Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer
Himisha Beltran, … , Matteo Benelli, Francesca Demichelis
Himisha Beltran, … , Matteo Benelli, Francesca Demichelis
Published February 24, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI131041.
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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 1

Frequencies of somatic aberrations in advanced prostate cancer driver genes.

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Frequencies of somatic aberrations in advanced prostate cancer driver ge...
(A) Schematic of study cohort. (B) WES segmented data for study cohort. WES segmented data are shown raw (inset) and ploidy- and TC-adjusted. (C) Distribution of somatic copy number loss and SNVs in CRPC-Adeno and CRPC-NE ctDNA and tumor tissue samples. Loss events include homozygous deletions (HomDel), heterozygous deletions (HetDel), copy number neutral losses (CNNL), and events defined by loss of one allele and gain of the other allele (Del|Gain). (D) AR somatic aberration status in CRPC-Adeno, CRPC-NE, and HNPC plasma and tumor tissue samples, ordered based on serial dates of collection. AR gain, focal gain, and SNV (L702H and T878A positional pileup calls) are shown together with sample ploidy and tumor class. Statistics are reported in Supplemental Table 6.