Whole exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors
TL;DR: Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors, representing a lower bound for fusion frequency at this locus and suggesting that the NAB2-STAT6 fusion is a distinct molecular feature of SFTs.
Abstract: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors. Here, we describe the identification of a NAB2-STAT6 fusion from whole-exome sequencing of 17 SFTs. Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors (55%), representing a lower bound for fusion frequency at this locus and suggesting that the NAB2-STAT6 fusion is a distinct molecular feature of SFTs.
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Harvard University1, University of California, San Francisco2, University of Düsseldorf3, Heidelberg University4, Aix-Marseille University5, Ludwig Institute for Cancer Research6, International Agency for Research on Cancer7, German Cancer Research Center8, University of Zurich9, St. Jude Children's Research Hospital10
TL;DR: The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor and is hoped that it will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
Abstract: The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
11,197 citations
Cites background from "Whole exome sequencing identifies a..."
...Nonetheless, both solitary fibrous tumors and hemangiopericytomas, including those occurring in the neuraxis, share inversions at 12q13, fusing the NAB2 and STAT6 genes [8, 41], which leads to STAT6 nuclear expression that can be detected by immunohistochemistry [45]....
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TL;DR: Recent advances in Jak–STAT biology are reviewed, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.
Abstract: Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.
712 citations
TL;DR: STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics.
559 citations
TL;DR: The spectrum of gene fusions in cancer and how the methods to identify them have evolved are described, and the conceptual implications of current, sequencing-based approaches for detection are discussed.
Abstract: Structural chromosome rearrangements may result in the exchange of coding or regulatory DNA sequences between genes. Many such gene fusions are strong driver mutations in neoplasia and have provided fundamental insights into the disease mechanisms that are involved in tumorigenesis. The close association between the type of gene fusion and the tumour phenotype makes gene fusions ideal for diagnostic purposes, enabling the subclassification of otherwise seemingly identical disease entities. In addition, many gene fusions add important information for risk stratification, and increasing numbers of chimeric proteins encoded by the gene fusions serve as specific targets for treatment, resulting in dramatically improved patient outcomes. In this Timeline article, we describe the spectrum of gene fusions in cancer and how the methods to identify them have evolved, and also discuss conceptual implications of current, sequencing-based approaches for detection.
514 citations
TL;DR: Changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume are reviewed, new molecular insights into these tumors, and associated surgical and clinical implications are reviewed.
Abstract: The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publication of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and associated surgical and clinical implications.
352 citations
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TL;DR: It is shown that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour.
Abstract: Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.
3,356 citations
TL;DR: Exome and genome sequences and whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases, which are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.
1,631 citations
TL;DR: SPOP mutations may define a new molecular subtype of prostate cancer, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts.
Abstract: Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.
1,370 citations
TL;DR: Recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1 are confirmed and a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression is identified.
Abstract: Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
1,132 citations
TL;DR: Together, this study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medullOBlastoma.
Abstract: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
692 citations