scholarly journals How Cancer Genomics Drives Cancer Biology: Does Synthetic Lethality Explain Mutually Exclusive Oncogenic Mutations?

2016 ◽  
Author(s):  
Harold Varmus ◽  
Arun M. Unni ◽  
William W. Lockwood
Keyword(s):  
Cancer Biology ◽  
Large Scale ◽  
Cancer Genomics ◽  
Synthetic Lethality ◽  
Mutual Exclusivity ◽  
Physiological Basis ◽  
Oncogenic Mutations ◽  
Mutational Pattern ◽  
Cancer Multiple ◽  
Lung Adenocarcinomas

AbstractLarge-scale analyses of cancer genomes are revealing patterns of mutations that suggest biologically significant ideas about many aspects of cancer, including carcinogenesis, classification, and preventive and therapeutic strategies. Among those patterns is “mutual exclusivity”, a phenomenon observed when two or more mutations that are commonly observed in samples of a type of cancer are not found combined in individual tumors. We have been studying a striking example of mutual exclusivity: the absence of co-existing mutations in theKRASandEGFRproto-oncogenes in human lung adenocarcinomas, despite the high individual frequencies of such mutations in this common type of cancer. Multiple lines of evidence suggest that toxic effects of the joint expression ofKRASandEGFRmutant oncogenes, rather than loss of any selective advantages conferred by a second oncogene that operates through the same signaling pathway, are responsible for the observed mutational pattern. We discuss the potential for understanding the physiological basis of such toxicity, for exploiting it therapeutically, and for extending the studies to other examples of mutual exclusivity.

scholarly journals Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Arun M Unni ◽  
William W Lockwood ◽  
Kreshnik Zejnullahu ◽  
Shih-Queen Lee-Lin ◽  
Harold Varmus
Keyword(s):  
Synthetic Lethality ◽  
Human Cancer ◽  
Mapk Signaling ◽  
Egfr Mutations ◽  
Mutual Exclusivity ◽  
Human Cancer Cell Lines ◽  
Activating Mutations ◽  
Oncogenic Mutations ◽  
Lung Adenocarcinomas ◽  
Dying Cells

Human lung adenocarcinomas (LUAD) contain mutations in EGFR in ∼15% of cases and in KRAS in ∼30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities.

scholarly journals Cytogenetics and Cytogenomics Evaluation in Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4711 ◽  
Author(s):  
Ilda Patrícia Ribeiro ◽  
Joana Barbosa Melo ◽  
Isabel Marques Carreira
Keyword(s):  
High Throughput ◽  
Cancer Biology ◽  
Large Scale ◽  
Cancer Genomics ◽  
Clonal Evolution ◽  
Chromosomal Rearrangements ◽  
Therapy Resistance ◽  
Cellular Heterogeneity ◽  
Comparative Genomic ◽  
Driver Genes

The availability of cytogenetics and cytogenomics technologies improved the detection and identification of tumor molecular signatures as well as the understanding of cancer initiation and progression. The use of large-scale and high-throughput cytogenomics technologies has led to a fast identification of several cancer candidate biomarkers associated with diagnosis, prognosis, and therapeutics. The advent of array comparative genomic hybridization and next-generation sequencing technologies has significantly improved the knowledge about cancer biology, underlining driver genes to guide targeted therapy development, drug-resistance prediction, and pharmacogenetics. However, few of these candidate biomarkers have made the transition to the clinic with a clear benefit for the patients. Technological progress helped to demonstrate that cellular heterogeneity plays a significant role in tumor progression and resistance/sensitivity to cancer therapies, representing the major challenge of precision cancer therapy. A paradigm shift has been introduced in cancer genomics with the recent advent of single-cell sequencing, since it presents a lot of applications with a clear benefit to oncological patients, namely, detection of intra-tumoral heterogeneity, mapping clonal evolution, monitoring the development of therapy resistance, and detection of rare tumor cell populations. It seems now evident that no single biomarker could provide the whole information necessary to early detect and predict the behavior and prognosis of tumors. The promise of precision medicine is based on the molecular profiling of tumors being vital the continuous progress of high-throughput technologies and the multidisciplinary efforts to catalogue chromosomal rearrangements and genomic alterations of human cancers and to do a good interpretation of the relation genotype—phenotype.

scholarly journals cbpManager: a web application to streamline the integration of clinical and genomic data in cBioPortal to support the Molecular Tumor Board

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Arsenij Ustjanzew ◽  
Alexander Desuki ◽  
Christoph Ritzel ◽  
Alina Corinna Dolezilek ◽  
Daniel-Christoph Wagner ◽  
...  
Keyword(s):  
Clinical Data ◽  
Web Application ◽  
Cancer Biology ◽  
Data Privacy ◽  
Large Scale ◽  
Cancer Genomics ◽  
Tumor Board ◽  
Data Formats ◽  
Tumor Boards ◽  
Data Files

