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1.
Nat Cancer ; 5(4): 673-690, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38347143

RESUMO

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.


Assuntos
Povo Asiático , Neoplasias da Mama , Receptor ErbB-2 , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Povo Asiático/genética , Receptor ErbB-2/genética , Mutação , Proteômica/métodos , Perfilação da Expressão Gênica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Pessoa de Meia-Idade , China/epidemiologia , Ferroptose/genética , Adulto , Metabolômica/métodos , Transcriptoma , Biomarcadores Tumorais/genética , População do Leste Asiático
2.
Nat Rev Cancer ; 24(2): 123-140, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38228901

RESUMO

Transposable elements (TEs) represent almost half of the human genome. Historically deemed 'junk DNA', recent technological advancements have stimulated a wave of research into the functional impact of TEs on gene-regulatory networks in evolution and development, as well as in diseases including cancer. The genetic and epigenetic evolution of cancer involves the exploitation of TEs, whereby TEs contribute directly to cancer-specific gene activities. This Review provides a perspective on the role of TEs in cancer as being a 'double-edged sword', both promoting cancer evolution and representing a vulnerability that could be exploited in cancer therapy. We discuss how TEs affect transcriptome regulation and other cellular processes in cancer. We highlight the potential of TEs as therapeutic targets for cancer. We also summarize technical hurdles in the characterization of TEs with genomic assays. Last, we outline open questions and exciting future research avenues.


Assuntos
Elementos de DNA Transponíveis , Neoplasias , Humanos , Elementos de DNA Transponíveis/genética , Redes Reguladoras de Genes , Genoma Humano , Oncogenes , Evolução Molecular , Neoplasias/genética , Neoplasias/terapia
3.
Nat Genet ; 55(4): 631-639, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36973455

RESUMO

Cryptic promoters within transposable elements (TEs) can be transcriptionally reactivated in tumors to create new TE-chimeric transcripts, which can produce immunogenic antigens. We performed a comprehensive screen for these TE exaptation events in 33 TCGA tumor types, 30 GTEx adult tissues and 675 cancer cell lines, and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Whole-lysate and HLA-pulldown mass spectrometry data confirmed that TS-TEAs are presented on the surface of cancer cells. In addition, we highlight tumor-specific membrane proteins transcribed from TE promoters that constitute aberrant epitopes on the extracellular surface of cancer cells. Altogether, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that could potentially be therapeutically exploited and targeted.


Assuntos
Elementos de DNA Transponíveis , Neoplasias , Adulto , Humanos , Elementos de DNA Transponíveis/genética , Antígenos de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Neoplasias/genética , Linhagem Celular
4.
Genome Res ; 32(7): 1424-1436, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35649578

RESUMO

Transposable elements (TEs) encode regulatory elements that impact gene expression in multiple species, yet a comprehensive analysis of zebrafish TEs in the context of gene regulation is lacking. Here, we systematically investigate the epigenomic and transcriptomic landscape of TEs across 11 adult zebrafish tissues using multidimensional sequencing data. We find that TEs contribute substantially to a diverse array of regulatory elements in the zebrafish genome and that 37% of TEs are positioned in active regulatory states in adult zebrafish tissues. We identify TE subfamilies enriched in highly specific regulatory elements among different tissues. We use transcript assembly to discover TE-derived transcriptional units expressed across tissues. Finally, we show that novel TE-derived promoters can initiate tissue-specific transcription of alternate gene isoforms. This work provides a comprehensive profile of TE activity across normal zebrafish tissues, shedding light on mechanisms underlying the regulation of gene expression in this widely used model organism.


