Single base substitution mutational signatures in pediatric acute myeloid leukemia based on whole genome sequencing.
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ABSTRACT:
SUBMITTER: Gunnarsson R
PROVIDER: S-EPMC8102186 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Single base substitution mutational signatures in pediatric acute myeloid leukemia based on whole genome sequencing.
Gunnarsson Rebeqa R Yang Minjun M Olsson-Arvidsson Linda L Biloglav Andrea A Behrendtz Mikael M Castor Anders A Paulsson Kajsa K Johansson Bertil B
Leukemia 20210416 5
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Project description:Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.
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Project description:Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.
| S-EPMC9206820 | biostudies-literature
Project description:BackgroundAlterations of 11q23/KMT2A are the most prevalent cytogenetic abnormalities in acute myeloid leukemia (AML) and the prognostic significance of 11q23/KMT2A-rearranged AML based on various translocation partners varies among different studies. However, few studies evaluated the molecular characteristics of 11q23/KMT2A-rearranged pediatric AML. We aim to analyze the mutational landscape of 11q23/KMT2A-rearranged AML and assess their prognostic value in outcomes.MethodsThe mutational landscape and clinical prognosis of 105 children with 11q23/KMT2A-rearranged AML in comparison with 277 children with non-11q23/KMT2A-rearranged AML were analyzed using publicly accessible next-generation sequencing data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset.ResultsPediatric AML patients with 11q23/KMT2A-rearrangements harbored a low number of mutations (Median, 1 mutation/patient, range, 1-22), 58% of which involved in RAS pathway mutations (KRAS, NRAS, and PTPN11) and 10.5% of which comprised of SETD2 mutations. Compared with non-11q23/KMT2A-rearranged AML, the incidence of KRAS (32.4% vs. 10.1%, P〈0.001) and SETD2 (10.5% vs. 1.4%, P=0.001) gene mutations in 11q23/KMT2A-rearranged AML was significantly higher. Both KRAS and SETD2 mutations occurred more often in t(10;11)(p12;q23). KRAS mutations were correlated with worse 5-year event-free survival [EFS] (Plog-rank = 0.001) and 5-year overall survival [OS] (Plog-rank = 0.009) and the presence of SETD2 mutations increases the 5-year relapse rate (PGray = 0.004). Multivariate analyses confirmed KRAS mutations in 11q23/KMT2A-rearranged AML as an independent predictor for poor EFS (hazard ratio [HR] = 2.10, P=0.05) and OS (HR = 2.39, P=0.054).ConclusionOur findings show that pediatric patients with 11q23/KMT2A rearrangements have characteristic mutation patterns and varying clinical outcomes depending on different translocation partners, which could be utilized to develop more accurate risk stratification and tailored therapies.
| S-EPMC9883550 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
| S-EPMC7787979 | biostudies-literature
Project description:Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390-400. ©2016 AACR.
| S-EPMC5243866 | biostudies-literature
Project description:Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
| S-EPMC7613262 | biostudies-literature
Project description:BackgroundIn Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols are used. CCAAT Enhancer Binding Protein Alpha (CEBPA) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies. CEBPA mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients.Aim of the studyTo identify the mutational landscape of the CEBPA gene in pediatric patients with de novo AML and assess its influence on clinical features and overall survival (OS).Materials and methodsDNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of CEBPA was performed in 80 patients.ResultsCEBPA was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14). CEBPA biallelic (CEBPA BI) mutations were identified in five patients. M2 subtype was the most common in CEBPA positive patients (CEBPA POS) (p = 0.009); 50% of the CEBPA POS patients had a WBC count > 100,000 at diagnosis (p = 0.004). OS > 1 year was significantly better in CEBPA negative (CEBPA NEG) patients (p = 0.0001). CEBPA POS patients (either bi- or monoallelic) had a significantly lower OS (p = 0.002). Concurrent mutations in FLT3, CSF3R, and WT1 genes were found in CEBPA POS individuals. Their contribution to poor OS cannot be ruled out.ConclusionCEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of CEBPA POS was in the range reported for pediatric AML (4.5-15%). CEBPA mutations showed a negative impact on OS as opposed to the results of other studies.
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Project description:New methods like panel-based RNA fusion sequencing (RNA-FS) promise improved diagnostics in various malignancies. We here analyzed the impact of RNA-FS on the initial diagnostics of 241 cases with pediatric acute myeloid leukemia (AML). We show that, compared to classical cytogenetics (CCG), RNA-FS reliably detected risk-relevant fusion genes in pediatric AML. In addition, RNA-FS strongly improved the detection of cryptic fusion genes like NUP98::NSD1, KMT2A::MLLT10 and CBFA2T3::GLIS2 and thereby resulted in an improved risk stratification in 25 patients (10.4%). Validation of additionally detected non-risk-relevant high confidence fusion calls identified PIM3::BRD1, C22orf34::BRD1, PSPC1::ZMYM2 and ARHGAP26::NR3C1 as common genetic variants and MYB::GATA1 as recurrent aberration, which we here describe in AML subtypes M0 and M7 for the first time. However, it failed to detect rare cytogenetically confirmed fusion events like MNX1::ETV6 and other chromosome 12p-abnormalities. As add-on benefit, the proportion of patients for whom measurable residual disease (MRD) monitoring became possible was increased by RNA-FS from 44.4 to 75.5% as the information on the fusion transcripts' sequence allowed the design of new MRD assays.
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Project description:Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.
| S-EPMC8229099 | biostudies-literature