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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 65,568 bioRxiv papers from 290,397 authors.

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in category cancer biology

2,137 results found. For more information, click each entry to expand.

61: Evolutionary dynamics of neoantigens in growing tumours
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Posted to bioRxiv 31 Jan 2019

Evolutionary dynamics of neoantigens in growing tumours
1,900 downloads cancer biology

Eszter Lakatos, Marc J Williams, Ryan O. Schenck, William C. H. Cross, Jacob Househam, Benjamin Werner, Chandler Dean Gatenbee, Mark Robertson-Tessi, Chris P Barnes, Alexander RA Anderson, Andrea Sottoriva, Trevor A. Graham

Cancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer-specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen-'hot'), or have no clonally-expanded neoantigens at all (antigen-'cold'), whereas antigen-'warm' tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen-warm or -hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively-neutral, and moreover, that stronger negative selection paradoxically leads to more neutral-like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results. Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patient-specific immunotherapy decision-making.

62: WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers
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Posted to bioRxiv 21 Dec 2018

WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers
1,896 downloads cancer biology

Edmond M. Chan, Tsukasa Shibue, James McFarland, Benjamin Gaeta, Justine S. McPartlan, Mahmoud Ghandi, Jie Bin Liu, Jean-Bernard Lazaro, Nancy Dumont, Alfredo Gonzalez, Annie Apffel, Syed O Ali, Lisa Leung, Emma A. Roberts, Elizaveta Reznichenko, Mirazul Islam, Maria Alimova, Monica Schenone, Yosef Maruvka, Yang Liu, Alan D’Andrea, David E Root, Jesse S Boehm, Gad Getz, Todd R. Golub, Aviad Tsherniak, Francisca Vazquez, Adam J. Bass

Synthetic lethality, an interaction whereby the co-occurrence of two or more genetic events lead to cell death but one event alone does not, can be exploited to develop novel cancer therapeutics. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cells to become dependent on specific repair proteins. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach in clinical oncology. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in cancers with microsatellite instability (MSI), which results from impaired DNA mismatch repair (MMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase was selectively essential in MSI cell lines, yet dispensable in microsatellite stable (MSS) cell lines. WRN depletion induced double-strand DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models specifically required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target in MSI cancers.

63: Multi-omic tumor data reveal diversity of molecular mechanisms that correlate with survival
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Posted to bioRxiv 16 Feb 2018

Multi-omic tumor data reveal diversity of molecular mechanisms that correlate with survival
1,886 downloads cancer biology

Daniele Ramazzotti, Avantika Lal, Bo Wang, Serafim Batzoglou, Arend Sidow

Outcomes for cancer patients vary greatly even within the same tumor type, and characterization of molecular subtypes of cancer holds important promise for improving prognosis and personalized treatment. This promise has motivated recent efforts to produce large amounts of multidimensional genomic ('multi-omic') data, but current algorithms still face challenges in the integrated analysis of such data. Here we present Cancer Integration via Multikernel Learning (CIMLR), a new cancer subtyping method that integrates multi-omic data to reveal molecular subtypes of cancer. We apply CIMLR to multi-omic data from 36 cancer types and show significant improvements in both computational efficiency and ability to extract biologically meaningful cancer subtypes. The discovered subtypes exhibit significant differences in patient survival for 27 of 36 cancer types. Our analysis reveals integrated patterns of gene expression, methylation, point mutations and copy number changes in multiple cancers and highlights patterns specifically associated with poor patient outcomes.

64: Cancer Genome Interpreter Annotates The Biological And Clinical Relevance Of Tumor Alterations
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Posted to bioRxiv 20 May 2017

Cancer Genome Interpreter Annotates The Biological And Clinical Relevance Of Tumor Alterations
1,871 downloads cancer biology

David Tamborero, Carlota Rubio-Perez, Jordi Deu-Pons, Michael P. Schroeder, Ana Vivancos, Ana Rovira, Ignasi Tusquets, Joan Albanell, Jordi Rodon, Josep Tabernero, Carmen de Torres, Rodrigo Dienstmann, Abel Gonzalez-Perez, Nuria Lopez-Bigas

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Most of the alterations observed in tumors, including those in well-known cancer genes, are of uncertain significance. Moreover, the information on tumor genomic alterations shaping the response to existing therapies is fragmented across the literature and several specialized resources. Here we present the Cancer Genome Interpreter (http://www.cancergenomeinterpreter.org), an open access tool that we have implemented to annotate genomic alterations and interpret their possible role in tumorigenesis and in the response to anti-cancer therapies.

