We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point ...mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.
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► Smokers with lung cancer show 10× the number of point mutations than never-smokers ► Novel lung cancer genes, including DACH1, CFTR, RELN, ABCB5, and HGF were identified ► Novel pathway alterations in lung cancer include cell-cycle and JAK-STAT pathways ► Alterations were identified in 54 genes for which targeted drugs are available
Whole-genome sequencing of 17 lung cancer patients reveals that smokers with lung cancer show 10× the number of point mutations than patients who were never smokers. Alterations were identified in 54 genes for which targeted drugs are available.
The unprecedented resolution of high-throughput genomics has enabled the recent discovery of a phenomenon by which specific regions of the genome are shattered and then stitched together via a single ...devastating event, referred to as chromothripsis. Potential mechanisms governing this process are now emerging, with implications for our understanding of the role of genomic rearrangements in development and disease.
Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors ...(TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.
Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells ...from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial-mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ-ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
While high-throughput sequencing (HTS) has been used successfully to discover tumor-specific mutant peptides (neoantigens) from somatic missense mutations, the field currently lacks a method for ...identifying which gene fusions may generate neoantigens.
We demonstrate the application of our gene fusion neoantigen discovery pipeline, called INTEGRATE-Neo, by identifying gene fusions in prostate cancers that may produce neoantigens.
INTEGRATE-Neo is implemented in C ++ and Python. Full source code and installation instructions are freely available from https://github.com/ChrisMaherLab/INTEGRATE-Neo .
christophermaher@wustl.edu.
Supplementary data are available at Bioinformatics online.
Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by ...which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion,
TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the
TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
► ETS gene fusion products physically interact with the enzymes PARP1 and DNA-PKcs ► PARP1 and DNA-PKcs are required for ETS-mediated transcription and invasion ► ETS-positive prostate cancer xenografts are susceptible to PARP inhibition ► Overexpression of ETS gene fusions causes DNA damage in prostate epithelial cells
Prostate cancer is a common heterogeneous disease, and most patients diagnosed in the post prostate-specific antigen (PSA) era present with clinically localized disease, the majority of which do well ...regardless of treatment regimen undertaken. Overall, those with advanced prostate cancer at time of diagnosis do poorly after androgen withdrawal therapy. Understanding the biologic underpinning of prostate cancer is necessary to best determine the risk of disease progression and would be advantageous for the development of novel therapeutic approaches to impede or prevent disease. This review focuses on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a detailed understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.
Massively-parallel sequencing at depth is now enabling tumor heterogeneity and evolution to be characterized in unprecedented detail. Tracking these changes in clonal architecture often provides ...insight into therapeutic response and resistance. In complex cases involving multiple timepoints, standard visualizations, such as scatterplots, can be difficult to interpret. Current data visualization methods are also typically manual and laborious, and often only approximate subclonal fractions.
We have developed an R package that accurately and intuitively displays changes in clonal structure over time. It requires simple input data and produces illustrative and easy-to-interpret graphs suitable for diagnosis, presentation, and publication.
The simplicity, power, and flexibility of this tool make it valuable for visualizing tumor evolution, and it has potential utility in both research and clinical settings. The fishplot package is available at https://github.com/chrisamiller/fishplot .
Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, ...EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.
► Coordinated regulation of EZH2 and MMSET in cancer progression ► EZH2 regulates MMSET and its H3K36me2 mark through microRNAs ► MMSET is a downstream mediator of EZH2 oncogenic function ► MMSET overexpression promotes diverse oncogenic phenotypes in vitro and in vivo
Next generation sequencing (NGS) technologies have enabled de novo gene fusion discovery that could reveal candidates with therapeutic significance in cancer. Here we present an open-source software ...package, ChimeraScan, for the discovery of chimeric transcription between two independent transcripts in high-throughput transcriptome sequencing data.
Availability:
http://chimerascan.googlecode.com
Contact:
cmaher@dom.wustl.edu
Supplementary Information:
Supplementary data are available at Bioinformatics online.
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