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1.
Nat Commun ; 9(1): 4439, 2018 10 25.
Article in English | MEDLINE | ID: mdl-30361512

ABSTRACT

We conducted an RNA sequencing study to identify novel gene fusions in 80 discovery dataset tumors collected from young patients with diffuse gastric cancer (DGC). Twenty-five in-frame fusions are associated with DGC, three of which (CLDN18-ARHGAP26, CTNND1-ARHGAP26, and ANXA2-MYO9A) are recurrent in 384 DGCs based on RT-PCR. All three fusions contain a RhoGAP domain in their 3' partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without. Ectopic expression of CLDN18-ARHGAP26 promotes the migration and invasion capacities of DGC cells. Parallel targeted RNA sequencing analysis additionally identifies TACC2-PPAPDC1A as a recurrent and poor prognostic in-frame fusion. Overall, PPAPDC1A fusions and in-frame fusions containing a RhoGAP domain clearly define the aggressive subset (7.5%) of DGCs, and their prognostic impact is greater than, and independent of, chromosomal instability and CDH1 mutations. Our study may provide novel genomic insights guiding future strategies for managing DGCs.


Subject(s)
GTPase-Activating Proteins/chemistry , Oncogene Proteins, Fusion/genetics , Phosphatidate Phosphatase/genetics , Stomach Neoplasms/pathology , Adult , Base Sequence , Cell Aggregation , Cell Line, Tumor , Cell Proliferation , Female , Humans , Male , Middle Aged , Prognosis , Protein Domains , Sequence Analysis, RNA , Young Adult
3.
Cell ; 172(5): 1050-1062.e14, 2018 02 22.
Article in English | MEDLINE | ID: mdl-29474906

ABSTRACT

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.


Subject(s)
Medulloblastoma/blood supply , Medulloblastoma/pathology , Meningeal Neoplasms/blood supply , Meningeal Neoplasms/secondary , Allografts , Animals , Cell Line, Tumor , Chemokine CCL2/metabolism , Chromosomes, Human, Pair 10/genetics , Female , Humans , Male , Medulloblastoma/genetics , Mice, SCID , Neoplastic Cells, Circulating , Parabiosis
4.
Article in English | MEDLINE | ID: mdl-28877932

ABSTRACT

Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer data set and complemented with detailed transcriptome sequencing and copy-number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events. Analysis of the transcriptome against a background of 27 TCGA cancer types led to reclassification of the tumor as a primary HER2+ mammary-like adenocarcinoma of the vulva. This revised diagnosis was subsequently confirmed by follow-up immunohistochemistry for a mammary-like adenocarcinoma. The patient was treated with chemotherapy and targeted therapies for HER2+ breast cancer. The detailed pathology and genomic findings of this case are presented herein.


Subject(s)
Adenocarcinoma/genetics , Vulva/pathology , Vulvar Neoplasms/genetics , Breast/pathology , Breast Neoplasms/genetics , Diagnosis, Differential , Female , Gene Expression Profiling , Genomics , Humans , Immunohistochemistry , Middle Aged , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Transcriptome , Whole Genome Sequencing
5.
Blood ; 121(16): 3161-4, 2013 Apr 18.
Article in English | MEDLINE | ID: mdl-23407552

ABSTRACT

We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted resequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53, and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2, and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Nonsynonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.


Subject(s)
Lymphoma, Mantle-Cell/genetics , Mutation , Ubiquitin-Protein Ligases/genetics , Amino Acid Sequence , Ataxia Telangiectasia Mutated Proteins , Base Sequence , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cohort Studies , Cyclin D1/genetics , DNA-Binding Proteins/genetics , Humans , Lymphoma, Mantle-Cell/chemistry , Molecular Sequence Data , Protein Serine-Threonine Kinases/genetics , Receptor, Notch1/genetics , Sequence Alignment , Sequence Deletion , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/genetics
6.
Leuk Lymphoma ; 49(3): 477-87, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18297524

ABSTRACT

The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3 Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3 - 24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 6 , Lymphoma, B-Cell/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Forkhead Box Protein O3 , Forkhead Transcription Factors/genetics , Genes, Tumor Suppressor , Humans , Lymphoma, B-Cell/etiology , Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Mantle-Cell , Positive Regulatory Domain I-Binding Factor 1 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Repressor Proteins/genetics , Transcription Factors/genetics , Ubiquitin-Protein Ligases/genetics
7.
Nat Genet ; 37(4): 418-22, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15735644

ABSTRACT

We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function.


Subject(s)
Cardiomyopathy, Dilated/genetics , Hearing Loss, Sensorineural/genetics , Mutation/genetics , Trans-Activators/genetics , Zebrafish/metabolism , Animals , Blotting, Northern , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Exons/genetics , Eye Proteins/genetics , Heart/physiopathology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Immunoprecipitation , In Situ Hybridization , Mice , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oligonucleotides, Antisense/pharmacology , Peptide Fragments/genetics , Peptide Fragments/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Zebrafish/embryology , Homeobox Protein SIX3
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