription factor. Some patients who present similarly have inherited mutations in
RUNX1
or
ANKRD26.
All three germline syndromes are also associated with a predisposition to myelodysplastic syndrome (MDS) and acute leukemia (AL). Since the first description of germline
ETV6
mutations, 18 families have been reported. The common phenotype is mild to moderate thrombocytopenia with a variable predisposition to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and MDS. This review will focus upon the role of
ETV6
in hematopoiesis, especially in myeloid differentiation and maturation, and will describe the functional effects of mutant ETV6. The review will also provide an overview of common clinical features as well as recommendations for patient screening and follow-up and will debate whether additional clinical features should be included with the germline
ETV6
syndrome.
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.
In this review, we provide an overview of familial myelodysplastic syndromes (MDS)/acute leukemia (AL) and bone marrow failure syndromes, as well as insights into familial myeloproliferative ...neoplasms (MPNs), familial multiple myeloma (MM), familial Waldenström macroglobulinemia (WM), familial lymphoma, and cancer predisposition syndromes with increased risk of MDS/AL. This field will continue to accelerate as next-generation sequencing (NGS) techniques identify novel predisposition alleles in families with a genetic predisposition to hematologic malignancies. Newly identified predisposition genes continue to inform the field of inherited leukemia and other hematologic malignancies. Current developments in clinical translation include techniques detailing the acquisition of appropriate germline material for patient work-ups, methods for genetic testing, and nuances essential for the treatment and clinical management of patients with a genetic predisposition to hematologic malignancies.
The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer ...predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9%; p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5%; p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
The broad use of next-generation sequencing and microarray platforms in research and clinical laboratories has led to an increasing appreciation of the role of germline mutations in genes involved in ...hematopoiesis and lineage differentiation that contribute to myeloid neoplasms. Despite implementation of the American College of Medical Genetics and Genomics and Association for Molecular Pathology 2015 guidelines for sequence variant interpretation, the number of variants deposited in ClinVar, a genomic repository of genotype and phenotype data, and classified as having uncertain significance or being discordantly classified among clinical laboratories remains elevated and contributes to indeterminate or inconsistent patient care. In 2018, the American Society of Hematology and the Clinical Genome Resource co-sponsored the Myeloid Malignancy Variant Curation Expert Panel to develop rules for classifying gene variants associated with germline predisposition to myeloid neoplasia. Herein, we demonstrate application of our rules developed for the
gene to variants in six examples to show how we would classify them within the proposed framework.
Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with clonal evolution and development of complex karyotypes. Deletion of 5q ...(del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze clonal evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of clonal evolution. There are two main routes of cytogenetic clonal evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene
, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of
is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes.
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