SEARCH · bioRxiv Science

Results for “Cancer Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources

bioRxiv2016

Clonal assessment of functional mutations in cancer based on a genotype-aware method for clonal reconstruction

In cancer, clonal evolution is characterized based on single nucleotide variants and copy number alterations. Nonetheless, previous methods failed to combine information from both sources to accurately reconstruct clonal populations in a given tumor sample or in a set of tumor samples coming from the same patient. Moreover, previous methods accepted as input all variants predicted by variant-callers, regardless of differences in dispersion of variant allele frequencies (VAFs) due to uneven depth of coverage and possible presence of strand bias, prohibiting accurate inference of clonal architecture. We present a general framework for assignment of functional mutations to specific cancer clones, which is based on distinction between passenger variants with expected low dispersion of VAF versus putative functional variants, which may not be used for the reconstruction of cancer clonal architecture but can be assigned to inferred clones at the final stage. The key element of our framework is QuantumClone, a method to cluster variants into clones, which we have thoroughly tested on simulated data. QuantumClone takes into account VAFs and genotypes of corresponding regions together with information about normal cell contamination. We applied our framework to whole genome sequencing data for 19 neuroblastoma trios each including constitutional, diagnosis and relapse samples. We discovered specific pathways recurrently altered by deleterious mutations in different clonal populations. Some such pathways were previously reported (e.g., MAPK and neuritogenesis) while some were novel (e.g., epithelial-mesenchymal transition, cell survival and DNA repair). Most pathways and their modules had more mutations at relapse compared to diagnosis.

Cancer Biology↗

bioRxiv2016

The landscape of gene fusions in hepatocellular carcinoma

Most hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages and suffer limited treatment options. Challenges in early stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated.Paired-end RNA sequencing was performed on noncancerous and cancerous lesions in two representative HBV-HCC patients. Potential fusion genes were identified by STAR-Fusion in STAR software and validated by four publicly available RNA-seq datasets. Fourteen pairs of frozen HBV-related HCC samples and adjacent non-tumor liver tissues were examined by RT-PCR analysis for gene fusion expression.We identified 2,354 different gene fusions in the two HBV-HCC patients. Validation analysis against the four RNA-seq datasets revealed only 1.8% (43/2,354) as recurrent fusions that were supported by public datasets. Comparison with four fusion databases demonstrated that three (HLA-DPB2-HLA-DRB1, CDH23-HLA-DPB1, and C15orf57-CBX3) out of 43 recurrent gene fusions were annotated as disease-related fusion events. Nineteen were novel recurrent fusions not previously annotated to diseases, including DCUN1D3-GSG1L and SERPINA5-SERPINA9. RT-PCR and Sanger sequencing of 14 pairs of HBV-related HCC samples confirmed expression of six of the new fusions, including RP11-476K15.1-CTD-2015H3.2.Our study provides new insights into gene fusions in HCC and could contribute to the development of anti-HCC therapy. RP11-476K15.1-CTD-2015H3.2 may serve as a new therapeutic biomarker in HCC.

Cancer Biology↗

bioRxiv2016

Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Programs cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.\n\nSUMMARYThe purpose of this communication is to report partial findings from a series of radiofrequency radiation (RFR) cancer studies in rats performed under the auspices of the U.S. National Toxicology Program (NTP).1 This report contains peer-reviewed, neoplastic and hyperplastic findings only in the brain and heart of Hsd:Sprague Dawley(R) SD(R) (HSD) rats exposed to RFR starting in utero and continuing throughout their lifetimes. These studies found low incidences of malignant gliomas in the brain and schwannomas in the heart of male rats exposed to RFR of the two types [Code Division Multiple Access (CDMA) and Global System for Mobile Communications (GSM)] currently used in U.S. wireless networks. Potentially preneoplastic lesions were also observed in the brain and heart of male rats exposed to RFR.\n\nThe review of partial study data in this report has been prompted by several factors. Given the widespread global usage of mobile communications among users of all ages, even a very small increase in the incidence of disease resulting from exposure to RFR could have broad implications for public health. There is a high level of public and media interest regarding the safety of cell phone RFR and the specific results of these NTP studies. Lastly, the tumors in the brain and heart observed at low incidence in male rats exposed to GSM-and CDMA-modulated cell phone RFR in this study are of a type similar to tumors observed in some epidemiology studies of cell phone use. These findings appear to support the International Agency for Research on Cancer (IARC) conclusions regarding the possible carcinogenic potential of RFR.2\n\nIt is important to note that this document reviews only the findings from the brain and heart and is not a complete report of all findings from the NTPs studies. Additional data from these studies in Hsd:Sprague Dawley(R) SD(R) (Harlan) rats and similar studies conducted in B6C3F1/N mice are currently under evaluation and will be reported together with the current findings in two forthcoming NTP Technical Reports.

