Liquid biopsy‐based targeted gene screening highlights tumor cell subtypes in patients with advanced prostate cancer

Abstract

Prostate cancer (PCa) clinical heterogeneity underscores tumor heterogeneity, which may be best defined by cell subtypes. To test if cell subtypes contributing to progression can be assessed noninvasively, we investigated whether 14 genes representing luminal, neuroendocrine, and stem cells are detectable in whole blood RNA of patients with advanced PCa. For each gene, reverse transcription quantitative polymerase chain reaction assays were first validated using RNA from PCa cell lines, and their traceability in blood was assessed in cell spiking experiments. These were next tested in blood RNA of 40 advanced PCa cases and 40 healthy controls. Expression in controls, which was low or negative, was used to define stringent thresholds for gene overexpression in patients to account for normal variation in white blood cells. Thirty-five of 40 patients overexpressed at least one gene. Patients with more genes overexpressed had a higher risk of death (hazard ratio 1.42, range 1.12-1.77). Progression on androgen receptor inhibitors was associated with overexpression of stem (odds ratio [OR] 7.74, range 1.68-35.61) and neuroendocrine (OR 13.10,) genes, while luminal genes were associated with taxanes (OR 2.7, range 1.07-6.82). Analyses in PCa transcriptomic datasets revealed that this gene panel was most prominent in metastases of advanced disease, with diversity among patients. Collectively, these findings support the contribution of the prostate cell subtypes to disease progression. Cell-subtype specific genes are traceable in blood RNA of patients with advanced PCa and are associated with clinically relevant end points. This opens the door to minimally invasive liquid biopsies for better management of this deadly disease.

Cell‐by‐cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression

“…As cell patterns were shown to differ between adjacent foci, choosing tumor areas to build TMAs or dissecting cancer cells for further analysis may have substantial consequences. Nonetheless, our observation of different cell subtype patterns within a same patient and among patients is aligned with our recent report highlighting these cell subtypes in PCa transcriptomic datasets and the traceability and clinical relevance of PCa cell-subtype genes in liquid biopsies of mCRPC patients [59].…”

Liquid Biopsy: A New Emerging Technique

“…This minimally invasive approach may predict treatment resistance and outcome and improves therapeutic options. [5] Studies support the idea that prostate cell subtype genes are traceable in the blood of patients with advanced disease. Liquid biopsies were developed as an alternative to conventional tissue biopsies since they can be obtained in a noninvasive or minimally invasive way, thus avoiding the risks related to the collection of tissue biopsies and allowing serial sampling during the course of disease.…”

“…Studies support the evidence that prostate cell subtype genes are traceable in the blood of patients with advanced disease. Data from over 1000 patients confirmed that overexpression patterns in the blood of 35 of 40 patients are best represented in metastases [5].…”

“…A major limitation of testing markers in advanced disease remains the invasiveness of biopsies of metastases. This can be overcome by liquid biopsies, particularly blood which contains Extracellular Vesicles (EVs), Circulating Tumor Cells (CTCs), and cell-free nucleic acids [5].…”

“…Tumor cells surviving Androgen-Deprivation Therapy (ADT) continue to grow despite inhibition of steroid synthesis and Androgen Receptor (AR) signaling. Resistance may involve the emergence of active AR variants (AR-Vs) and/or cell plasticity, a concept based on the relationship among reserve stem, neuroendocrine, and luminal cells in glandular acini, which remain relevant in cancer [5]. Studies support the evidence that prostate cell subtype genes are traceable in the blood of patients with advanced disease.…”