Post-Biopsy Cell-Free DNA From Blood: An Open Window on Primary Prostate Cancer Genetics and Biology.

Marinella Corbetta,Stefano Duga,Paolo Casale,Rodolfo Hurle,Massimo Lazzeri,Rosanna Asselta,Monica Zuradelli,Chiara Chiereghin,Giulia Soldà,Giorgio Guazzoni,Nicolò Maria Buffi,Michele Giunta,Giovanni Lughezzani,Alberto Saita,Ilaria De Simone

doi:10.3389/fonc.2021.654140

Marinella Corbetta, Stefano Duga + Show 13 more

Open Access

https://doi.org/10.3389/fonc.2021.654140

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Abstract

Circulating cell-free DNA (ccfDNA), released from normal and cancerous cells, is a promising biomarker for cancer detection as in neoplastic patients it is enriched in tumor-derived DNA (ctDNA). ctDNA contains cancer-specific mutations and epigenetic modifications, which can have diagnostic/prognostic value. However, in primary tumors, and in particular in localized prostate cancer (PCa), the fraction of ctDNA is very low and conventional strategies to study ccfDNA are unsuccessful. Here we demonstrate that prostate biopsy, by causing multiple injuries to the organ, leads to a significant increase in plasma concentration of ccfDNA (P<0.0024) in primary PCa patients. By calculating the minor allele fraction at patient-specific somatic mutations pre- and post-biopsy, we show that ctDNA is significantly enriched (from 3.9 to 164 fold) after biopsy, representing a transient “molecular window” to access and analyze ctDNA. Moreover, we show that newly released ccfDNA contains a larger fraction of di-, tri- and multi-nucleosome associated DNA fragments. This feature could be exploited to further enrich prostate-derived ccfDNA and to analyze epigenetic markers. Our data represent a proof-of-concept that liquid tumor profiling from peripheral blood performed just after the biopsy procedure can open a “valuable molecular metastatic window” giving access to the tumor genetic asset, thus providing an opportunity for early cancer detection and individual genomic profiling in the view of PCa precision medicine.

Highlights

The analysis of circulating cell-free DNA represents one of the most promising strategies for non-invasive disease monitoring [1]
Subjects with chronic renal failure, marked blood protein alterations, hemophiliacs, or those previously submitted to multiple blood transfusions were not included in the study, as these conditions may alter the analysis. mpMRI/ TRUS software assisted fusion-guided biopsy was performed in 31 patients by two experienced urologists (ML and GL) with more than 500 procedure each one
A total of 38 patients referred to prostate biopsy for suspected prostate cancer (PCa) were enrolled in the study (Table 1)

Summary

Introduction

The analysis of circulating cell-free DNA (ccfDNA) represents one of the most promising strategies for non-invasive disease monitoring [1]. The fraction of cancerderived ccfDNA is highly variable, and mainly depends on two factors: i) the advancement of the disease, with more ctDNA reflecting a greater disease burden, and ii) the location of the tumor, with colon, gastroduodenal tract, breast, pancreas, liver, and skin cancers releasing large amounts of ctDNA, whereas glioma, thyroid, kidney, and prostate tumors are associated with the smallest amount of ctDNA in plasma [8, 9]. These tissue differences have been explained by the presence of the bloodbrain barrier for gliomas and of an organ capsule/pseudocapsule for thyroid, prostate, and kidney cancer, limiting the diffusion of ctDNA into blood [9]

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