Cancer Biology↗

bioRxiv2016

Enhancing synergy of CAR T cell therapy and oncolytic virus therapy for pancreatic cancer.

The poor immunogenicity of pancreatic tumors makes them particularly difficult to treat. Standard chemotherapies and single agent immunotherapies have had notoriously little success in this arena. Oncolytic virus therapy has the potential to enhance the penetration of immunotherapeutically-delivered CAR T cells into the tumor and improve treatment outcomes. We evaluate this potential by combining two different mathematical approaches: an ordinary differential equation model to simulate population level tumor response to cytotoxic activity of T cells, coupled with an agent-based model to simulate the enhancement of CAR T cell penetration by oncolytic virus therapy.

Cancer Biology↗

bioRxiv2016

Game theoretic methods in population dynamics

Game theoretic methods are used to model the dynamics of cellular populations (tissues) in which it is necessary to account for changes in cellular phenotype (usually proliferation) resulting from cell-cell interaction. Results include prediction of long-term steady-state \"equilibria\" and transient dynamics. These results can be useful for predicting relapse after cytoreduction, assessing the efficacy of alternating combination therapy, and interpreting biopsy specimens obtained from spatially heterogeneous tissues. Mathematical tools range from simple systems of differential equations to computational techniques (individual-based models).

Cancer Biology↗

bioRxiv2016

Parallel, independent reversions to an embryonic expression phenotype in multiple types of cancer.

Changes in gene expression provide a valuable frame of reference for explaining the development and progression of cancer. Many tissue types radically alter their gene expression profile after becoming oncogenic. We evaluate this change in gene expression in 8 different cancer lines by comparing their expression profiles to that of their associated differentiated tissues as well as profiles for proliferative human embryonic stem cells. We find that, for non-proliferative tissues, the alterations in expression after oncogenesis result in a profile that is significantly more similar to the embryonic expression profile than to the original tissue profile. Wealso find that the lists of co-similar genes among embryonic and tumor cells are clustered within gene regulatory, protein interaction and metabolicnetworks. There is however little overlap in these lists between cancer lines and no pattern shared among all cancers in this analysis. We conclude that the manner in which cancers instantiate a proliferative pattern of expression following oncogenesis is diverse and we find no uniform proliferative program among the cancers in this analysis.

Cancer Biology↗

bioRxiv2016

Stem Cell Plasticity and Niche Dynamics in Cancer Progression

ObjectiveCancer stem cells (CSCs) have been hypothesized to initiate and drive tumor growth and recurrence due to their self-renewal ability. If correct, this hypothesis implies that successful therapy must focus primarily on eradication of this CSC fraction. However, recent evidence suggests stemness is niche dependent and may represent one of many phenotypic states that can be accessed by many cancer genotypes when presented with specific environmental cues. A better understanding of the relationship of stemness to niche-related phenotypic plasticity could lead to alternative treatment strategies.\n\nMethodsHere we investigate the role of environmental context in the expression of stem-like cell properties through in-silico simulation of ductal carcinoma. We develop a two-dimensional hybrid discrete-continuum cellular automata model to describe the single cell scale dynamics of multi-cellular tissue formation. Through a suite of simulations we investigate interactions between a phenotypically heterogeneous cancer cell population and a dynamic environment.\n\nResultsWe generate homeostatic ductal structures that consist of a mixture of stem and differentiated cells governed by both intracellular and environmental dynamics. We demonstrate that a wide spectrum of tumor-like histologies can result from these structures by varying microenvironmental parameters.\n\nConclusionNiche driven phenotypic plasticity offers a simple first-principle explanation for the diverse ductal structures observed in histological sections from breast cancer.\n\nSignificanceConventional models of carcinogenesis largely focus on mutational events. We demonstrate that variations in the environmental niche can produce intraductal cancers independent of genetic changes in the resident cells. Therapies targeting the microenvironmental niche, may offer an alternative cancer prevention strategy.

