Cancer genomes contain large numbers of somatic mutations but few of these mutations drive tumor development. Current approaches either identify driver genes on the basis of mutational recurrence or approximate the functional consequences of nonsynonymous mutations by using bioinformatic scores. Passenger mutations are enriched in characteristic nucleotide contexts, whereas driver mutations occur in functional positions, which are not necessarily surrounded by a particular nucleotide context. We observed that mutations in contexts that deviate from the characteristic contexts around passenger mutations provide a signal in favor of driver genes. We therefore developed a method that combines this feature with the signals traditionally used for driver-gene identification. We applied our method to whole-exome sequencing data from 11,873 tumor-normal pairs and identified 460 driver genes that clustered into 21 cancer-related pathways. Our study provides a resource of driver genes across 28 tumor ...
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, ,1 coding base substitution/tumor is lost through negative selection, with purifying selection only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver mutations, including outside known cancer genes. On average, tumors carry ~4 coding substitutions under positive selection, ranging from ,1/tumor in thyroid and testicular cancers to ,10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that ...
Author Summary Loss of gene expression in association with aberrant accumulation of 5-methylcytosine in gene promoter CpG islands is a common feature of human cancer. Here, we describe a method to discover these genes that permits identification of hundreds of novel candidate cancer genes in any cancer cell line. We now estimate that as much as 5% of colon cancer genes may harbor aberrant gene hypermethylation and we term these the cancer
The clinical success of targeted therapies along with technological advances in genome-wide profiling have spurred large-scale efforts to systematically map the molecular landscape of human cancers. These approaches nominate candidate essential or tumor suppressor genes, but are not able to identify all types of acquired vulnerabilities, such as synthetic lethal relationships between aberrantly regulated pathways.. Functional studies are therefore an essential complement to these approaches, serving both to confirm the biological roles of candidate cancer genes, and also to identify other vulnerabilities that are acquired as a consequence of observed genetic alterations.. Pooled short hairpin RNAi screening is proving to be a powerful method by which loss-of-function studies can identify new cancer targets. We are developing novel in vivo methods to identify genes which are essential for lung tumorigenesis, using mini-libraries of short hairpins against selected genes of interest.. ...
Interpreting cancer mutations is a complex task as only few mutations are cancer drivers while most are functionally inactive passengers (6). We can improve driver discovery by focusing on mutations in small sites involved in interactions of networks, as these mutations are more likely important in cancer. We used this idea to build the mutation enrichment model ActiveDriver (7) that analyses mutations in protein sites of post-translational modifications (PTMs). PTMs such as phosphorylation are involved in cellular signalling and cancer pathways. We applied ActiveDriver in the TCGA pan-cancer project to characterise the mutational landscape of signalling networks and to detect known and candidate cancer driver genes (8,9). In another study, we analysed population-wide genome variation and found that PTM sites are strongly conserved among humans and enriched in germline disease variants, emphasizing their importance in physiology and predisposition to disease (10). We recently developed the ...
These tables are generated from a working list of known cancer genes. The list has been annotated with information concerning chromosomal location, tumour types in which mutations are found, classes of mutation that contribute to oncogenesis and other genetic properties. We have sorted the data in a number of ways to list subsets of cancer genes with similar features. However, we would recommend that those wishing to scrutinise the list in detail should download it in its entirety from ten table in the Census tab. These tables can be searched, sorted or exported in csv or tsv formats. ...
Large-scale cancer genome sequencing has uncovered thousands of gene mutations, but distinguishing tumor driver genes from functionally neutral passenger mutations is a major challenge. We analyzed 800 cancer genomes of eight types to find single-nucleotide variants (SNVs) that precisely target phos …
But occasionally they occur in a cancer driver gene, that s bad luck , he said.Said while this study is useful in attempting to integrate epidemiological and genome sequencing data , the message is complex and does not diminish to need to focus on improved approaches to both primary and secondary cancer prevention.
