Publications by authors named "Reanne Bowlby"

26 Publications

  • Page 1 of 1

Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Clin Cancer Res 2021 01 4;27(2):522-531. Epub 2020 Nov 4.

Department of Medical Oncology, BC Cancer, Vancouver, Canada.

Purpose: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.

Results: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were in thoracic malignancies (9/69, 13%), and in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as (novel partners: , and (novel partners: ).

Conclusions: Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1900DOI Listing
January 2021

Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes.

Nat Genet 2020 08 3;52(8):800-810. Epub 2020 Aug 3.

Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.
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http://dx.doi.org/10.1038/s41588-020-0673-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498180PMC
August 2020

Tumor microRNA profile and prognostic value for lymph node metastasis in oral squamous cell carcinoma patients.

Oncotarget 2020 Jun 9;11(23):2204-2215. Epub 2020 Jun 9.

Department of Oral Medical and Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada.

Neck lymph node metastasis (LN+) is one of the most significant prognostic factors affecting 1-in-2 patients diagnosed with oral squamous cell carcinoma (OSCC). The different LN outcomes between clinico-pathologically similar primary tumors suggest underlying molecular signatures that could be associated with the risk of nodal disease development. MicroRNAs (miRNAs)are short non-coding molecules that regulate the expression of their target genes to maintain the balance of cellular processes. A plethora of evidence has indicated that aberrantly expressed miRNAs are involved in cancers with either an antitumor or oncogenic role. In this study, we characterized miRNA expression among OSCC fresh-frozen tumors with known outcomes of nodal disease (82 LN+, 76 LN0). We identified 49 differentially expressed miRNAs in tumors of the LN+ group. Using penalized lasso Cox regression, we identified a group of 10 miRNAs of which expression levels were highly associated with nodal-disease free survival. We further reported a 4-miRNA panel (miR-21-5p, miR-107, miR-1247-3p, and miR-181b-3p) with high accuracy in discriminating LN status, suggesting their potential application as prognostic biomarkers for nodal disease.
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http://dx.doi.org/10.18632/oncotarget.27616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289532PMC
June 2020

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration.

Cell Rep 2019 11 7;29(8):2338-2354.e7. Epub 2019 Nov 7.

Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.
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http://dx.doi.org/10.1016/j.celrep.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905433PMC
November 2019

Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

Cancer Discov 2018 12 15;8(12):1548-1565. Epub 2018 Oct 15.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with and mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with and mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene in epithelioid MPM...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310008PMC
December 2018

Integrated Molecular Characterization of Testicular Germ Cell Tumors.

Cell Rep 2018 06;23(11):3392-3406

The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.
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http://dx.doi.org/10.1016/j.celrep.2018.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075738PMC
June 2018

The Immune Landscape of Cancer.

Immunity 2018 04 5;48(4):812-830.e14. Epub 2018 Apr 5.

Department of Systems Biology and Department of Electrical Engineering, Columbia University, New York, NY 10027, USA.

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
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http://dx.doi.org/10.1016/j.immuni.2018.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982584PMC
April 2018

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

Cell 2018 04;173(2):291-304.e6

Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
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http://dx.doi.org/10.1016/j.cell.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957518PMC
April 2018

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.

Cancer Cell 2018 04 2;33(4):721-735.e8. Epub 2018 Apr 2.

Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
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http://dx.doi.org/10.1016/j.ccell.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966039PMC
April 2018

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

Cancer Cell 2018 04 2;33(4):690-705.e9. Epub 2018 Apr 2.

Department of Epidemiology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
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http://dx.doi.org/10.1016/j.ccell.2018.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959730PMC
April 2018

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Cell Rep 2018 04;23(1):313-326.e5

Leukemia Therapeutics LLC., Hull, MA 02045, USA.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
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http://dx.doi.org/10.1016/j.celrep.2018.03.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075733PMC
April 2018

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

Cell Rep 2018 04;23(1):194-212.e6

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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http://dx.doi.org/10.1016/j.celrep.2018.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002769PMC
April 2018

The Integrated Genomic Landscape of Thymic Epithelial Tumors.

Cancer Cell 2018 02;33(2):244-258.e10

National Cancer Institute, Bethesda, MD 20892, USA.

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
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http://dx.doi.org/10.1016/j.ccell.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994906PMC
February 2018

Indoleamine 2,3-Dioxygenase 1, Increased in Human Gastric Pre-Neoplasia, Promotes Inflammation and Metaplasia in Mice and Is Associated With Type II Hypersensitivity/Autoimmunity.

Gastroenterology 2018 01 11;154(1):140-153.e17. Epub 2017 Sep 11.

Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background & Aims: Chronic gastrointestinal inflammation increases the risk of cancer by mechanisms that are not well understood. Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-binding enzyme that regulates the immune response via catabolization and regulation of tryptophan availability for immune cell uptake. IDO1 expression is increased during the transition from chronic inflammation to gastric metaplasia. We investigated whether IDO1 contributes to the inflammatory response that mediates loss of parietal cells leading to metaplasia.