65: Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks
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Posted to bioRxiv 22 Jul 2015

Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks
1,849 downloads cancer biology

Endre Sebestyén, Babita Singh, Belén Miñana, Amadís Pagès, Francesca Mateo, Miguel Angel Pujana, Juan Valcárcel, Eduardo Eyras

Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We systematically analyzed mutation, copy number and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alternatively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferentiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome amplification in non-tumorigenic mammary epithelial cells. Our study uncovers novel splicing networks that potentially contribute to cancer development and progression.

66: Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity
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Posted to bioRxiv 21 Oct 2019

Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity
1,841 downloads cancer biology

Gabriela S Kinker, Alissa C Greenwald, Rotem Tal, Zhanna Orlova, Michael S Cuoco, James M McFarland, Allison Warren, Christopher Rodman, Jennifer A Roth, Samantha A Bender, Bhavna Kumar, James W. Rocco, Pedro ACM Fernandes, Christopher C Mader, Hadas Keren-Shaul, Alexander Plotnikov, Haim Barr, Aviad Tsherniak, Orit Rozenblatt-Rosen, Valery Krizhanovsky, Sidharth V Puram, Aviv Regev, Itay Tirosh

Cultured cell lines are the workhorse of cancer research, but it is unclear to what extent they recapitulate the cellular heterogeneity observed among malignant cells in tumors, given the absence of a native tumor microenvironment. Here, we used multiplexed single cell RNA-Seq to profile ~200 cancer cell lines. We uncovered expression programs that are recurrently heterogeneous within many cancer cell lines and are largely independent of observed genetic diversity. These programs of heterogeneity are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-to-mesenchymal transition (EMT), and protein maturation and degradation. Notably, some of these recurrent programs recapitulate those seen in human tumors, suggesting a prominent role of intrinsic plasticity in generating intra-tumoral heterogeneity. Moreover, the data allowed us to prioritize specific cell lines as model systems of cellular plasticity. We used two such models to demonstrate the dynamics, regulation and vulnerabilities associated with a cancer senescence program observed both in cell lines and in human tumors. Our work describes the landscape of cellular heterogeneity in diverse cancer cell lines, and identifies recurrent patterns of expression heterogeneity that are shared between tumors and specific cell lines and can thus be further explored in follow up studies.

67: iTALK: an R Package to Characterize and Illustrate Intercellular Communication
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Posted to bioRxiv 04 Jan 2019

iTALK: an R Package to Characterize and Illustrate Intercellular Communication
1,786 downloads cancer biology

Yuanxin Wang, Ruiping Wang, Shaojun Zhang, Shumei Song, Changying Jiang, Guangchun Han, Michael Wang, Jaffer Ajani, Andy Futreal, Linghua Wang

Crosstalk between tumor cells and other cells within the tumor microenvironment (TME) plays a crucial role in tumor progression, metastases, and therapy resistance. We present iTALK, a computational approach to characterize and illustrate intercellular communication signals in the multicellular tumor ecosystem using single-cell RNA sequencing data. iTALK can in principle be used to dissect the complexity, diversity, and dynamics of cell-cell communication from a wide range of cellular processes.

68: ModulOmics: Integrating Multi-Omics Data to Identify Cancer Driver Modules
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Posted to bioRxiv 24 Mar 2018

ModulOmics: Integrating Multi-Omics Data to Identify Cancer Driver Modules
1,777 downloads cancer biology

Dana Silverbush, Simona Cristea, Gali Yanovich, Tamar Geiger, Niko Beerenwinkel, Roded Sharan

The identification of molecular pathways driving cancer progression is a fundamental unsolved problem in tumorigenesis, which can substantially further our understanding of cancer mechanisms and inform the development of targeted therapies. Most current approaches to address this problem use primarily somatic mutations, not fully exploiting additional layers of biological information. Here, we describe ModulOmics, a method to de novo identify cancer driver pathways, or modules, by integrating multiple data types (protein-protein interactions, mutual exclusivity of mutations or copy number alterations, transcriptional co-regulation, and RNA co-expression) into a single probabilistic model. To efficiently search the exponential space of candidate modules, ModulOmics employs a two-step optimization procedure that combines integer linear programming with stochastic search. Across several cancer types, ModulOmics identifies highly functionally connected modules enriched with cancer driver genes, outperforming state-of-the-art methods. For breast cancer subtypes, the inferred modules recapitulate known molecular mechanisms and suggest novel subtype-specific functionalities. These findings are supported by an independent patient cohort, as well as independent proteomic and phosphoproteomic datasets.

