Clinical and biological implications of driver mutations in myelodysplastic syndromes

Key Points MDS is characterized by mutations in >40 genes, a complex structure of gene-gene interactions and extensive subclonal diversification. The total number of oncogenic mutations and early detection of subclonal mutations are significant prognostic variables in MDS.

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Molecular disease monitoring using circulating tumor DNA in myelodysplastic syndromes

Blood ◽

10.1182/blood-2016-09-740308 ◽

2017 ◽

Vol 129 (12) ◽

pp. 1685-1690 ◽

Cited By ~ 29

Author(s):

Paul Yeh ◽

Michael Dickinson ◽

Sarah Ftouni ◽

Tane Hunter ◽

Devbarna Sinha ◽

...

Keyword(s):

Treatment Failure ◽

Myelodysplastic Syndromes ◽

Circulating Tumor Dna ◽

Driver Mutations ◽

Disease Monitoring ◽

Key Points ◽

Tumor Dna ◽

Predict Treatment Failure

Key PointsCirculating tumor DNA can monitor disease and predict treatment failure by tracking driver mutations and karyotypic abnormalities in MDS.

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High Throughput Targeted Gene Sequencing in 738 Myelodysplastic Syndromes Patients Reveals Novel Oncogenic Genes, Rare Driver Mutations and Complex Molecular Signatures with Potential Impact for Patient Diagnosis and Prognosis in the Clinic

Blood ◽

10.1182/blood.v120.21.lba-5.lba-5 ◽

2012 ◽

Vol 120 (21) ◽

pp. LBA-5-LBA-5

Author(s):

Elli Papaemmanuil ◽

Moritz Gerstung ◽

Luca Malcovati ◽

Sudhir Tauro ◽

Gunes Gundem ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Peripheral Blood ◽

Gene Mutations ◽

Gene Sequencing ◽

Driver Mutations ◽

Sequencing Analysis ◽

Sequencing Data ◽

Diverse Range ◽

Free Survival ◽

Oncogenic Mutations

Abstract Abstract LBA-5 Myelodysplastic syndromes (MDS) are a diverse group of chronic hematological malignancies characterised by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia (AML). Recent screens of MDS genomes have identified a diverse range of mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation and cell signalling. Whilst these findings improve our understanding in the molecular aetiology of this disease a detailed understanding of the specific genetic contributions, genotype-phenotype relationships and prognostic value of this heterogeneous genomic landscape is warranted. To evaluate the genomic architecture of MDS in more detail, targeted sequencing analysis was performed for 111 genes implicated in myeloid malignancy across 738 MDS patients. Sequencing data were assessed for the presence of oncogenic mutations and detection of regional copy number changes. High-confidence oncogenic mutations (n = 1155) were identified in 41 genes. Of these 41 genes, only 4 (SF3B1, TET2, SRSF2, ASXL1) were mutated in >10% of patients with 15 genes mutated between 10% and 1% of patients and 22 in < 1%. Overall, oncogenic lesions are identified in 78% of MDS patients with 43% of the patients displaying two or three oncogenic events and approximately 10% of patients harbouring four or more oncogenic mutations. Amongst the less characterised genes, we confirm inactivating mutations in CUX1 and IRF1 in 2% and 0.5% of the patients respectively and provide strong evidence that these two genes are bona-fide rare tumour suppressors in MDS. We observe complex patterns of pairwise association between genes, including co-mutation and mutual-exclusivity. Of 325 possible pairwise associations, 47 driver gene mutations pairs were significant (FDR < 10%). Mutations in components of the U2-spliceosome machinery are characteristic of 51% of patients with MDS and whilst mutually exclusive with one another, spliceosome mutations show a strong tendency to co-occur with genes implicated in DNA methylation. Of 24 genes mutated in >5 patients, 8 genes were associated with significantly worse leukemia-free survival if mutated and one gene (SF3B1) with a better leukemia-free survival replicating findings from previous studies. For the new MDS genes described, loss of function truncating mutations in CUX1 are associated with a poor prognosis (p=0.02). Additionally, clinical outcome analysis identifies functional non-canonical mutations within well-characterised driver genes. We find that there is an inverse correlation of leukemia-free survival with the total number of oncogenic lesions observed (p<0.0001). Patients with fewer oncogenic events display lower rates of leukemic transformation and better overall survival, whereas patients with higher number of mutations have a significantly worse outcome (p<0.0001). We evaluate the prognostic potential of targeted genomic sequencing data by means of the area under the receiver operating characteristic (AUC) and compare the predictive value to that of conventional markers utilised in the clinic, including the IPSS classification, peripheral blood counts, bone marrow morphology and cytogenetic analysis. Strikingly we find that the prognostic information contained within the gene sequencing data and peripheral blood counts at diagnosis appears to be equivalent to that derived from existing outcome indicators, suggestive of a potential redundancy between the molecular markers and the morphological variables used to classify patients. Most importantly the number of oncogenic point mutations is an independent biomarker and may therefore be used to refine the prognosis based on existing IPSS categories. The present study provides an unprecedented characterisation of the genomic lesions implicated in MDS pathogenesis, refines the classification of oncogenic driver mutations and reveals a diverse molecular landscape of mostly rare mutations with valuable insights on the operating biological networks. The absence of known oncogenic mutations in 22% of MDS indicates that additional yet uncharacterised genomic events are likely to be operating in MDS pathogenesis. Most importantly our data highlight the potential of well-defined gene mutations as reproducible diagnostic and predictive biomarkers to support MDS patient management and clinical decision-making in the future. Disclosures: No relevant conflicts of interest to declare.