Methods: Chronic gastric inflammation was induced in Ido1 and CB57BL/6 (control) mice by gavage with Helicobacter felis or overexpression of interferon gamma in gastric parietal cells. We also performed studies in Jh mice, which are devoid of B cells. Gastric tissues were collected and analyzed by flow cytometry, immunostaining, and real-time quantitative polymerase chain reaction. Plasma samples were analyzed by enzyme-linked immunosorbent assay. Gastric tissues were obtained from 20 patients with gastric metaplasia and 20 patients without gastric metaplasia (controls) and analyzed by real-time quantitative polymerase chain reaction; gastric tissue arrays were analyzed by immunohistochemistry. We collected genetic information on gastric cancers from The Cancer Genome Atlas database.

Results: H felis gavage induced significantly lower levels of pseudopyloric metaplasia in Ido1 mice, which had lower frequencies of gastric B cells, than in control mice. Blood plasma from H felis-infected control mice had increased levels of autoantibodies against parietal cells, compared to uninfected control mice, but this increase was lower in Ido1 mice. Chronically inflamed stomachs of Ido1 mice had significantly lower frequencies of natural killer cells in contact with parietal cells, compared with stomachs of control mice. Jh mice had lower levels of pseudopyloric metaplasia than control mice in response to H felis infection. Human gastric pre-neoplasia and carcinoma specimens had increased levels of IDO1 messenger RNA compared with control gastric tissues, and IDO1 protein colocalized with B cells. Co-clustering of IDO1 messenger RNA with B-cell markers was corroborated by The Cancer Genome Atlas database.

Conclusions: IDO1 mediates gastric metaplasia by regulating the B-cell compartment. This process appears to be associated with type II hypersensitivity/autoimmunity. The role of autoimmunity in the progression of pseudopyloric metaplasia warrants further investigation.
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http://dx.doi.org/10.1053/j.gastro.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742059PMC
January 2018

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Cell Rep 2017 03;18(11):2780-2794

Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
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http://dx.doi.org/10.1016/j.celrep.2017.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493145PMC
March 2017

Integrated Molecular Characterization of Uterine Carcinosarcoma.

Cancer Cell 2017 03;31(3):411-423

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address:

We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
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http://dx.doi.org/10.1016/j.ccell.2017.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599133PMC
March 2017

miR-509-3p is clinically significant and strongly attenuates cellular migration and multi-cellular spheroids in ovarian cancer.

Oncotarget 2016 May;7(18):25930-48

Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.

Ovarian cancer presents as an aggressive, advanced stage cancer with widespread metastases that depend primarily on multicellular spheroids in the peritoneal fluid. To identify new druggable pathways related to metastatic progression and spheroid formation, we integrated microRNA and mRNA sequencing data from 293 tumors from The Cancer Genome Atlas (TCGA) ovarian cancer cohort. We identified miR-509-3p as a clinically significant microRNA that is more abundant in patients with favorable survival in both the TCGA cohort (P = 2.3E-3), and, by in situ hybridization (ISH), in an independent cohort of 157 tumors (P < 1.0E-3). We found that miR-509-3p attenuated migration and disrupted multi-cellular spheroids in HEYA8, OVCAR8, SKOV3, OVCAR3, OVCAR4 and OVCAR5 cell lines. Consistent with disrupted spheroid formation, in TCGA data miR-509-3p's most strongly anti-correlated predicted targets were enriched in components of the extracellular matrix (ECM). We validated the Hippo pathway effector YAP1 as a direct miR-509-3p target. We showed that siRNA to YAP1 replicated 90% of miR-509-3p-mediated migration attenuation in OVCAR8, which contained high levels of YAP1 protein, but not in the other cell lines, in which levels of this protein were moderate to low. Our data suggest that the miR-509-3p/YAP1 axis may be a new druggable target in cancers with high YAP1, and we propose that therapeutically targeting the miR-509-3p/YAP1/ECM axis may disrupt early steps in multi-cellular spheroid formation, and so inhibit metastasis in epithelial ovarian cancer and potentially in other cancers.
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http://dx.doi.org/10.18632/oncotarget.8412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041955PMC
May 2016

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Cell 2015 Oct;163(2):506-19

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
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http://dx.doi.org/10.1016/j.cell.2015.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603750PMC
October 2015

Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas.

Gastric Cancer 2016 Apr 23;19(2):676-681. Epub 2015 Jun 23.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

The Epstein-Barr virus (EBV)-positive subtype of gastric adenocarcinoma is conventionally identified by in situ hybridization (ISH) for viral nucleic acids, but next-generation sequencing represents a potential alternative. We therefore determined normalized EBV read counts by whole-genome, whole-exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases. In pairwise comparisons, individual samples were either concordantly high or concordantly low by all genomic methods for which data were available. Empiric cutoffs of sequencing counts identified 26 (9 %) tumors as EBV positive. EBV positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa = 0.91). EBV-positive gastric tumors can be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research.
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http://dx.doi.org/10.1007/s10120-015-0508-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689675PMC
April 2016

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

N Engl J Med 2015 Jun 10;372(26):2481-98. Epub 2015 Jun 10.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.

Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.

Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.

Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1402121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530011PMC
June 2015

Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.

Cancer Cell 2015 Feb;27(2):286-97

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA.

We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.
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http://dx.doi.org/10.1016/j.ccell.2015.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800737PMC
February 2015
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