69: Sex Differences in Oncogenic Mutational Processes
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Posted to bioRxiv 23 Jan 2019

Sex Differences in Oncogenic Mutational Processes
1,776 downloads cancer biology

Constance H Li, Stephenie D. Prokopec, Ren X. Sun, Fouad Yousif, Nathaniel Schmitz, Paul C. Boutros, PCAWG Molecular Subtypes and Clinical Correlates Working Group, ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here, we describe the first pan-cancer analysis of sex differences in whole genomes of 1,983 tumours of 28 subtypes from the ICGC Pan-Cancer Analysis of Whole Genomes project. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in cancer research.

70: The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients
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Posted to bioRxiv 12 Dec 2017

The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients
1,772 downloads cancer biology

Oliver Zill, Kimberly C. Banks, Stephen R. Fairclough, Stefanie A. Mortimer, James V. Vowles, Reza Mokhtari, David R Gandara, Philip C Mack, Justin I Odegaard, Rebecca J. Nagy, Arthur M. Baca, Helmy Eltoukhy, Darya I. Chudova, Richard B Lanman, AmirAli Talasaz

Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity pose analytical challenges. We present the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC), with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naive tumors. To facilitate interpretation of this added complexity, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality. Upon applying these methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations, in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations. Together these retrospective analyses of a large set of cfDNA deep-sequencing data reveal subclonal structures and emerging resistance in advanced solid tumors.

71: Transcription factor activities enhance markers of drug response in cancer
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Posted to bioRxiv 21 Apr 2017

Transcription factor activities enhance markers of drug response in cancer
1,763 downloads cancer biology

Luz Garcia-Alonso, Francesco Iorio, Angela Matchan, Nuno Fonseca, Patricia Jaaks, Fiamenta Falcone, Graham Bignell, Simon S McDade, Mathew J Garnett, Julio Saez-Rodriguez

Transcriptional dysregulation is a key feature of cancer. Transcription factors (TFs) are the main link between signalling pathways and the transcriptional regulatory machinery of the cell, positioning them as key oncogenic inductors and therefore potential targets of therapeutic intervention. We implemented a computational pipeline to infer TF regulatory activities from basal gene expression and applied it to publicly available and newly generated RNA-seq data from a collection of 1,010 cancer cell lines and 9,250 primary tumors. We show that the predicted TF activities recapitulate known mechanisms of transcriptional dysregulation in cancer and dissect mutant-specific effects in driver genes. Importantly, we show the potential for predicted TF activities to be used as markers of sensitivity to the inhibition of their upstream regulators. Furthermore, combining these inferred activities with existing pharmacogenomic markers significantly improves the stratification of sensitive and resistant cell lines for several compounds. Our approach provides a framework to link driver genomic alterations with transcriptional dysregulation that helps to predict drug sensitivity in cancer and to dissect its mechanistic determinants.

72: Childhood cerebellar tumors mirror conserved fetal transcriptional programs
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Posted to bioRxiv 19 Jun 2018

Childhood cerebellar tumors mirror conserved fetal transcriptional programs
1,762 downloads cancer biology

Maria C Vladoiu, Ibrahim El-Hamamy, Laura K Donovan, Hamza Farooq, Borja L Holgado, Vijay Ramaswamy, Stephen C Mack, John JY Lee, Sachin Kumar, David Przelicki, Antony Michealraj, Kyle Juraschka, Patryk Skowron, Betty Luu, Hiromichi Suzuki, A Sorana Morrissy, Florence MG Cavalli, Livia Garzia, Craig Daniels, Xiaochong Wu, Maleeha A Qazi, Sheila K Singh, Jennifer A Chan, Marco A Marra, David Malkin, Peter Dirks, Trevor Pugh, Faiyaz Notta, Claudia L. Kleinman, Alexandra Joyner, Nada Jabado, Lincoln Stein, Michael D Taylor

The study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumors mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Group 3 medulloblastoma resemble Nestin+ve stem cells, Group 4 medulloblastomas resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the pre-natal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumors demonstrates that many bulk tumors contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumors as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumors in early childhood.