British scientists have found a new and faster way of studying a crucial class of cancer cells, called cancer stem cells, which they say should speed up work on developing drugs against them.
I recently made the decision to seek genetic counseling and testing to determine if, given my history of cancer, my daughter was also at risk for cont...
产品介绍. ExProfile™ Cancer Gene qPCR Arrays专用于对癌症相关基因进行表达量差异分析。这些基因的选择均基于对权威文献的深入挖掘和仔细挑选,可用于各种特定癌症相关基因的表达量差异分析。. 对于目录产品,每块96孔板包含84对PCR引物(384孔板包含360对PCR引物),在同一块96孔(或384孔)板上,设置有12个(384孔板有24个)反应孔包被了不同类型的对照,用以检测从反转录到qPCR整个过程的反应效率。. 了解其他ExProfile gene qPCR array, 请点击:. ...
PURPOSE: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. EXPERIMENTAL DESIGN: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature and we assessed its representation in 4 independent human datasets comprising 324 patients using weighted voting and Gene Set Enrichment Analysis (GSEA). Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A qRT-PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an ...
We have developed FISH Oracle, an interactive web-based application to visualize segment data from an unlimited number of array CGH experiments in the context of gene annotations. Functional elements and segments are presented in a clear and concise fashion. Moreover, the zooming capability of the system makes it possible to display all elements at the resolution desired by the user. Easy to use filters allow to select groups of segments to be visualized. We expect that the high quality of the visualization and the flexibility of the software will enable life scientists to quickly derive interesting hypotheses about candidate cancer genes occurring in amplified or deleted regions. To communicate their findings, users can quickly export the generated images in different high quality formats, e.g. for publication or post-processing using standard graphics software. FISH Oracle is flexible regarding the underlying genome as long as the segment data refer to the same sequence basis as an annotation ...
COSMIC, the Catalogue Of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk/), is the worlds largest database of curated somatic mutations. The current version (v62, Nov 2012) has over a million mutations across 800000 samples from 15327 peer-reviewd publications, online data portals such as TCGA, ICGC, the IARC p53 database and the Cancer Genome Project (CGP) at the Sanger Institute, UK. The project aims to build a comprehensive catalogue of somatic mutations prioritized by the Cancer Gene Census (http://cancer.sanger.ac.uk/cancergenome/projects/census/), allowing users to explore correlations between cancer phenotypes and mutant genotypes. At present, a full distribution of somatic mutations have been curated across 116 known cancer genes and 169 gene fusion pairs. A focus on cancer genomes has recently emerged from the rapid expansion of whole genome/exome resequencing, as shown by our "COSMIC Genomes" website (http://cancer.sanger.ac.uk/cancergenome/projects/studies/), already ...
Clinical researchers interested in studying driver mutations suspected in hematological malignancies now have access to a new targeted next-generation sequencing (NGS) research panel
annotations (the reliablity of the annotated protein expression using immunohistochemically (IH) stained on human tissues, the reliablity of the annotated protein expression in immunofluorescently (IF) stained human cell lines, tissue specificity (the distribution of antibody staining or protein expression in human cell types), cell line specificity (the distribution of RNA abundance in cell lines) and subcellular location (based on immunofluorescent staining of cell lines ...
annotations (the reliablity of the annotated protein expression using immunohistochemically (IH) stained on human tissues, the reliablity of the annotated protein expression in immunofluorescently (IF) stained human cell lines, tissue specificity (the distribution of antibody staining or protein expression in human cell types), cell line specificity (the distribution of RNA abundance in cell lines) and subcellular location (based on immunofluorescent staining of cell lines ...
