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  • 1
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    Genomic Profiling of Merkel Cell Carcinomas (2015)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2015-12-16
    Description: Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 5228–34. ©2015 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 2
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    Socrates: identification of genomic rearrangements in tumour genomes by re-aligning soft clipped reads (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-11
    Description: Motivation: Methods for detecting somatic genome rearrangements in tumours using next-generation sequencing are vital in cancer genomics. Available algorithms use one or more sources of evidence, such as read depth, paired-end reads or split reads to predict structural variants. However, the problem remains challenging due to the significant computational burden and high false-positive or false-negative rates. Results: In this article, we present Socrates (SOft Clip re-alignment To idEntify Structural variants), a highly efficient and effective method for detecting genomic rearrangements in tumours that uses only split-read data. Socrates has single-nucleotide resolution, identifies micro-homologies and untemplated sequence at break points, has high sensitivity and high specificity and takes advantage of parallelism for efficient use of resources. We demonstrate using simulated and real data that Socrates performs well compared with a number of existing structural variant detection tools. Availability and implementation: Socrates is released as open source and available from http://bioinf.wehi.edu.au/socrates . Contact: papenfuss@wehi.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 3
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    Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML (2015)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2015-05-01
    Description: Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5) P 3 and PtdIns(3,4) P 2 , leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5) P 3 3-phosphatase (PTEN), PtdIns(3,4,5) P 3 5-phosphatases (eg, SHIP), and PtdIns(3,4) P 2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry–based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B . Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.
    Keywords: Myeloid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 4
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    Mutation Load in BRAF/NRAS Wild-Type Melanomas (2013)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2013-09-04
    Description: Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF / NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin ( P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS –mutant tumors (27 vs. 5.6 mutations per Mb; P = 0.0001). Tandem CC〉TT/GG〉AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin ( P = 0.0008) and in BRAF/NRAS WT tumors ( P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1 , KIT , and NOTCH1 , were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF - and NRAS -mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 4589–98. ©2013 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 5
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    GRIDSS: sensitive and specific genomic rearrangement detection using positional de Bruijn graph assembly [METHOD] (2017)
    Cold Spring Harbor Laboratory Press
    Details
    Publication Date: 2017-12-02
    Description: The identification of genomic rearrangements with high sensitivity and specificity using massively parallel sequencing remains a major challenge, particularly in precision medicine and cancer research. Here, we describe a new method for detecting rearrangements, GRIDSS (Genome Rearrangement IDentification Software Suite). GRIDSS is a multithreaded structural variant (SV) caller that performs efficient genome-wide break-end assembly prior to variant calling using a novel positional de Bruijn graph-based assembler. By combining assembly, split read, and read pair evidence using a probabilistic scoring, GRIDSS achieves high sensitivity and specificity on simulated, cell line, and patient tumor data, recently winning SV subchallenge #5 of the ICGC-TCGA DREAM8.5 Somatic Mutation Calling Challenge. On human cell line data, GRIDSS halves the false discovery rate compared to other recent methods while matching or exceeding their sensitivity. GRIDSS identifies nontemplate sequence insertions, microhomologies, and large imperfect homologies, estimates a quality score for each breakpoint, stratifies calls into high or low confidence, and supports multisample analysis.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
    Published by Cold Spring Harbor Laboratory Press
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  • 6
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    Sustainability, Vol. 9, Pages 1214: Measures of a Sustainable Commute as a Predictor of Happiness (2017)
    MDPI Publishing
    Details
    Publication Date: 2017-07-14
    Description: The ways in which we travel—by what mode, for how long, and for what purpose—can affect our sense of happiness and well-being. This paper assesses the relationships between measures of the sustainability of transportation systems in U.S. metropolitan areas and subjective well-being. Associations between self-reported happiness levels from the Gallup Healthways Well-being Index and commute data were examined for 187 core-based statistical areas (CBSA). We also supplement this quantitative analysis through brief case studies of high- and low-performing happiness cities. Our quantitative results indicate that regions with higher commute mode shares by non-automobile modes generally had higher well-being scores, even when controlling for important economic predictors of happiness. We also find that pro-sustainable transportation policies can have implications for population-wide happiness and well-being. Our case studies indicate that both high and low scoring happiness cities demonstrate a dedicated commitment to improving sustainable transportation infrastructure. Our study suggests that cities that provide incentives for residents to use more sustainable commute modes may offer greater opportunity for happiness than those that do not.
    Electronic ISSN: 2071-1050
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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  • 7
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    The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells [Research Papers] (2015)
    Cold Spring Harbor Laboratory Press
    Details
    Publication Date: 2015-01-16
    Description: Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc- and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of self-renewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance.
    Print ISSN: 0890-9369
    Topics: Biology
    Published by Cold Spring Harbor Laboratory Press
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  • 8
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    C271 Instability and Melanoma Tumorigenicity (2016)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2016-07-02
    Description: The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271− and CD271+ melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271− or CD271+ cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271− and CD271+ melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271− or CD271+ cells showed large pairwise differences in copy number (28%–48%). Differences were also apparent in the copy number profiles of CD271− and CD271+ cells purified directly from each of the four melanomas (1.4%–23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965–77. ©2016 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 9
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    Synergetic Use of Multispectral and Hyperspectral Spaceborne Sensors for the Mapping of Natural Resources with the Sensor Pairs: Landsat-8 and Hyperion; Sentinel-2 and EnMAP (2016)
    In:  Proceedings | Special publications / European Space Agency : ESA SP
    Details
    Publication Date: 2020-02-12
    Type: info:eu-repo/semantics/conferenceObject
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  • 10
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    Multi- and hyperspectral spaceborne remote sensing of the Aggeneys base metal sulphide mineral deposit sites in the Lower Orange River region, South Africa (2016)
    In:  South African Journal of Geology
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    Publication Date: 2020-02-12
    Type: info:eu-repo/semantics/article
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