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1.
Cell ; 186(18): 3945-3967.e26, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37582358

RESUMO

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.


Assuntos
Neoplasias , Processamento de Proteína Pós-Traducional , Proteômica , Humanos , Acetilação , Histonas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação , Proteômica/métodos
2.
Cell ; 186(18): 3921-3944.e25, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37582357

RESUMO

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.


Assuntos
Neoplasias , Proteogenômica , Humanos , Neoplasias/genética , Oncogenes , Transformação Celular Neoplásica/genética , Variações do Número de Cópias de DNA
3.
Cell ; 184(16): 4348-4371.e40, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34358469

RESUMO

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Proteogenômica , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neoplasias/metabolismo , Fosforilação , Ligação Proteica , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Ubiquitinação
4.
Cell ; 182(1): 200-225.e35, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649874

RESUMO

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteogenômica , Adenocarcinoma de Pulmão/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Fusão Oncogênica , Fenótipo , Fosfoproteínas/metabolismo , Proteoma/metabolismo
5.
Cell ; 183(5): 1436-1456.e31, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33212010

RESUMO

The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/patologia , Terapia de Alvo Molecular , Proteogenômica , Desaminases APOBEC/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Estudos de Coortes , Dano ao DNA , Reparo do DNA , Feminino , Humanos , Imunoterapia , Metabolômica , Pessoa de Meia-Idade , Mutagênese/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Receptor ErbB-2/metabolismo , Proteína do Retinoblastoma/metabolismo , Microambiente Tumoral/imunologia
6.
Nature ; 499(7457): 214-218, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23770567

RESUMO

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.


Assuntos
Heterogeneidade Genética , Mutação/genética , Neoplasias/genética , Oncogenes/genética , Artefatos , Período de Replicação do DNA , Exoma/genética , Reações Falso-Positivas , Expressão Gênica , Genoma Humano/genética , Humanos , Neoplasias Pulmonares/genética , Taxa de Mutação , Neoplasias/classificação , Neoplasias/patologia , Neoplasias de Células Escamosas/genética , Reprodutibilidade dos Testes , Tamanho da Amostra
7.
Genome Res ; 22(12): 2478-88, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22813931

RESUMO

Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites.


Assuntos
Evolução Molecular , Genoma Fúngico , Microsporídios/crescimento & desenvolvimento , Microsporídios/genética , Animais , Caenorhabditis/parasitologia , Montagem e Desmontagem da Cromatina , Mapeamento Cromossômico , DNA Fúngico/genética , Bases de Dados Genéticas , Deleção de Genes , Genes Supressores de Tumor , Variação Genética , Heterozigoto , Hexoquinase/metabolismo , Microsporídios/classificação , Microsporídios/patogenicidade , Família Multigênica , Filogenia , Polimorfismo de Nucleotídeo Único , Retinoblastoma/genética , Análise de Sequência de RNA
8.
PLoS Genet ; 7(10): e1002345, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22046142

RESUMO

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.


Assuntos
Onygenales/genética , Paracoccidioides/genética , Paracoccidioidomicose/microbiologia , Proteínas Quinases/genética , Metabolismo dos Carboidratos/genética , Sistemas de Liberação de Medicamentos , Evolução Molecular , Genoma Fúngico , Genoma Mitocondrial/genética , Humanos , Família Multigênica/genética , Onygenales/enzimologia , Paracoccidioides/enzimologia , Filogenia , Proteólise , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de DNA
9.
PLoS Pathog ; 7(7): e1002137, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21829347

RESUMO

The vascular wilt fungi Verticillium dahliae and V. albo-atrum infect over 200 plant species, causing billions of dollars in annual crop losses. The characteristic wilt symptoms are a result of colonization and proliferation of the pathogens in the xylem vessels, which undergo fluctuations in osmolarity. To gain insights into the mechanisms that confer the organisms' pathogenicity and enable them to proliferate in the unique ecological niche of the plant vascular system, we sequenced the genomes of V. dahliae and V. albo-atrum and compared them to each other, and to the genome of Fusarium oxysporum, another fungal wilt pathogen. Our analyses identified a set of proteins that are shared among all three wilt pathogens, and present in few other fungal species. One of these is a homolog of a bacterial glucosyltransferase that synthesizes virulence-related osmoregulated periplasmic glucans in bacteria. Pathogenicity tests of the corresponding V. dahliae glucosyltransferase gene deletion mutants indicate that the gene is required for full virulence in the Australian tobacco species Nicotiana benthamiana. Compared to other fungi, the two sequenced Verticillium genomes encode more pectin-degrading enzymes and other carbohydrate-active enzymes, suggesting an extraordinary capacity to degrade plant pectin barricades. The high level of synteny between the two Verticillium assemblies highlighted four flexible genomic islands in V. dahliae that are enriched for transposable elements, and contain duplicated genes and genes that are important in signaling/transcriptional regulation and iron/lipid metabolism. Coupled with an enhanced capacity to degrade plant materials, these genomic islands may contribute to the expanded genetic diversity and virulence of V. dahliae, the primary causal agent of Verticillium wilts. Significantly, our study reveals insights into the genetic mechanisms of niche adaptation of fungal wilt pathogens, advances our understanding of the evolution and development of their pathogenesis, and sheds light on potential avenues for the development of novel disease management strategies to combat destructive wilt diseases.


