Genome-wide plasma DNA methylation features of metastatic prostate cancer.
J Clin Invest
; 130(4): 1991-2000, 2020 04 01.
Article
em En
| MEDLINE
| ID: mdl-32149736
ABSTRACT
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Regulação Neoplásica da Expressão Gênica
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Metilação de DNA
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Epigênese Genética
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DNA Tumoral Circulante
Limite:
Adult
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Aged
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Aged80
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article