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

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 291 - 304.e6

Published: April 1, 2018

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

Language: Английский

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BAP1 links metabolic regulation of ferroptosis to tumour suppression

Nature Cell Biology, Journal Year: 2018, Volume and Issue: 20(10), P. 1181 - 1192

Published: Sept. 3, 2018

Language: Английский

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Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients

Cancer Cell, Journal Year: 2018, Volume and Issue: 34(2), P. 211 - 224.e6

Published: Aug. 1, 2018

Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects events and tumor variants by reanalyzing RNA whole-exome sequencing data. Tumors have up to 30% more than normal samples. Association somatic with confirmed known trans associations in SF3B1 U2AF1 identified additional trans-acting (e.g., TADA1, PPP2R1A). Many tumors thousands not detectable samples; on average, we ≈930 exon-exon junctions ("neojunctions") typically found GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast ovarian samples, ≈1.7 neojunction- ≈0.6 single nucleotide variant-derived peptides per sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens").

Language: Английский

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Uveal melanoma

Nature Reviews Disease Primers, Journal Year: 2020, Volume and Issue: 6(1)

Published: April 9, 2020

Language: Английский

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Roles and mechanisms of alternative splicing in cancer — implications for care

Nature Reviews Clinical Oncology, Journal Year: 2020, Volume and Issue: 17(8), P. 457 - 474

Published: April 17, 2020

Language: Английский

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Neoantigens: promising targets for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 6, 2023

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by cells as a result various tumor-specific alterations, such genomic mutation, dysregulated RNA splicing, disordered post-translational modification, integrated viral open reading frames. recognized non-self trigger an immune response that is not subject to central peripheral tolerance. The quick identification prediction neoantigens been made possible advanced next-generation sequencing bioinformatic technologies. Compared tumor-associated antigens, highly immunogenic provide emerging targets personalized serve prospective predictors survival prognosis checkpoint blockade responses. therapies will be aided understanding mechanism underlying neoantigen-induced anti-tumor streamlining process neoantigen-based immunotherapies. This review provides overview on characterization outlines clinical applications immunotherapeutic strategies based neoantigens. We also explore their current status, inherent challenges, translation potential.

Language: Английский

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Single-cell analysis reveals new evolutionary complexity in uveal melanoma

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Jan. 24, 2020

Abstract Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, largely unresponsive checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 and non-neoplastic cells from 8 primary 3 samples. Tumor reveal novel subclonal genomic complexity transcriptional states. Tumor-infiltrating immune comprise previously unrecognized diversity cell types, including CD8 + T predominantly expressing marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded cells, indicating that they are capable mounting an response. An indolent liver metastasis class 1B UM infiltrated with plasma indicative antibody-mediated immunity. This complex ecosystem provides new insights into biology, LAG3 identified as potential candidate for blockade patients high risk UM.

Language: Английский

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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 15, 2023

Abstract The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. quality control systems involve ER-associated degradation, chaperons, and autophagy. ER stress is activated when proteostasis broken with an accumulation of misfolded unfolded proteins in the ER. activates adaptive response to restore by initiating kinase R-like kinase, activating transcription factor 6, inositol requiring enzyme 1. multifaceted, acts on aspects at epigenetic level, including processing. Accumulated data indicates its key role homeostasis other diverse involved various ocular diseases, such glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, tumors, surface myopia. This review summarizes molecular mechanisms underlying aforementioned diseases from perspective. Drugs (chemicals, neurotrophic factors, nanoparticles), gene therapy, stem cell therapy are used treat alleviating stress. We delineate advancement targeting provide new treatment strategies diseases.

Language: Английский

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Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2018, Volume and Issue: 9(4)

Published: April 25, 2018

Defects in alternative splicing are frequently found human tumors and result either from mutations splicing‐regulatory elements of specific cancer genes or changes the regulatory machinery. RNA regulators have emerged as a new class oncoproteins tumor suppressors, contribute to disease progression by modulating isoforms involved hallmark pathways. Thus, dysregulation is fundamental provides potentially rich source novel therapeutic targets. Here, we review alterations factors detected tumors, well resulting alternatively spliced that impact hallmarks, discuss how they pathogenesis. highly regulated process and, such, themselves tightly regulated. Differential transcriptional posttranscriptional regulation modulates their levels activities cells. Furthermore, composition microenvironment can also influence which expressed given cell type drug responses. Finally, summarize current efforts targeting splicing, including global inhibition using small molecules blocking spliceosome splicing‐factor‐modifying enzymes, splice‐switching RNA‐based therapeutics modulate cancer‐specific isoforms. This article categorized under: Disease Development > Processing Splicing Regulation/Alternative

Language: Английский

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Aberrant RNA Splicing in Cancer

Annual Review of Cancer Biology, Journal Year: 2018, Volume and Issue: 3(1), P. 167 - 185

Published: Nov. 28, 2018

RNA splicing, the enzymatic process of removing segments premature to produce mature RNA, is a key mediator proteome diversity and regulator gene expression. Increased systematic sequencing genome transcriptome cancers has identified variety means by which splicing altered in cancer relative normal cells. These findings, combination with discovery recurrent change-of-function mutations factors cancers, suggest that alterations are drivers tumorigenesis. Greater characterization parallels increasing efforts pharmacologically perturb early-phase clinical development small molecules disrupt patients cancer. Here we review recent studies global changes cancer, regulation mitogenic pathways critical transformation, therapeutically target

Language: Английский

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