Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Kim, Borahm; Yun, Woobin; Lee, Seung Tae; Choi, Jong Rok; Yoo, Keon Hee; Koo, Hong Hoe; Jung, Chul Won; Kim, Sun Hee

doi:10.1038/s41598-020-71386-z

Cited by 28 publications

(27 citation statements)

References 20 publications

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“…We excluded 77 publications, including 41 animal studies, 20 about irrelevant subjects, 13 reviews, and three in languages other than English and Chinese. The remaining 30 were next given full-text reviews and all were considered eligible for this study, including nine case series, 12 , 14 – 21 11 case reports, 22 – 32 four reports about DDX41 -related solid cancers, 33 – 36 and six rare case reports 37 – 42 ( Figure 1 ). No extra study was identified from the references listed in the relevant reviews and the included studies.…”

Section: Resultsmentioning

confidence: 99%

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

Wan

Han

2021

Therapeutic Advances in Hematology

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Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms. Methods: In this study, “ DDX41” was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary. Results: Pooled incidence was 3.3% (95% confidence interval 2.4–4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20–88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed. Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886)

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Section: Resultsmentioning

confidence: 99%

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

Wan

Han

2021

Therapeutic Advances in Hematology

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“…These pathways may be explored in future for the various anticancer therapies. Bloom syndrome patients, develop haematologic malignancies frequently [54,55]. The yeast-two hybrid assay, coimmunoprecipitation and far western analysis con rmed the C-terminal region of blm to interact directly with mlh1 to maintain genomic stability [56].…”

Section: Discussionmentioning

confidence: 98%

Deregulation of MMR-Related Pathways and Anticancer Potential of Curcuma Derivatives– A Computational Approach

Bhattacharya¹,

Patel²

2021

Preprint

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Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that, there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

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“…Nonetheless, discerning how these mechanisms occur is also of fundamental importance to develop strategies to predict and prevent disease progression. Indeed, some mutations, particularly in the genes involved in DNA repair ( FANC genes), telomere biology disorder ( CTC1 , RTEL1 , WRAP53 ), germline myeloid neoplasm-associated genes ( DDX41 , RUNX1 ) and others such as C/EBPA and WT1 , are associated with a predisposition to an earlier onset of AML and cases of familial AML [ 42 , 43 , 44 ]. One of the most interesting ways to apply clonal evolution studies and high throughput technologies to the clinic is represented by the future perspective to be able to investigate AML response to different treatments, in particular by analyzing those clones emerging after therapy, which are often involved in relapse.…”

Section: Identifying Genetic Heterogeneity and Subclones Populations Exploiting High Throughput Techniquesmentioning

confidence: 99%

Exploiting Clonal Evolution to Improve the Diagnosis and Treatment Efficacy Prediction in Pediatric AML

Bertuccio

Anselmi

Masetti³

et al. 2021

Cancers

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Despite improvements in therapeutic protocols and in risk stratification, acute myeloid leukemia (AML) remains the leading cause of childhood leukemic mortality. Indeed, the overall survival accounts for ~70% but still ~30% of pediatric patients experience relapse, with poor response to conventional chemotherapy. Thus, there is an urgent need to improve diagnosis and treatment efficacy prediction in the context of this disease. Nowadays, in the era of high throughput techniques, AML has emerged as an extremely heterogeneous disease from a genetic point of view. Different subclones characterized by specific molecular profiles display different degrees of susceptibility to conventional treatments. In this review, we describe in detail this genetic heterogeneity of pediatric AML and how it is linked to relapse in terms of clonal evolution. We highlight some innovative tools to characterize minor subclones that could help to enhance diagnosis and a preclinical model suitable for drugs screening. The final ambition of research is represented by targeted therapy, which could improve the prognosis of pediatric AML patients, as well as to limit the side toxicity of current treatments.

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Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Cited by 28 publications

References 20 publications

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

Deregulation of MMR-Related Pathways and Anticancer Potential of Curcuma Derivatives– A Computational Approach

Exploiting Clonal Evolution to Improve the Diagnosis and Treatment Efficacy Prediction in Pediatric AML

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