Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild‐type TP53 and mutant KRAS, G3BP1 and IL7R

Goldgraben, Mae A.; Fewings, Eleanor; Larionov, Alexey; Scarth, James; Redman, James; Telford, Nick; Arkwright, Peter D.; Bonney, Denise; Wilks, Deepti P; Kulkarni, Samar; Taylor, Alexander M.; Tischkowitz, Marc; Meyer, Stefan

doi:10.1002/pbc.28354

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…Biallelic mutations of ATM gene are responsible for ataxia-telangiectasia syndrome, a condition associated to a high risk for development of lymphoid malignancies and carcinoma, 31 although rare cases of AML have also been reported. 32 , 33 , 34 , 35 , 36 In heterozygous state, many ATM germ line mutations have been associated with an increased risk for breast, prostate, and pancreatic cancer and melanoma. 37 , 38 , 39 , 40 For this reason, ATM should be routinely tested in hereditary cancer NGS studies, although it was recently found that 25% of HHMS-targeted sequencing panels do not include this gene.…”

Section: Discussionmentioning

confidence: 99%

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

et al. 2023

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Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

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Section: Discussionmentioning

confidence: 99%

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

et al. 2023

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“…Interaction between G3BP1 and lncRNA P53RRA traps TP53 in the nucleus, leading to TP53-mediated cell cycle arrest, ferroptosis, as well as apoptosis [ 45 ]. It is reported that low G3BP1 expression is related to poor AML survival, highlighting the protective role of G3BP1 [ 46 ]. Another TP53 regulator, SOCS1, is required for p53 activation and the regulation of cellular senescence and modulates p53 target genes expression (e.g., SLC7A11) and sensitizes cells to ferroptosis [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Construction of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in acute myeloid leukemia

Huang

Zhou

et al. 2021

Bosn J of Basic Med Sci

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy that strongly correlates with poor clinical outcomes. Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death which plays an important role in various human cancers. Nevertheless, the prognostic significance and functions of ferroptosis-related genes (FRGs) in AML have not received sufficient attention. The aim of this article was to evaluate the association between FRGs levels and AML prognosis using publicly available RNA-sequencing datasets. The univariate Cox regression analysis identified 20 FRGs that correlate with patient overall survival. The LASSO Cox regression model was used to construct a prognostic 12-gene risk model using a TCGA cohort, and internal and external validation proved the signature efficient. The 12-FRGs signature was then used to assign patients into high- and low-risk groups, with the former exhibiting markedly reduced overall survival, compared to the low-risk group. ROC curve analysis verified the predictive ability of the risk model. Functional analysis showed that immune status and drug sensitivity differed between the 2 risk groups. In summary, FRGs is a promising candidate biomarker and therapeutic target for AML.

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The natural history of ataxia-telangiectasia (A-T): A systematic review

et al. 2022

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Background Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition. Objectives Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature. Search methods 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 –present, Web of Science core collection, Elsevier Scopus, and Cochrane Library. Selection criteria All human studies that report any aspect of A-T. Data collection and analysis Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest. Main results 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months). Conclusions This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

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Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild‐type TP53 and mutant KRAS, G3BP1 and IL7R

Cited by 4 publications

References 19 publications

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

Construction of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in acute myeloid leukemia

The natural history of ataxia-telangiectasia (A-T): A systematic review

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