Acquired somatic variants in inherited myeloid malignancies

Armes, Hannah; Río-Machín, Ana; Krizsán, Szilvia; Bödör, Csaba; Kaya, Fadimana; Bewicke-Copley, Findlay; Alnajar, Jenna; Walne, Amanda J.; Péterffy, Borbála; Tummala, Hemanth; Rouault-Pierre, Kevin; Dokal, Inderjeet; Vulliamy, Tom; Fitzgibbon, Jude

doi:10.1038/s41375-022-01515-2

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…Recurrent CDC25C variants were reported in ~50% of RUNX1 -mutated patients and hierarchical architecture analysis showed that these variants represent an early event during transformation, defining a pre-leukemic clone ( 140 ). Other studies have frequently detected variants in TET2, BCOR , PHF6, CDC25C, SRSF2 , and GATA2 ( 13 , 37 , 184 ). In one study, BCOR variants were particularly common with up to four different variants per patients, however, presence, number or VAF did not correlate with clonal evolution or disease progression ( 185 ).…”

Section: Germline Runx1 Variants Frequently Displa...mentioning

confidence: 96%

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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Section: Germline Runx1 Variants Frequently Displa...mentioning

confidence: 96%

Germline and somatic drivers in inherited hematologic malignancies

Zoller,

Trajanova,

Feurstein

2023

Front. Oncol.

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“…Most MDS patients have a single CEBPA mutation, but both mutations were observed in AML cases secondary to MDS. The presence of a single CEBPA mutation coupled with mutations in different genes showed a poor prognosis in MDS [ 69 , 70 , 71 ]. The study of Shih revealed that the frequency of CEBPA gene mutations was 8% at the moment of MDS diagnosis and 12% at the progression from MDS to AML [ 69 ] and considered that CEBPA mutations might be involved in the pathogenesis of a subgroup of MDS cases with the progression of the disease [ 69 ].…”

Section: Molecular Signaturementioning

confidence: 99%

“…The study of Shih revealed that the frequency of CEBPA gene mutations was 8% at the moment of MDS diagnosis and 12% at the progression from MDS to AML [ 69 ] and considered that CEBPA mutations might be involved in the pathogenesis of a subgroup of MDS cases with the progression of the disease [ 69 ]. CEBPA mutations are more common in secondary AML, indicating that these gene mutations are attained later during the progression of the disease to AML in a subgroup of cells that extend [ 17 , 70 ].…”

Section: Molecular Signaturementioning

confidence: 99%

The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia

Bănescu

Tripon

Muntean

2023

IJMS

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Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.

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“…Moreover, the veracity of the loss‐of‐function nature of VUS‐predicted pathogenic variants and therefore the accuracy of the in silico classification was confirmed through an in vitro functional assay in primary CLL samples measuring the ATM kinase activity by flow cytometry (Figure 1C). Interestingly, the high frequency of somatic loss of the second ATM allele in patients with ATM germline pathogenic mutations is reminiscent of other genes predisposing to haematological malignancies, such as DDX41 , CEBPA or RUNX1 , where the germline variant seems to require the acquisition of a second mutation in the other allele for onset of overt symptoms 8 …”

Section: Figurementioning

confidence: 99%

“…Interestingly, the high frequency of somatic loss of the second ATM allele in patients with ATM germline pathogenic mutations is reminiscent of other genes predisposing to haematological malignancies, such as DDX41, CEBPA or RUNX1, where the germline variant seems to require the acquisition of a second mutation in the other allele for onset of overt symptoms. 8 CLL has one of the strongest inherited components of any cancer, with evidence of a Mendelian inheritance pattern and relatives of patients having an eight-fold increased risk of developing the disease. Common genetic variants and rare germline mutations in several loci have been identified as predisposing factors over the last few years, including ATM, POT1 and other components of the shelterin complex.…”

mentioning

confidence: 99%