Abstract Background Extensive sequencing of tumor tissues has greatly improved our understanding of cancer biology over the past years. The integration of genomic and clinical data is increasingly used to select personalized therapies in dedicated tumor boards (Molecular Tumor Boards) or to identify patients for basket studies. Genomic alterations and clinical information can be stored, integrated and visualized in the open-access resource cBioPortal for Cancer Genomics. cBioPortal can be run as a local instance enabling storage and analysis of patient data in single institutions, in the respect of data privacy. However, uploading clinical input data and genetic aberrations requires the elaboration of multiple data files and specific data formats, which makes it difficult to integrate this system into clinical practice. To solve this problem, we developed cbpManager. Results cbpManager is an R package providing a web-based interactive graphical user interface intended to facilitate the maintenance of mutations data and clinical data, including patient and sample information, as well as timeline data. cbpManager enables a large spectrum of researchers and physicians, regardless of their informatics skills to intuitively create data files ready for upload in cBioPortal for Cancer Genomics on a daily basis or in batch. Due to its modular structure based on R Shiny, further data formats such as copy number and fusion data can be covered in future versions. Further, we provide cbpManager as a containerized solution, enabling a straightforward large-scale deployment in clinical systems and secure access in combination with ShinyProxy. cbpManager is freely available via the Bioconductor project at https://bioconductor.org/packages/cbpManager/ under the AGPL-3 license. It is already used at six University Hospitals in Germany (Mainz, Gießen, Lübeck, Halle, Freiburg, and Marburg). Conclusion In summary, our package cbpManager is currently a unique software solution in the workflow with cBioPortal for Cancer Genomics, to assist the user in the interactive generation and management of study files suited for the later upload in cBioPortal.

scholarly journals A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy.

2021 ◽  
Author(s):  
Christopher H Yogodzinski ◽  
Abolfazl Arab ◽  
Justin R Pritchard ◽  
Hani Goodarzi ◽  
Luke Gilbert
Keyword(s):  
Cancer Cell ◽  
Cell Biology ◽  
Cancer Biology ◽  
Large Scale ◽  
Synthetic Lethality ◽  
Data Retrieval ◽  
Lethal Gene ◽  
Synthetic Lethal ◽  
Cancer Data ◽  
Sex Disparity

Advances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Beyond a database search, our approach empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Our approach is straightforward to implement, well documented and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology.

scholarly journals A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Christopher Yogodzinski ◽  
Abolfazl Arab ◽  
Justin R. Pritchard ◽  
Hani Goodarzi ◽  
Luke A. Gilbert
Keyword(s):  
Cancer Cell ◽  
Cell Biology ◽  
Cancer Biology ◽  
Large Scale ◽  
Synthetic Lethality ◽  
Data Retrieval ◽  
Lethal Gene ◽  
Cancer Data ◽  
Rapid Generation ◽  
Sex Disparity

Abstract Background Advances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large-scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. Results We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Our approach, which we have named the cancer data integrator (CanDI), is straightforward to implement, is well documented, and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology. We show that CanDI empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Conclusions CanDI provides a flexible approach for large-scale data integration in cancer research enabling rapid generation of hypotheses. The CanDI data integrator is available at https://github.com/GilbertLabUCSF/CanDI.

What Has Direct Cortical and Subcortical Electrostimulation Taught Us about Neurolinguistics?

2019 ◽  
pp. 185-211
Author(s):  
Hugues Duffau
Keyword(s):  
White Matter ◽  
Large Scale ◽  
Functional Neuroimaging ◽  
Great Accuracy ◽  
Subcortical White Matter ◽  
Cerebral Lesions ◽  
Physiological Basis ◽  
Postoperative Mri ◽  
The Brain

Investigating the neural and physiological basis of language is one of the most important challenges in neurosciences. Direct electrical stimulation (DES), usually performed in awake patients during surgery for cerebral lesions, is a reliable tool for detecting both cortical and subcortical (white matter and deep grey nuclei) regions crucial for cognitive functions, especially language. DES transiently interacts locally with a small cortical or axonal site, but also nonlocally, as the focal perturbation will disrupt the entire subnetwork sustaining a given function. Thus, in contrast to functional neuroimaging, DES represents a unique opportunity to identify with great accuracy and reproducibility, in vivo in humans, the structures that are actually indispensable to the function, by inducing a transient virtual lesion based on the inhibition of a subcircuit lasting a few seconds. Currently, this is the sole technique that is able to directly investigate the functional role of white matter tracts in humans. Thus, combining transient disturbances elicited by DES with the anatomical data provided by pre- and postoperative MRI enables to achieve reliable anatomo-functional correlations, supporting a network organization of the brain, and leading to the reappraisal of models of language representation. Finally, combining serial peri-operative functional neuroimaging and online intraoperative DES allows the study of mechanisms underlying neuroplasticity. This chapter critically reviews the basic principles of DES, its advantages and limitations, and what DES can reveal about the neural foundations of language, that is, the large-scale distribution of language areas in the brain, their connectivity, and their ability to reorganize.

scholarly journals The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2042 ◽  
Author(s):  
Máté A. Demény ◽  
László Virág
Keyword(s):  
Cancer Biology ◽  
Cancer Metabolism ◽  
Replicative Senescence ◽  
Synthetic Lethality ◽  
Family Members ◽  
Hallmarks Of Cancer ◽  
Novel Therapy ◽  
Cancer Hallmarks ◽  
Enzyme Family ◽  
Wide Range

The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

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.

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