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Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2703 ◽

2013 ◽

Vol 98 (2) ◽

pp. E364-E369 ◽

Cited By ~ 120

Author(s):

Nishant Agrawal ◽

Yuchen Jiao ◽

Mark Sausen ◽

Rebecca Leary ◽

Chetan Bettegowda ◽

...

Keyword(s):

Thyroid Cancer ◽

Somatic Mutations ◽

Medullary Thyroid Cancer ◽

Driver Mutations ◽

High Confidence ◽

Kras Mutations ◽

Protein Coding ◽

Medullary Thyroid ◽

Oncogenic Mutations ◽

Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

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Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽

10.3390/cancers13133296 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3296

Author(s):

Ioannis Chanias ◽

Kristina Stojkov ◽

Gregor Stehle ◽

Michael Daskalakis ◽

Helena Simeunovic ◽

...

Keyword(s):

Precision Medicine ◽

Myelodysplastic Syndromes ◽

Clonal Evolution ◽

Driver Mutations ◽

Future Perspectives ◽

Hematopoietic Stem ◽

Secondary Acute Myeloid Leukemia ◽

Stem And Progenitor Cells ◽

Unfit Patients ◽

Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

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Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.6038 ◽

2010 ◽

Vol 28 (30) ◽

pp. 4616-4620 ◽

Cited By ~ 229

Author(s):

Yihua Sun ◽

Yan Ren ◽

Zhaoyuan Fang ◽

Chenguang Li ◽

Rong Fang ◽

...

Keyword(s):

East Asian ◽

Egfr Mutations ◽

Driver Mutations ◽

Single Institution ◽

Pik3ca Mutations ◽

Oncogenic Mutations ◽

Oncogenic Driver ◽

Never Smokers ◽

Lung Adenocarcinomas ◽

Concurrent Analysis

Purpose To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations. Patients and Methods In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. Results Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations. Conclusion To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases.

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The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽

10.3390/genes12081144 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1144

Author(s):

Chiara Chiereghin ◽

Erica Travaglino ◽

Matteo Zampini ◽

Elena Saba ◽

Claudia Saitta ◽

...

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Clinical Relevance ◽

Driver Mutations ◽

Significant Information ◽

Hematopoietic Stem ◽

Probability Of Survival ◽

Mutational Status ◽

Increased Risk ◽

Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

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Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Applied Microbiology and Biotechnology ◽

10.1007/s00253-020-11022-y ◽

2020 ◽

Vol 105 (1) ◽

pp. 55-66

Author(s):

Wolfgang Hüttel

Keyword(s):

Isotope Labeling ◽

Current Knowledge ◽

Complex Structure ◽

Hydrolytic Stability ◽

Structural Diversity ◽

Gene Clusters ◽

Special Focus ◽

Key Points ◽

Invasive Mycosis ◽

History Of

Abstract Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure−activity relationships. Key points • Complex and highly oxidized lipopeptides produced by fungi. • Crucial in the design of drugs: side chain, solubility, and hydrolytic stability. • Genetic methods for engineering biosynthesis have recently become available.

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Vision Screening

Pediatric Care Online ◽

10.1542/aap.ppcqr.396022 ◽

2020 ◽

Keyword(s):

Primary Care ◽

Early Detection ◽

Physical Examination ◽

Vision Loss ◽

Light Reflection ◽

Primary Care Visit ◽

Vision Screening ◽

Care Visit ◽

Test Instrument ◽

Key Points

Key Points Vision screening should be a routine part of every primary care visit, with physical examination from birth and formal acuity testing from 3 years on. Elements of the physical examination include inspection, red reflex evaluation, corneal light reflection, cover-uncover test. Instrument-based testing can begin at 1 year of age until chart-based acuity testing is possible from 3 years on. Amblyopia, which results in permanent vision loss, is preventable with early detection—before 5 years of age.

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DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes

Blood Advances ◽

10.1182/bloodadvances.2019000192 ◽

2019 ◽

Vol 3 (19) ◽

pp. 2845-2858 ◽

Cited By ~ 6

Author(s):

Brian Reilly ◽

Tiffany N. Tanaka ◽

Dinh Diep ◽

Huwate Yeerna ◽

Pablo Tamayo ◽

...

Keyword(s):

Dna Methylation ◽

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Mononuclear Cells ◽

Scoring Systems ◽

Bone Marrow Mononuclear Cells ◽

Key Points ◽

Prognostic Scoring Systems

Key Points Targeted DNAm profiling of MDS patient bone marrow mononuclear cells identifies several distinct DNAm clusters. Clusters enrich for specific genetic lesions and show differences in survival independent of clinical prognostic scoring systems..

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