Cancer Research UK-funded scientists have discovered that women who carry a faulty copy of a gene called RAD51D have almost a one in 11 chance of developing ovarian cancer, the most significant ovarian cancer gene discovery for more than a decade, reveals a study in Nature Genetics* today.. The team at The Institute of Cancer Research (ICR) examined DNA from women from 911 families with ovarian and breast cancer and compared differences in DNA with a control group of 1060 people from the general population.. The team discovered eight gene faults in the RAD51D gene in women with cancer, compared with one in the control group.. Ovarian cancer is the fifth most common cancer in women - around 6,500 cases are diagnosed annually in the UK. The researchers estimate that RAD51D gene faults are present in almost one per cent of women with ovarian cancer - around 50 UK women each year.. Around one woman in 70 in the general population is at risk of developing ovarian cancer, but for those with a RAD51D ...
GIST refers to a Tumour (lump or abnormal growth in the body) that starts in the digestive system (Gastrointestinal Tract). Stromal implies that the tumour develops from tissues that support the connective tissues, controlling the movement of the GI tract. GIST generally affect people between 50 to 70 years of age, but can sometimes develop in kids as well.Some of the most common symptoms of advanced GIST are:. ...
Daily News How Gaining and Losing Weight Affects the Body Millions of measurements from 23 people who consumed extra calories every day for a month reveal changes in proteins, metabolites, and gut microbiota that accompany shifts in body mass.. ...
The superiority of KNN over KM is not surprising. With KNN, a protein of interest is clustered with the top K most signature-similar proteins in the network. With KM, a protein of interest is clustered with a signature-closest centre protein, i.e. with the centre protein having the highest signature similarity with it (see §3). However, the signature-closest centre protein is not necessarily the most signature-similar protein in the network. Additionally, KNN allows for overlap between clusters, whereas KM does not. Thus, with KNN, known cancer genes can be positioned in multiple clusters, and therefore the number of possible clusters that are significantly enriched with cancer genes might be higher for KNN than for KM. Additionally, proteins perform the function or participate in a disease by interacting with other proteins within a functional module, but also with proteins across modules. Thus, it might be biologically relevant to allow for the overlap between clusters. The better performance ...
Large-scale cancer genome projects provide an extraordinary mine of molecular information on a vast range of cancer types and samples and offer the exciting potential of understanding the molecular mechanisms of cancer. Much knowledge is however still hidden in the data and this significantly reduces the effective contribution of cancer molecular profiling to the personalised medicine agenda. In my lecture I will review some of the technical, analytical and scientific challenges in cancer genomic data analysis. I will also provide examples of how this type of analysis can contribute effectively to unravel cancer driver mechanisms and potential targets for anti-cancer therapy.
Tumor cells stably transfected with fluorescent proteins enable scientists to visualize many important aspects of cancer in real time at the single cell level. For example, transfected tumor cells have been visualized either through surgically created chronic-transparent windows or directly through the opened skin of living animals [29]. This intravital imaging provides a powerful tool for observing cancer initiation and progression and evaluating the efficacy of candidate cancer drugs in vivo. On the other hand, assays using tumor cells grown in culture provide reliable information about cancer mechanisms, and are amenable to automated high-throughput screening [16-20]. Using a modified fluorescent indicator of cell cycle progression (Fucci2) and cultured immortalized cells, we investigated the mechanism(s) by which anticancer drugs modulate the cell cycle. While population analysis provided statistical data, time-lapse high-resolution imaging analysis allowed us to explore the processes of ...
The milieu of cytokines by which cells within tissues and organism modify their collective behavior plays a key role to change cancer processes. Cytokines both guard the bodies immune response against cancer or they are directly involved in pathogenesis of oncologic processes. Cytokines control for example core cancer pathways such as RAS/RAF, PI3K-PTEN-mTOR or JAK-STAT signaling, they change cell invasion, cell adhesion or DNA damage response. Moreover, cytokines are crucial in regulation of survival and control of G1-S progression or they are dominant factors to execute or prevent senescence. Importantly, cytokine action can be a cancer driver or a cancer cell blocker, often incompletely understood and dependent on the cancer type associated with microenvrionmental signaling pathways. We are starting to recognize that cytokines can affect the sensitivity of cancers to drug treatment, often by a complex cancer cell-stroma cell interaction. Moreover, the status of the cytokine response in an ...