73: Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution
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Posted to bioRxiv 04 Feb 2019

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution
1,758 downloads cancer biology

Abdel Nasser Hosein, Huocong Huang, Zhaoning Wang, Kamalpreet Parmar, Wenting Du, Jonathan Huang, Anirban Maitra, Eric Olson, Udit Verma, Rolf Brekken

Background & Aims: Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression. Methods: We employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models. Results: Our data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms. Conclusion: This study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.

74: Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas
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Posted to bioRxiv 02 Dec 2013

Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas
1,753 downloads cancer biology

Alejandro Reyes, Carolin Blume, Vincent Pelechano, Petra Jakob, Lars M Steinmetz, Thorsten Zenz, Wolfgang Huber

Background: Genome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown. Results: To start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing. Among these genes, we found UQCC and RPL31 ; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1. Conclusions: Our results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis. Validation studies on larger cohorts and model systems are required to extend these findings.

75: A molecular portrait of microsatellite instability across multiple cancers
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Posted to bioRxiv 04 Oct 2016

A molecular portrait of microsatellite instability across multiple cancers
1,746 downloads cancer biology

Isidro Cortes-Ciriano, Sejoon Lee, Woong-Yang Park, Tae-Min Kim, Peter J Park

Microsatellite instability (MSI) refers to the hypermutability of the cancer genome due to impaired DNA mismatch repair. Although MSI has been studied for decades, the large amount of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyze ~8000 exome and ~1000 whole-genome pairs across 23 cancer types. Our pan-cancer analysis reveals that the prevalence of MSI events is highly variable within and across tumor types including some in which MSI is not typically examined. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI events. Finally, we propose an exome-based predictive model for the MSI phenotype that achieves high sensitivity and specificity. These results advance our understanding of the genomic drivers and consequences of MSI, and a comprehensive catalog of tumor-type specific MSI loci we have generated enables efficient panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.

76: Ultra-sensitive sequencing for cancer detection reveals progressive clonal selection in normal tissue over a century of human lifespan
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Posted to bioRxiv 04 Nov 2018

Ultra-sensitive sequencing for cancer detection reveals progressive clonal selection in normal tissue over a century of human lifespan
1,704 downloads cancer biology

Jesse J. Salk, Kaitlyn Loubet-Senear, Elisabeth Maritschnegg, Charles C Valentine, Lindsey N Williams, Reinhard Horvat, Adriaan Vanderstichele, Daniela Nachmanson, Kathryn T. Baker, Mary J Emond, Emily Loter, Thierry Soussi, Lawrence A Loeb, Robert Zeillinger, Paul Speiser, Rosa Ana Risques

High accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally-invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer detection using ultra-accurate Duplex Sequencing to identify TP53 mutations in uterine lavage. However, in addition to tumor DNA, we also detect low frequency TP53 mutations in nearly all lavages from women with and without cancer. These mutations increase with age and share the selection traits of clonal TP53 mutations commonly found in human tumors. We show that low frequency TP53 mutations exist in multiple healthy tissues, from newborn to centenarian, and progressively increase in abundance and pathogenicity with older age across tissue types. Our results illustrate that subclonal cancer evolutionary processes are a ubiquitous part of normal human aging and great care must be taken to distinguish tumor-derived, from age-associated mutations in high sensitivity clinical cancer diagnostics.

77: Personally tailored cancer management based on knowledge banks of genomic and clinical data
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Posted to bioRxiv 07 Jun 2016

Personally tailored cancer management based on knowledge banks of genomic and clinical data
1,697 downloads cancer biology

Moritz Gerstung, Elli Papaemmanuil, Inigo Martincorena, Lars Bullinger, Verena I Gaidzik, Peter Paschka, Michael Heuser, Felicitas Thol, Niccolo Bolli, Peter Ganly, Arnold Ganser, Ultan McDermott, Konstanze Döhner, Richard F Schlenk, Hartmut Döhner, Peter J. Campbell

Sequencing of cancer genomes, or parts thereof, has become widespread and will soon be implemented as part of routine clinical diagnostics. However the clinical ramifications of this have not been fully assessed. Here we assess the utility of sequencing large and clinically well-annotated cancer cohorts to derive personalized predictions about treatment outcome. To this end we study a cohort of 1,540 patients with AML (acute myeloid leukemia) with genetic profiles from 111 cancer genes, cytogenetic data and diagnostic blood counts. We test existing and develop new models to compute the probability of six different clinical outcomes based on more than 100 genetic and clinical variables. The predictions derived from our knowledge bank are more detailed and outperform strata currently used in clinical practice (concordance C=72% v C=64%), and are validated on three cohorts and data from TCGA (C=70%). Our prognostic algorithm is available as an online tool (http://cancer.sanger.ac.uk/aml-multistage). A simulation of different treatment scenarios indicates that a refined risk stratification could reduce the number of bonemarrow transplants by up to 25%, while achieving the same survival. Power calculation show that the inclusion of further genes most likely has small effects on the prognostic accuracy; increasing the number of cases will further reduce the error of personalized predictions.

