Cell-Free DNA Detection of Tumor Mutations in Heterogeneous, Localized Prostate Cancer Via Targeted, Multiregion Sequencing.

Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue.

Low-pass whole-genome and targeted sequencing with a machine-learning guided 2.5-Mb targeted panel were used to identify single nucleotide variants, small insertions and deletions (indels), and copy-number alterations in cfDNA. The majority of this study focuses on the subset of 21 patients with localized disease, although 45 total individuals were evaluated, including 15 healthy controls and nine men with metastatic castration-resistant prostate cancer. Plasma cfDNA was barcoded with duplex unique molecular identifiers. For localized cases, matched tumor tissue was collected from multiple regions (one to nine samples per patient) for comparison.

Somatic tumor variants present in heterogeneous tumor foci from patients with localized disease were detected in cfDNA, and cfDNA mutational burden was found to track with disease severity. Somatic tissue alterations were identified in cfDNA, including nonsynonymous variants in FOXA1, PTEN, MED12, and ATM. Detection of these overlapping variants was associated with seminal vesicle invasion (P = .019) and with the number of variants initially found in the matched tumor tissue samples (P = .0005).

Our findings demonstrate the potential of targeted cfDNA sequencing to detect somatic tissue alterations in heterogeneous, localized prostate cancer, especially in a setting where matched tumor tissue may be unavailable (ie, active surveillance or treatment monitoring).

JCO precision oncology. 2021 Apr 27*** epublish ***

Emmalyn Chen, Clinton L Cario, Lancelote Leong, Karen Lopez, César P Márquez, Patricia S Li, Erica Oropeza, Imelda Tenggara, Janet Cowan, Jeffry P Simko, Robin Kageyama, Daniel K Wells, June M Chan, Terence Friedlander, Rahul Aggarwal, Pamela L Paris, Felix Feng, Peter R Carroll, John S Witte

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA., Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA., Division of Hematology/Oncology, University of California, San Francisco, CA., Parker Institute for Cancer Immunotherapy, San Francisco, CA.

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