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1.
Nat Commun ; 14(1): 2017, 2023 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-37037826

RESUMO

Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.


Assuntos
Ácidos Nucleicos Livres , Neoplasias , Humanos , Ácidos Nucleicos Livres/genética , Epigenoma , Neoplasias/diagnóstico , Neoplasias/genética , Genômica/métodos , Mutação , Biomarcadores Tumorais/genética
2.
Clin Epigenetics ; 9: 73, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28748001

RESUMO

BACKGROUND: Most DNA cancer methylation markers are based on the transcriptional regulation of the promoter-gene relationship. Recently, the importance of long-range interactions between distal CpGs and target genes has been revealed. Here, we attempted to identify methylation markers for breast cancer that interact with distant genes. RESULTS: We performed integrated analysis using chromatin interactome data, methylome data, transcriptome data, and clinical information for breast cancer from public databases. Using the chromatin interactome and methylome data, we defined CpG-distant target gene relationships. After determining the differences in methylation between tumor and paired normal samples, the survival association, and the correlation between CpG methylation and distant target gene expression, we selected CpG methylation marker candidates. Using Cox proportional hazards models, we combined the selected markers and evaluated the prognostic model. We identified six methylation markers in HOXA9 and HOXA10 promoter regions and their long-range target genes. We experimentally validated the chromatin interactions, methylation status, and transcriptional regulation. A prognostic model showed that the combination of six methylation markers was highly associated with poor survival in independent datasets. According to our multivariate analysis, the prognostic model showed significantly better prognostic ability than other histological and molecular markers. CONCLUSIONS: The combination of long-range interacting HOXA9 and HOXA10 promoter CpGs predicted the survival of breast cancer patients, providing a comprehensive and novel approach for discovering new methylation markers.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Proteínas de Homeodomínio/genética , Ilhas de CpG , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Homeobox A10 , Humanos , Células MCF-7 , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Análise de Sobrevida
3.
Nat Commun ; 7: 12914, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27694942

RESUMO

Although several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberration have not been well studied. Here, we demonstrate that overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes. H3.3 globally activates gene expression through the occupation of intronic regions in lung cancer cells. Moreover, H3.3 binding regions show characteristics of regulatory DNA elements. We show that H3.3 is deposited at a specific intronic region of GPR87, where it modifies the chromatin status and directly activates GPR87 transcription. The expression levels of H3F3A and GPR87, either alone or in combination, are robust prognostic markers for early-stage lung cancer, and may indicate potential for the development of treatments involving GPR87 antagonists. In summary, our results demonstrate that intronic regulation by H3F3A may be a target for the development of novel therapeutic strategies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Histonas/metabolismo , Íntrons , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Cromatina/química , Progressão da Doença , Dosagem de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Mutação , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Ácidos Lisofosfatídicos/metabolismo , Elementos Reguladores de Transcrição
4.
Nat Genet ; 48(11): 1321-1326, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723759

RESUMO

Recurrence is a hallmark of cancer-driving mutations. Recurrent mutations can arise at the same site or affect the same gene at different sites. Here we identified a set of mutations arising in individual samples and altering different cis-regulatory elements that converge on a common gene via chromatin interactions. The mutations and genes identified in this fashion showed strong relevance to cancer, in contrast to noncoding mutations with site-specific recurrence only. We developed a prediction method that identifies potentially recurrent mutations on the basis of the features shared by mutations whose recurrence is observed in a given cohort. Our method was capable of accurately predicting recurrent mutations at the level of target genes but not mutations recurring at the same site. We experimentally validated predicted mutations in distal regulatory regions of the TERT gene. In conclusion, we propose a novel approach to discovering potential cancer-driving mutations in noncoding regions.


Assuntos
Cromatina , Análise Mutacional de DNA/métodos , Mutação , Neoplasias/genética , Cromatina/química , Estudos de Coortes , DNA de Neoplasias , Elementos Facilitadores Genéticos , Testes Genéticos/métodos , Humanos , Sequências Reguladoras de Ácido Nucleico
5.
BMC Med Genomics ; 4: 82, 2011 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-22133303

RESUMO

BACKGROUND: Epigenetic alteration of gene expression is a common event in human cancer. DNA methylation is a well-known epigenetic process, but verifying the exact nature of epigenetic changes associated with cancer remains difficult. METHODS: We profiled the methylome of human gastric cancer tissue at 50-bp resolution using a methylated DNA enrichment technique (methylated CpG island recovery assay) in combination with a genome analyzer and a new normalization algorithm. RESULTS: We were able to gain a comprehensive view of promoters with various CpG densities, including CpG Islands (CGIs), transcript bodies, and various repeat classes. We found that gastric cancer was associated with hypermethylation of 5' CGIs and the 5'-end of coding exons as well as hypomethylation of repeat elements, such as short interspersed nuclear elements and the composite element SVA. Hypermethylation of 5' CGIs was significantly correlated with downregulation of associated genes, such as those in the HOX and histone gene families. We also discovered long-range epigenetic silencing (LRES) regions in gastric cancer tissue and identified several hypermethylated genes (MDM2, DYRK2, and LYZ) within these regions. The methylation status of CGIs and gene annotation elements in metastatic lymph nodes was intermediate between normal and cancerous tissue, indicating that methylation of specific genes is gradually increased in cancerous tissue. CONCLUSIONS: Our findings will provide valuable data for future analysis of CpG methylation patterns, useful markers for the diagnosis of stomach cancer, as well as a new analysis method for clinical epigenomics investigations.


Assuntos
Metilação de DNA/genética , Neoplasias Gástricas/genética , Bioensaio , Cromossomos Humanos/genética , Análise por Conglomerados , Ilhas de CpG/genética , Mucosa Gástrica/metabolismo , Inativação Gênica , Genoma Humano/genética , Humanos , Metástase Linfática/genética , Anotação de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de DNA , Estômago/patologia
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