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 2

Similarity of somatic aberration profiles across plasma and metastatic tumor tissue samples.

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Similarity of somatic aberration profiles across plasma and metastatic t...
(A) Intrapatient somatic copy number aberrations (SCNAs, Loss and Gain) and single nucleotide variants (SNVs) similarity across metastatic biopsies stratified by patient’s tumor class at plasma collection (Supplemental Table 2). (B) Inter- and intrapatient measures of SCNA similarity per site and across sites of metastasis. (C) Intrapatient loss and gain SCNA similarities (left) and SNV (right) similarities (fraction of SNVs in plasma detected also in tissues and fraction of SNVs in tissues detected also in plasma) across tissue and plasma samples stratified by patient’s tumor class at plasma collection. Only samples of patients with estimated ctDNA greater than 10% are considered. The same trends are also obtained with a more restrictive filter on TC greater than 50%. (D) SCNA similarity among plasma and tumor tissue samples of patient WCM0 (left); private and shared SNVs comparison between WCM0 plasma and selected tumor tissue samples. Reported P values are computed using 2-tailed Wilcoxon Mann-Whitney U test.