Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer
Himisha Beltran, Alessandro Romanel, Vincenza Conteduca, Nicola Casiraghi, Michael Sigouros, Gian Marco Franceschini, Francesco Orlando, Tarcisio Fedrizzi, Sheng-Yu Ku, Emma Dann, Alicia Alonso, Juan Miguel Mosquera, Andrea Sboner, Jenny Xiang, Olivier Elemento, David M. Nanus, Scott T. Tagawa, Matteo Benelli, Francesca Demichelis
Himisha Beltran, Alessandro Romanel, Vincenza Conteduca, Nicola Casiraghi, Michael Sigouros, Gian Marco Franceschini, Francesco Orlando, Tarcisio Fedrizzi, Sheng-Yu Ku, Emma Dann, Alicia Alonso, Juan Miguel Mosquera, Andrea Sboner, Jenny Xiang, Olivier Elemento, David M. Nanus, Scott T. Tagawa, Matteo Benelli, Francesca Demichelis
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Research Article Oncology

Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer

Abstract

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%–20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE–associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.

Authors

Himisha Beltran, Alessandro Romanel, Vincenza Conteduca, Nicola Casiraghi, Michael Sigouros, Gian Marco Franceschini, Francesco Orlando, Tarcisio Fedrizzi, Sheng-Yu Ku, Emma Dann, Alicia Alonso, Juan Miguel Mosquera, Andrea Sboner, Jenny Xiang, Olivier Elemento, David M. Nanus, Scott T. Tagawa, Matteo Benelli, Francesca Demichelis

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Figure 5

Differential methylation signal is detected in the circulation of patients.

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Differential methylation signal is detected in the circulation of patien...
(A) PAMES purity estimation of plasma WGBS plasma and PBMC samples. Top 10 most informative hypermethylated CpG Island were used. (B) Ward’s hierarchical clustering of 25 samples using 1-Pearson’s correlation coefficient as distance measure. The annotation tracks include information on sample tumor purity and on the site of the relative sequenced tissue biopsy for all tissue samples and on the presence or absence of lymph node, bone, or visceral metastases in the corresponding patient for the plasma samples. (C) Evaluation of DMR concordance in matched plasma and tissue samples. Two distinct DMR sets were nominated applying the Rocker-meth algorithm on tissue samples, and single-sample Z scores were computed for each DMR. Comparison among values detected in ctDNA and tissue biopsy are reported for 3 representative patients: WCM90, CRPC-Adeno; WCM0, CRPC-NE; and WCM119, CRPC-Adeno with radiographic progression on enzalutamide, PSA 3.5, and elevated serum NSE. Color density is proportional to point density to the power of 1/4 to improve visualization. First, order linear regression R2 is reported. (D) Comparison of average absolute Z score based on CRPC-NE|CRPC-Adeno DMR in plasma samples from this cohort and from a set of patients treated with abiraterone acetate (reported in ref. 31). To maximize the compatibility of clinical history and disease stage, only end-of-treatment samples with an estimated TC greater than 10% were included. Significance was assessed using 2-tailed unpaired Wilcoxon Mann-Whitney U test without continuity correction. (E) NEPC feature scores are plotted as assessed in plasma data of CRPC-Adeno and CRPC-NE patients.