News Analysis The Rising Research Profile of 23andMe An exploration of the genetics of earlobe attachment is just the latest collaborative research project to come out of the personal genetic testing company.. ...
Profiling the somatic mutations of genes which may inform about tumor evolution, prognostics and treatment is becoming a standard tool in clinical oncology. Commercially available cancer gene panels rely on manually gathered cancer-related genes, in a
Large-scale loss of function RNAi screening has the greatest potential for the discovery of novel gene function and the identification of new protein targets wi...
This article is from Bioessays, volume 33.AbstractRecent technological advances have opened the door for the fast and cost-effective generation of genetically...
Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two
article{196b1da1-ab49-4c82-9de0-aca4138cf71a, abstract = {,p,Purpose: Germline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours. Methods: After excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5′- and 3′-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed. Results: TBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64-0.92, dominant model) and with less aggressive tumour characteristics. ...
Cleary, S. P., Jeck, W. R., Zhao, X., Chen, K., Selitsky, S. R., Savich, G. L., Tan, T.-X., Wu, M. C., Getz, G., Lawrence, M. S., Parker, J. S., Li, J., Powers, S., Kim, H., Fischer, S., Guindi, M., Ghanekar, A. and Chiang, D. Y. (2013), Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology, 58: 1693-1702. doi: 10.1002/hep.26540 ...
In an international genetic study (International Sarcoma Kindred Study) reported in The Lancet Oncology, Ballinger et al found that approximately half of all patients with sarcoma harbored potentially pathogenic monogenic and polygenic variation in known and novel cancer genes.. Study Details. The study included 1,162 patients with sarcoma aged ≥ 15 years from 4 cohorts. Targeted exon sequencing using blood (n = 1,114) or saliva (n = 48) was performed for 72 genes selected on the basis of association with increased cancer risk. A case-control rare variant burden analysis included 6,545 white controls from 3 cohorts. Rare variants were classified as known, expected, or predicted.. Excess of Pathogenic Variants. Median age at cancer diagnosis was 46 years in the sarcoma probands. Multiple primary cancers were found in 170 patients (15%), and 155 (17%) of 911 families with informative pedigrees fitted recognizable cancer syndromes. On case-control rare variant burden analysis, 638 (55%) of the ...
EKF Diagnostics, the global in vitro diagnostics company, announces that two research posters supporting the application of its PointMan™ DNA enrichment technology, for rapid and sensitive detection of lung cancer mutations, have been delivered at key conferences.
Multiple factors can cause cancer and it is difficult to know whether a particular case of cancer has been caused by work. However, we can estimate the proportion of all new cancer cases that could be due to work by looking at the number of workers who have been exposed to known cancer causing agents and the risk of cancer from that exposure.
I recently discovered that my colon cancer had gone into my lower spine. My oncologist stated this is could be a direct extension from my known cancer. They started 10 treatments of radiation. However, she also stated that there is a high likely this is metastatic and incurable disease currently. I plan on seeing MD Anderson in Houston for another opinion and other treatment options. Technically I guess Im considered Stage IV since its reappeared now in my spine. Her approach now
Regulators approved a new test that looks for mutations in hundreds of cancer genes and gives a better picture of a patients tumor.
Researchers have created a promising new method to accurately and more comprehensively analyze and interpret DNA sequence information from cancer patients.
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Transposons are mobile DNA segments that can disrupt gene function by inserting in or near genes. Here, we show that insertional mutagenesis by the PiggyBac transposon can be used for cancer gene discovery in mice. PiggyBac transposition in genetically engineered transposon-transposase mice induced cancers whose type (hematopoietic versus solid) and latency were dependent on the regulatory elements introduced into transposons. Analysis of 63 hematopoietic tumors revealed that PiggyBac is capable of genome-wide mutagenesis. The Piggybac screen uncovered many cancer genes not identified in previous retroviral or Sleeping Beauty transposon screens, including Spic, which encodes a PU.1-related transcription factor, and Hdac7, a histone deacetylase gene. PiggyBac and Sleeping Beauty have different integration preferences. To maximize the utility of the tool, we engineered 20 mouse lines to be compatible with both transposases in constitutive, tissue-, or temporal-specific mutagenesis. Mice with ...
Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of beta-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited ...
Somatic mutations in epigenetic enzymes are frequently found in cancer tissues. The MLL3 H3K4-specific protein lysine monomethyltransferase is an important epigenetic enzyme, and it is among the most recurrently mutated enzymes in cancers. MLL3 mainly introduces H3K4me1 at enhancers. We investigated the enzymatic properties of MLL3 variants that carry somatic cancer mutations. Asn4848 is located at the cofactor binding sites, and the N4848S exchange renders the enzyme inactive. Tyr4884 is part of an aromatic pocket at the active center of the enzyme, and Y4884C converts MLL3 from a monomethyltransferase with substrate preference for H3K4me0 to a trimethyltransferase with H3K4me1 as preferred substrate. Expression of Y4884C leads to aberrant H3K4me3 formation in cells. Our data show that different somatic cancer mutations of MLL3 affect the enzyme activity in distinct and opposing manner highlighting the importance of experimentally studying the effects of somatic cancer mutations in key regulatory
Somatic mutations in epigenetic enzymes are frequently found in cancer tissues. The MLL3 H3K4-specific protein lysine monomethyltransferase is an important epigenetic enzyme, and it is among the most recurrently mutated enzymes in cancers. MLL3 mainly introduces H3K4me1 at enhancers. We investigated the enzymatic properties of MLL3 variants that carry somatic cancer mutations. Asn4848 is located at the cofactor binding sites, and the N4848S exchange renders the enzyme inactive. Tyr4884 is part of an aromatic pocket at the active center of the enzyme, and Y4884C converts MLL3 from a monomethyltransferase with substrate preference for H3K4me0 to a trimethyltransferase with H3K4me1 as preferred substrate. Expression of Y4884C leads to aberrant H3K4me3 formation in cells. Our data show that different somatic cancer mutations of MLL3 affect the enzyme activity in distinct and opposing manner highlighting the importance of experimentally studying the effects of somatic cancer mutations in key regulatory
Graduate students in the Marra lab are in the UBC Bioinformatics Training Program; UBC Genome Sciences and Technology Program (GSAT); and the UBC Medical Genetics Program. Trainees are working on characterizing cancer driver mutations and other alterations relevant to cancer, or on projects designed to identify and study critical cancer genes and pathways.
The Cancer Genome Atlas (TCGA) has reported results from its first comprehensive study which focused on the deadly brain cancer glioblastoma.
Researchers at the University of Minnesota have uncovered a human enzyme responsible for causing DNA mutations found in the majority of breast cancers. The discovery of this enzyme - called APOBEC3B - may change the way ...
Scientists have discovered how genetic cancer mutations systematically attack the networks controlling human cells, knowledge critical for the future development of personalized precision cancer treatments.
BIRMINGHAM, Ala., March 10, 2011 /PRNewswire/ -- PNP Therapeutics Meets Important Financial and Regulatory Objectives in Development of New Cancer Therapies.
Thesis Defense. Title: Computational Detection of Driver Mutations in Cancer Genomes. Abstract: Cancer is caused largely by the accumulation of somatic mutations during the lifetime of an individual. Recent advances in next generation sequencing (NGS) enable measurement of somatic mutations in a cohort of samples. Large-scale cancer sequencing projects like The Cancer Genome Atlas (TCGA) have generated a huge amount of somatic mutations in thousands of tumors. This thesis addresses two challenges. The first challenge is to distinguish driver mutations that are responsible for cancer development from passenger mutations, random events that do not contribute to the cancer phenotype in a cohort of samples. This is a difficult problem because most somatic mutations measured in tumor samples are passenger mutations, and only a small portion of these mutations are driver mutations. The second challenge is to accurately identify larger genomic variants, also known as structural variants (SV), one type ...
Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often