Cancer Biology↗

bioRxiv2016

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

Approximately 75% of breast cancers express estrogen receptor (ER) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance--especially epigenetic events that alter gene expression--are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ER-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

Cancer Biology↗

bioRxiv2016

Impact of Image Gently Campaign at a Medium-Sized Teaching Hospital

Introduction Introduction Materials and Methods Results Discussion Conclusions References More than 62 million computed tomography (CT) scans are performed each year in the United States, compared with 3 million in 1980. Approximately 4 million CT scans per year are performed on children.1 Recent literature suggests that approximately 2% of future cancers may be directly attributable to CT scanning in children. One study estimated 4,350 future cancers could be induced by 1 year of pediatric CT imaging in the United States.2 Pediatric patients are at higher risk for developing cancer because they are more radiosensitive and have longer postradiation life spans than adults. The Society for Pediatric Radiology implemented the Image Gently Campaign on January 2 ...

Cancer Biology↗

bioRxiv2016

Personally tailored cancer management based on knowledge banks of genomic and clinical data

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.

Cancer Biology↗

bioRxiv2016

Identification of Novel and Differentially Expressed MicroRNAs in Goat Enzootic Nasal Adenocarcinoma

Enzootic nasal adenocarcinoma (ENA), an epithelial tumor induced in goats and sheep by enzootic nasal tumor virus (ENTV), is a chronic, progressive,contact transmitted disease. This study aimed to identify novel and differentially expressed miRNAs in the tumor and para-carcinoma nasal tissuesofNanjiang yellow goats with ENA. Small RNA Illumina high-throughput sequencing was used to construct a goat nasal miRNA library.\n\n406 known miRNAs and 29 novel miRNAs were identified. A total of 116 miRNAs were significantly differentially expressed in para-carcinoma nasal tissues and ENA; Target gene prediction and functional analysis revealed that 6176 non-redundancy target genes, 1792 significant GO and 97 significant KEGG pathway for 121 miRNAs were predicted.

Cancer Biology↗

bioRxiv2016

Comparison of 3.0 T PAC versus 1.5 T ERC MRI in Detecting Local Prostate Carcinoma.

Increased utilization of prostate-specific antigen screening and prostate imaging has led to detection of smaller indolent tumors that traditional brachytherapy and prostectomy may be too aggressive for. New targeted techniques require greater locational accuracy of tumor detection to guide treatment. Prostate MRIs can be important for initial staging and for guiding targeted biopsies and treatments. We compared the accuracy of local staging of prostate cancer using 1.5 Tesla MRI with endorectal coil (ERC) versus 3 Tesla MRI with pelvic array coil (PAC) to the gold standard of trans-rectal US guided biopsies (TRUS). ERC is uncomfortable and has many imaging artifacts that may limit detection, so we hypothesize that 3 T MRI with PAC will have improved performance. 72 patients underwent prostate MRIs and TRUS prostate biopsies from 2008-2011 (33 were excluded due to prior radiation therapy, 24 patients underwent 1.5 T ERC and 15 underwent 3.0 T PAC.) 3.0 T PAC was trending towards greater sensitivity although we lack the statistical power for significance.

Cancer Biology↗

bioRxiv2016

Maintaining proton homeostasis is an essential role of glucose metabolism in cell survival

Aerobic glycolysis, termed \"the Warburg Effect\", supports cell proliferation, and glucose deprivation directly elicits necrosis or shifts stimuli-induced apoptosis to necrosis. However, how glucose metabolism regulates cell survival or death choice remains largely unclear. Here we use our recently developed method to monitor in real-time cellular apoptosis and necrosis, and uncover a metabolic homeostasis linked to cell death control. We show that glucose metabolism is the major source to maintain both intracellular and extracellular proton homeostasis. Glucose deficiency leads to lack of proton provision, which provokes a compensatory lysosomal proton efflux and resultant increased lysosomal pH. This lysosomal alkalinization can trigger necrosis. Furthermore, artificial proton supplement enables cells to survive glucose deprivation. Taken together, our results reveal a critical role of glucose metabolism in maintaining cellular microenvironment, and provide a better understanding of the essential requirement of aerobic glycolysis for proliferating cells whose active anabolism consumes a great many protons.

