Journal Article

Genome-wide plasma DNA methylation features of metastatic prostate cancer

Sandhu, Shahneen, Demichelis, Francesca, Wong, Stephen Q., Benelli, Matteo, Lise, Stefano, Attard, Gerhardt, Gonzalez-Billalebeitia, Enrique, Kleftogiannis, Dimitrios, Jayaram, Anuradha, Wetterskog, Daniel, Cremaschi, Paolo, Conteduca, Vincenza, De Giorgi, Ugo, Franceschini, Gian Marco, Pereira, Mariana Buongermino, Feber, Andrew, Wu, Anjui, Salvi, Samanta, Gurioli, Giorgia, Wingate, Anna Maria

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Abiraterone / Adult / Aged / Aged, 80 and over / Analysis / Androgen receptors / Androgens / Biomarkers / Biomedical research / Bisulfite / Blood / Cancer genetics / Cancer metastasis / Cancer patients / Cancer treatment / Care and treatment / Castration / Chemotherapy / Circulating Tumor DNA - blood / Circulating Tumor DNA - genetics / Copy number / Deoxyribonucleic acid / DNA / DNA Methylation / DNA sequencing / Enzalutamide / Epigenesis, Genetic / Epithelium / Gene Expression Regulation, Neoplastic / Genome-Wide Association Study / Genomes / Genomics / Humans / Information processing / Male / Metastases / Metastasis / Methylation / Middle Aged / Mutation / Neoplasm Metastasis / Next-generation sequencing / Patients / Phenotypes / Polycomb group proteins / Prostate cancer / Prostatic Neoplasms - blood / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Ratios / Setting (Literature) / Sulfites / Tumors