Assuntos
Elementos de DNA Transponíveis , Epigenômica , Animais , Elementos de DNA Transponíveis/genética , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico , Peixe-Zebra/genética
5.
Exp Hematol ; 111: 50-65, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35429619

RESUMO

The molecular events responsible for decitabine responses in myelodysplastic syndrome and acute myeloid leukemia patients are poorly understood. Decitabine has a short serum half-life and limited stability in tissue culture. Therefore, theoretical pharmacologic differences may exist between patient molecular changes in vitro and the consequences of in vivo treatment. To systematically identify the global genomic and transcriptomic alterations induced by decitabine in vivo, we evaluated primary bone marrow samples that were collected during patient treatment and applied whole-genome bisulfite sequencing, RNA-sequencing, and single-cell RNA sequencing. Decitabine induced global, reversible hypomethylation after 10 days of therapy in all patients, which was associated with induction of interferon-induced pathways, the expression of endogenous retroviral elements, and inhibition of erythroid-related transcripts, recapitulating many effects seen previously in in vitro studies. However, at relapse after decitabine treatment, interferon-induced transcripts remained elevated relative to day 0, but erythroid-related transcripts now were more highly expressed than at day 0. Clinical responses were not correlated with epigenetic or transcriptional signatures, although sample size and interpatient variance restricted the statistical power required for capturing smaller effects. Collectively, these data define global hypomethylation by decitabine and find that erythroid-related pathways may be relevant because they are inhibited by therapy and reverse at relapse.


Assuntos
Decitabina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Decitabina/uso terapêutico , Humanos , Interferons , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Recidiva
6.
Nature ; 580(7801): 93-99, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238934

RESUMO

Prostate cancer is the second most common cancer in men worldwide1. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients2,3. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.


Assuntos
Povo Asiático/genética , Epigênese Genética , Epigenômica , Genoma Humano/genética , Genômica , Mutação , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , Proteínas de Transporte/genética , Transformação Celular Neoplásica/genética , China , Estudos de Coortes , DNA Helicases/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Neoplasias da Próstata/patologia , RNA-Seq , Transcriptoma/genética
7.
Nat Genet ; 51(5): 920, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30992544

RESUMO

In the version of this article initially published, grant PF-17-201-01-TBG from the American Cancer Society to author Erica C. Pehrsson was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.

8.
Nat Genet ; 51(4): 611-617, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926969

RESUMO

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences1-3. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation4. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter-activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.


Assuntos
Elementos de DNA Transponíveis/genética , Neoplasias/genética , Oncogenes/genética , Linhagem Celular , Linhagem Celular Tumoral , Metilação de DNA/genética , Evolução Molecular , Células HEK293 , Humanos , Células K562 , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética
9.
Cell Rep ; 22(6): 1374-1383, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29425494

RESUMO

RNAP II switching from the paused to the productive transcription elongation state is a pivotal regulatory step that requires specific phosphorylations catalyzed by the P-TEFb kinase. Nucleosolic P-TEFb activity is inhibited by its interaction with the ribonuclear protein complex built around the 7SK small nuclear RNA (7SK snRNP). MePCE is the RNA methyltransferase that methylates and stabilizes 7SK in the nucleosol. Here, we report that MePCE also binds chromatin through the histone H4 tail to serve as a P-TEFb activator at specific genes important for cellular identity. Notably, this histone binding abolishes MePCE's RNA methyltransferase activity toward 7SK, which explains why MePCE-bound P-TEFb on chromatin may not be associated with the full 7SK snRNP and is competent for RNAP II activation. Overall, our results suggest that crosstalk between the histone-binding and RNA methylation activities of MePCE regulates P-TEFb activation on chromatin in a 7SK- and Brd4-independent manner.


Assuntos
Regulação da Expressão Gênica/fisiologia , Histonas/metabolismo , Metiltransferases/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , RNA/metabolismo , Linhagem Celular , Cromatina/metabolismo , Humanos , Metilação , Receptor Cross-Talk
11.
Nat Genet ; 49(7): 1052-1060, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604729

RESUMO

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.


Assuntos
DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Proteínas Quinases Associadas com Morte Celular/genética , Código das Histonas , Inibidores de Histona Desacetilases/farmacologia , Sequências Repetidas Terminais/genética , Sítio de Iniciação de Transcrição/efeitos dos fármacos , Processamento Alternativo/genética , Animais , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/fisiologia , Metilação de DNA , Proteínas Quinases Associadas com Morte Celular/antagonistas & inibidores , Repressão Epigenética , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Ácidos Hidroxâmicos/farmacologia , Íntrons/genética , Camundongos , Camundongos Nus , Interferência de RNA , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Vorinostat
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