The Dicentric Chromosome dic(20;22) Is a Recurrent Abnormality in Myelodysplastic Syndromes and Is a Product of Telomere Fusion

2016 ◽  
Vol 150 (3-4) ◽  
pp. 262-272 ◽  
Author(s):  
Ruth N. MacKinnon ◽  
Hendrika M. Duivenvoorden ◽  
Lynda J. Campbell ◽  
Meaghan Wall
Keyword(s):  
Myelodysplastic Syndromes ◽  
Dicentric Chromosome ◽  
Driver Mutations ◽  
Chromosome 22 ◽  
Fusion Event ◽  
Sequence Of Events ◽  
Nucleolus Organiser ◽  
Oncogenic Driver ◽  
Recurrent Patterns ◽  
Selection Of

We describe a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in 4 cases of myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). In particular, the presence of residual telomere sequences at the site of translocation in 3 of the 4 cases makes a compelling case for telomere fusion. This is the first description of a recurrent telomere fusion event in any malignant condition. The 20q subtelomeric region was retained in all 4 examples despite deletion of the 20q12 region closer to the centromere. The original dicentric chromosome in all 4 cases contained nucleolus organiser region material from the short arm of chromosome 22 and had also undergone secondary rearrangements that produced amplification of the common gained region on 20q. We propose that the sequence of events producing this chromosome abnormality is: degradation of the telomeres, formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, breakage-fusion-bridge cycles causing copy number aberration between the centromeres, selection of cells with 20q12 deletion, and further selection of cells with 20q11.2 gain. The last 2 steps are driver events responsible for the abnormal chromosomes found in the malignant cells. Finding recurrent patterns in the complex genome reorganisation events that characterise poor-prognosis, complex-karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies.

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

Cancers ◽  
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.

scholarly journals Molecular disease monitoring using circulating tumor DNA in myelodysplastic syndromes

Blood ◽  
2017 ◽  
Vol 129 (12) ◽  
pp. 1685-1690 ◽  
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.

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

2010 ◽  
Vol 28 (30) ◽  
pp. 4616-4620 ◽  
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.

scholarly journals The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽  
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.

scholarly journals Clinical and biological implications of driver mutations in myelodysplastic syndromes

Blood ◽  
2013 ◽  
Vol 122 (22) ◽  
pp. 3616-3627 ◽  
Author(s):  
Elli Papaemmanuil ◽  
Moritz Gerstung ◽  
Luca Malcovati ◽  
Sudhir Tauro ◽  
Gunes Gundem ◽  
...  
Keyword(s):  
Early Detection ◽  
Myelodysplastic Syndromes ◽  
Complex Structure ◽  
Driver Mutations ◽  
Gene Interactions ◽  
Prognostic Variables ◽  
Oncogenic Mutations ◽  
Key Points

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.

scholarly journals Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Kashyap Dave ◽  
Inderpreet Sur ◽  
Jian Yan ◽  
Jilin Zhang ◽  
Eevi Kaasinen ◽  
...  
Keyword(s):  
Human Cancer ◽  
Cancer Chemoprevention ◽  
Driver Mutations ◽  
Gene Desert ◽  
Enhancer Region ◽  
Myc Oncogene ◽  
Super Enhancer ◽  
High Conservation ◽  
Oncogenic Driver ◽  
Differential Control

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

scholarly journals The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

Oncogene ◽  
2020 ◽  
Vol 39 (32) ◽  
pp. 5455-5467
Author(s):  
Natascha Hruschka ◽  
Mark Kalisz ◽  
Maria Subijana ◽  
Osvaldo Graña-Castro ◽  
Francisco Del Cano-Ochoa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptors ◽  
Transcriptional Response ◽  
Molecular Data ◽  
Fine Tuning ◽  
Driver Mutations ◽  
Breast Cancer Patients ◽  
Oncogenic Driver ◽  
Functional Analyses

Abstract As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.

scholarly journals Use of Oncogenic Driver Mutations in Staging of Multiple Primary Lung Carcinomas: A Single-Center Experience

2017 ◽  
Vol 12 (10) ◽  
pp. 1524-1535 ◽  
Author(s):  
Ramsey Asmar ◽  
Joshua R. Sonett ◽  
Gopal Singh ◽  
Mahesh M. Mansukhani ◽  
Alain C. Borczuk
Keyword(s):  
Driver Mutations ◽  
Single Center ◽  
Lung Carcinomas ◽  
Single Center Experience ◽  
Multiple Primary ◽  
Oncogenic Driver

scholarly journals Contributions from the 2019 Literature on Bioinformatics and Translational Informatics

2020 ◽  
Vol 29 (01) ◽  
pp. 188-192
Author(s):  
Malika Smaïl-Tabbone ◽  
Bastien Rance ◽  
Keyword(s):  
Open Data ◽  
Leading Edge ◽  
Open Science ◽  
Editorial Committee ◽  
Cancer Pathways ◽  
Sequence Of Events ◽  
Independent Review ◽  
Logical Modeling ◽  
Translational Informatics ◽  
Selection Of

Objectives: Summarize recent research and select the best papers published in 2019 in the field of Bioinformatics and Translational Informatics (BTI) for the corresponding section of the International Medical Informatics Association Yearbook. Methods: A literature review was performed for retrieving from PubMed papers indexed with keywords and free terms related to BTI. Independent review allowed the section editors to select a list of 15 candidate best papers which were subsequently peer-reviewed. A final consensus meeting gathering the whole Yearbook editorial committee was organized to finally decide on the selection of the best papers. Results: Among the 931 retrieved papers covering the various subareas of BTI, the review process selected four best papers. The first paper presents a logical modeling of cancer pathways. Using their tools, the authors are able to identify two known behaviours of tumors. The second paper describes a deep-learning approach to predicting resistance to antibiotics in Mycobacterium tuberculosis. The authors of the third paper introduce a Genomic Global Positioning System (GPS) enabling comparison of genomic data with other individuals or genomics databases while preserving privacy. The fourth paper presents a multi-omics and temporal sequence-based approach to provide a better understanding of the sequence of events leading to Alzheimer’s Disease. Conclusions: Thanks to the normalization of open data and open science practices, research in BTI continues to develop and mature. Noteworthy achievements are sophisticated applications of leading edge machine-learning methods dedicated to personalized medicine.

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