78: Epigenetic Regulation of Gene Expression in Cancer: Techniques, Resources, and Analysis
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Posted to bioRxiv 08 Mar 2017

Epigenetic Regulation of Gene Expression in Cancer: Techniques, Resources, and Analysis
1,683 downloads cancer biology

Luciane T Kagohara, Genevieve L. Stein-O'Brien, Dylan Kelley, Emily Flam, Heather C Wick, Ludmila Danilova, Hariharan Easwaran, Alexander Favorov, Jiang Qian, Daria A Gaykalova, Elana J. Fertig

Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. Epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. Changes in DNA methylation, histone acetylation and methylation, non-coding RNAs, post-translational modifications are all epigenetic drivers in cancer, independent of changes in the DNA sequence. These epigenetic alterations, once thought to be crucial only for the malignant phenotype maintenance, are now recognized as critical also for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. In this review, we focus on DNA methylation and chromatin structure in cancer. While associated with cancer, the precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. Therefore, this review describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems, and bioinformatics algorithms for their analysis. Advances in bioinformatics data integration techniques that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer, and are therefore also a focus of this review. Future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations to cause tumorigenesis initiation and progression. This deeper understanding is essential to future studies that will precisely infer patients prognosis and select patients who will be responsive to emerging epigenetic therapies.

79: Small Molecule Inhibitors of the Human Histone Lysine Methyltransferase NSD2 / WHSC1 / MMSET Identified from a Quantitative High-Throughput Screen with Nucleosome Substrate
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Posted to bioRxiv 24 Oct 2017

Small Molecule Inhibitors of the Human Histone Lysine Methyltransferase NSD2 / WHSC1 / MMSET Identified from a Quantitative High-Throughput Screen with Nucleosome Substrate
1,675 downloads cancer biology

Nathan P. Coussens, Stephen C. Kales, Mark J. Henderson, Olivia W Lee, Kurumi Y. Horiuchi, Yuren Wang, Qing Chen, Ekaterina Kuznetsova, Jianghong Wu, Dorian M Cheff, Ken Chih-Chien Cheng, Paul Shinn, Kyle R Brimacombe, Min Shen, Anton Simeonov, Haiching Ma, Ajit Jadhav, Matthew D Hall

The activity of the histone lysine methyltransferase NSD2 is thought to play a driving role in oncogenesis. Both overexpression of NSD2 and point mutations that increase its catalytic activity are associated with a variety of human cancers. While NSD2 is an attractive therapeutic target, no potent, selective and cell-active inhibitors have been reported to date, possibly due to the challenging nature of developing high-throughput assays for NSD2. To establish a platform for the discovery and development of selective NSD2 inhibitors, multiple assays were optimized and implemented. Quantitative high-throughput screening was performed with full-length wild-type NSD2 and a nucleosome substrate against a diverse collection of known bioactives comprising 16,251 compounds. Actives from the primary screen were further interrogated with orthogonal and counter assays, as well as activity assays with the clinically relevant NSD2 mutants E1099K and T1150A. Five confirmed inhibitors were selected for follow-up, which included a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in cells. The identification of NSD2 inhibitors that bind the catalytic SET domain and demonstrate activity in cells validates the workflow, providing a template for identifying selective NSD2 inhibitors.

80: HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
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Posted to bioRxiv 09 Aug 2018

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
1,674 downloads cancer biology

Yilong Zou, Michael J Palte, Amy A Deik, Haoxin Li, John K Eaton, Wenyu Wang, Yuen-Yi Tseng, Rebecca Deasy, Maria Alimova, Vlado Dančík, Elizaveta S Leshchiner, Vasanthi S Viswanathan, Sabina Signoretti, Toni K Choueiri, Jesse S Boehm, Bridget K Wagner, John Doench, Clary B Clish, Paul A Clemons, Stuart L Schreiber

Kidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2α - HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1β - 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.

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