Cancer Biology↗

bioRxiv2017

Bayesian Inference Of Cancer Driver Genes Using Signatures Of Positive Selection

Tumors are composed of an evolving population of cells subjected to tissue-specific selection, which fuels tumor heterogeneity and ultimately complicates cancer driver gene identification. Here, we integrate cancer cell fraction, population recurrence, and functional impact of somatic mutations as signatures of selection into a Bayesian inference model for driver prediction. In an in-depth benchmark, we demonstrate that our model, cDriver, outperforms competing methods when analyzing solid tumors, hematological malignancies, and pan-cancer datasets. Applying cDriver to exome sequencing data of 21 cancer types from 6,870 individuals revealed 98 unreported tumor type-driver gene connections. These novel connections are highly enriched for chromatin-modifying proteins, hinting at a universal role of chromatin regulation in cancer etiology. Although infrequently mutated as single genes, we show that chromatin modifiers are altered in a large fraction of cancer patients. In summary, we demonstrate that integration of evolutionary signatures is key for identifying mutational driver genes, thereby facilitating the discovery of novel therapeutic targets for cancer treatment.

cancer biology↗

bioRxiv2016

Fitting the Erlang distribution to cancer incidence by age may predict key carcinogenic events

Cancer is the second-leading cause of death worldwide, after cardiovascular diseases. Cancers arise from various cells and organs at different ages and develop at different rates. However, the reasons for this variation in the cancer progression rate and the age of onset are poorly understood. Especially puzzling is the late-life decrease in cancer incidence, which cannot be explained by previously proposed power law or exponential growth equations. By using the latest publicly available USA cancer incidence statistics, comprised of 20 million cancer cases documented over 14 years, I show that cancer incidence by age closely follows the Erlang probability distribution (R2=0.9543-0.9999), which is a special case of the gamma distribution. The Erlang distribution describes the probability y of k independent random events occurring by the time x, but not earlier or later, with each event happening on average every b time intervals. This fits well with the multiple-hit hypothesis, and potentially allows to predict the number k of key carcinogenic events and the average time interval b between them, for each cancer type. Moreover, the amplitude parameter A likely predicts maximal populational susceptibility to a given type of cancer. These parameters are estimated for 20 most common cancer types, and provide clues for further research on cancer development.

Cancer Biology↗

bioRxiv2016

IL-1α induces cathepsin K in oral cancer cells − the invasion is unaffected

BackgroundTo study cathepsin K location in oral tongue squamous cell carcinoma (OTSCC), its traffic and expression levels in cultured oral cell lines; and to analyze the effect of interleukin (IL)-1 on OTSCC invasion.\n\nMethodsCathepsin K expression in OTSCC tissue samples was analyzed with immunostaining; its intracellular traffic was followed in HSC-3 cells after PMA treatment. HSC-3 and two oral keratinocyte cell lines, oral carcinoma associated fibroblasts (CAFs) and primary gingival fibroblasts (GF) were treated with IL-1. Cathepsin K expression was measured using PCR and ELISA. Lastly, the effects of IL-1 on HSC-3 invasiveness, alone and in co-cultures with fibroblasts in the 3D myoma invasion model, were determined.\n\nResultsCathepsin K in OTSCC cells was found in vesicles close to cell membrane and within exosomes. While cathepsin K was expressed at the basal level in both epithelial cells and fibroblasts, basal IL-1 levels were higher in epithelial cells compared with GFs and CAFs. Cathepsin K expression was slightly induced by IL-1 in all cell lines, but it did not affect HSC-3 invasiveness.\n\nConclusionIn OTSCC, cathepsin K remains mostly intracellular and it is slightly secreted within exosomes. IL-1 treatment has no effect on HSC-3 invasiveness in 3D myoma model.

Cancer Biology↗

bioRxiv2016

Comments on: "A comprehensive repertoire of tRNA-derived fragments in prostate cancer"

We evaluated the deep-sequencing (RNA-seq) data from human prostate tissue that were reported in [1] and the tRNA-derived fragments described in the original analysis. Our study of the same RNA-seq datasets reveals a considerably different pool of tRNA fragments, many of them with higher abundances than the fragments reported in [1]. We also evaluated the q-PCR approach proposed in [1]. As the approach lacks 5-endpoint specificity, it will not estimate correctly the abundance of many of the tRFs that are present in the sampled RNA populations from human prostate tissue.

Cancer Biology↗

bioRxiv2016

Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3

The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.

Cancer Biology↗