Assuntos
Adaptação Fisiológica/genética , Genoma Fúngico/fisiologia , Nicotiana/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Verticillium/genética , Verticillium/patogenicidade , Genômica , Nicotiana/genética
10.
Cancer Res ; 82(21): 3917-3931, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36040373

RESUMO

Lung adenocarcinoma (LUAD) is one of the most common cancer types and has various treatment options. Better biomarkers to predict therapeutic response are needed to guide choice of treatment modality and to improve precision medicine. Here, we used a consensus hierarchical clustering approach on 509 LUAD cases from The Cancer Genome Atlas to identify five robust LUAD expression subtypes. Genomic and proteomic data from patient samples and cell lines was then integrated to help define biomarkers of response to targeted therapies and immunotherapies. This approach defined subtypes with unique proteogenomic and dependency profiles. Subtype 4 (S4)-associated cell lines exhibited specific vulnerability to loss of CDK6 and CDK6-cyclin D3 complex gene (CCND3). Subtype 3 (S3) was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, leading to increased expression of programmed death-ligand 1 (PD-L1). In an independent real-world patient dataset, patients with S3 tumors were enriched with responders to immune checkpoint blockade. Genomic features in S3 and S4 were further identified as biomarkers for enabling clinical diagnosis of these subtypes. Overall, our consensus hierarchical clustering approach identified robust tumor expression subtypes, and our subsequent integrative analysis of genomics, proteomics, and CRISPR screening data revealed subtype-specific biology and vulnerabilities. These LUAD expression subtypes and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome. SIGNIFICANCE: Integrative analysis of multiomic and drug dependency data uncovers robust lung adenocarcinoma expression subtypes with unique therapeutic vulnerabilities and subtype-specific biomarkers of response.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Proteômica , Biomarcadores Tumorais/genética , Mutação , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/patologia , Prognóstico , Perfilação da Expressão Gênica
11.
Cell Syst ; 9(1): 24-34.e10, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344359

RESUMO

We present a systematic analysis of the effects of synchronizing a large-scale, deeply characterized, multi-omic dataset to the current human reference genome, using updated software, pipelines, and annotations. For each of 5 molecular data platforms in The Cancer Genome Atlas (TCGA)-mRNA and miRNA expression, single nucleotide variants, DNA methylation and copy number alterations-comprehensive sample, gene, and probe-level studies were performed, towards quantifying the degree of similarity between the 'legacy' GRCh37 (hg19) TCGA data and its GRCh38 (hg38) version as 'harmonized' by the Genomic Data Commons. We offer gene lists to elucidate differences that remained after controlling for confounders, and strategies to mitigate their impact on biological interpretation. Our results demonstrate that the hg19 and hg38 TCGA datasets are very highly concordant, promote informed use of either legacy or harmonized omics data, and provide a rubric that encourages similar comparisons as new data emerge and reference data evolve.


Assuntos
Genoma/genética , MicroRNAs/genética , Neoplasias/genética , Software , Estudos Controlados Antes e Depois , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Genoma Humano , Genômica , Troca de Informação em Saúde , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Anotação de Sequência Molecular , Reprodutibilidade dos Testes
12.
Cell Rep ; 23(11): 3392-3406, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29898407

RESUMO

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.


Assuntos
Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/patologia , Variações do Número de Cópias de DNA , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Seminoma/metabolismo , Seminoma/patologia , Neoplasias Testiculares/classificação , Neoplasias Testiculares/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
13.
Science ; 332(6032): 930-6, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21511999

RESUMO

The fission yeast clade--comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus--occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.


Assuntos
Genoma Fúngico , Schizosaccharomyces/genética , Centrômero/genética , Centrômero/fisiologia , Centrômero/ultraestrutura , Elementos de DNA Transponíveis , Evolução Molecular , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Genes Fúngicos Tipo Acasalamento , Genômica , Glucose/metabolismo , Meiose , Anotação de Sequência Molecular , Dados de Sequência Molecular , Filogenia , RNA Antissenso/genética , RNA Fúngico/genética , RNA Interferente Pequeno/genética , RNA não Traduzido/genética , Elementos Reguladores de Transcrição , Schizosaccharomyces/crescimento & desenvolvimento , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Análise de Sequência de DNA , Especificidade da Espécie , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica
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