scholarly journals Pervasive Conditional Selection of Driver Mutations and Modular Epistasis Networks in Cancer

2022 ◽  
Author(s):  
Jaime Iranzo ◽  
George Gruenhagen ◽  
Jorge Calle-Espinosa ◽  
Eugene Koonin
Keyword(s):  
Driver Mutations ◽  
Conditional Selection ◽  
Selection Of

scholarly journals Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies

Cancer Cell ◽  
2017 ◽  
Vol 32 (2) ◽  
pp. 155-168.e6 ◽  
Author(s):  
Marco Mina ◽  
Franck Raynaud ◽  
Daniele Tavernari ◽  
Elena Battistello ◽  
Stephanie Sungalee ◽  
...  
Keyword(s):  
Cancer Evolution ◽  
Genomic Alterations ◽  
Conditional Selection ◽  
Selection Of

scholarly journals The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Ugo Testa ◽  
Elvira Pelosi
Keyword(s):  
Therapeutic Targets ◽  
Driver Mutations ◽  
Causative Role ◽  
Genetic Studies ◽  
Internal Tandem Duplication ◽  
Genetic Abnormalities ◽  
Myeloid Leukemias ◽  
The Impact ◽  
Selection Of ◽  
Acute Myeloid

The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients.

scholarly journals A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sanju Sinha ◽  
Karina Barbosa ◽  
Kuoyuan Cheng ◽  
Mark D. M. Leiserson ◽  
Prashant Jain ◽  
...  
Keyword(s):  
Genome Editing ◽  
Cell Types ◽  
Selective Advantage ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Oncogenic Mutation ◽  
Genome Wide ◽  
Selection For ◽  
Mutant Cells ◽  
Selection Of

AbstractRecent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

scholarly journals Biomarkers for Selection of Therapy for Adenocarcinoma of the Lung

2017 ◽  
Vol 13 (4) ◽  
pp. 221-227 ◽  
Author(s):  
Eric H. Bernicker ◽  
Ross A. Miller ◽  
Phillip T. Cagle
Keyword(s):  
Kinase Inhibitors ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Clinical Predictors ◽  
Adenocarcinoma Of The Lung ◽  
The Many ◽  
Work Up ◽  
Selection Of

To suggest that the discovery of targetable driver mutations in many patients with advanced adenocarcinoma of the lung has completely transformed the work-up and therapeutic options for this disease would not be hyperbole. Although not curative, small-molecule tyrosine kinase inhibitors directed at oncogene-addicted tumors have led to significantly improved response rates compared with cytotoxic chemotherapy, with often manageable toxicities and better tolerance. However, the absence of reliable clinical predictors has made molecular testing essential to ensure that patients receive the proper medical management. We outline the many recent advances with regard to diagnosis and treatment of oncogene-addicted advanced nonsquamous non–small-cell lung cancer.

scholarly journals A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

2021 ◽  
Author(s):  
Sanju Sinha ◽  
Karina Guerra ◽  
Kuoyuan Cheng ◽  
Mark Leiserson ◽  
Prashant Jain ◽  
...  
Keyword(s):  
Genome Editing ◽  
Cell Types ◽  
Selective Advantage ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Oncogenic Mutation ◽  
Genome Wide ◽  
Selection For ◽  
Mutant Cells ◽  
Selection Of

Abstract Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

scholarly journals Conditional Selection of B Cells in Mice With an Inducible B Cell Development

2018 ◽  
Vol 9 ◽  
Author(s):  
Elias Hobeika ◽  
Marcel Dautzenberg ◽  
Ella Levit-Zerdoun ◽  
Roberta Pelanda ◽  
Michael Reth
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Conditional Selection ◽  
Selection Of

scholarly journals Pairwise tests for conditional selection use evolutionary logic to predict intrinsic drug resistance in ALK alterations

2019 ◽  
Author(s):  
Haider Inam ◽  
Justin Pritchard
Keyword(s):  
Cell Transformation ◽  
Single Agent ◽  
Genomic Data ◽  
Cellular Transformation ◽  
Driver Mutations ◽  
Alternative Transcript ◽  
Pairwise Comparisons ◽  
Mutual Exclusivity ◽  
Conditional Selection

AbstractBackgroundGenomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection (encompassing both mutual exclusivity and co-occurrence) is commonly used to consider rare genomic variants relative to established cancer drivers. However, the direct comparison of p-values across multiple pairs of genes is confounded by the often-dramatic differences in sample size between established driver mutations and novel findings.MethodsWe develop a resampling based method for the direct pairwise comparisons of conditional selection between sets of gene pairs. This effectively creates quantitative positive control guideposts of conditional selection that normalize differences in population size. We applied this method to a transcript variant of ALK in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed drug response data to revisit the original ALKATI findings.FindingWe found that we are powered to quantitatively compare the degree of relative mutual exclusivity (down to an abundance of 10 patients in a cohort of 500) between novel gene variants and positive controls. We also found that ALKATI is not as mutually exclusive as BRAF and NRAS are with each other. Our in vitro transformation assays and rescue assays suggested that alternative transcript initiation in ALK is not likely to be necessary or sufficient for cellular transformation or growth.InterpretationPairwise comparisons of conditional selection represent a sensitive method of utilizing existing genomic data to directly and quantitatively compare relative levels of conditional selection. The results of using our method in ALKATI and our experiments strongly disfavor the role of ALKATI as a targetable oncogenic driver. The progress of other experimental agents in late stage melanoma and our experimental and computational re-analysis led us to conclude that further single agent testing of ALK inhibitors in patients with ALKATI should be limited to cases where no other treatment hypotheses can be identified.

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