Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer

Abstract

The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression.

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets

“…In cancer, MMP-9 is associated with genetic instability, tissue remodeling, tumor cell proliferation, invasion and motility, progression, extravasation, metastasis, epithelial-mesenchymal transition, angiogenesis, apoptosis, inflammation, and immunosurveillance (36). MMP-9 in PBLs, serum, and tumors predicts prognosis, invasiveness, grade and differentiation, recurrence, metastasis, and treatment resistance, for bladder, lung, blood, colorectal, prostate, and liver cancers (42)(43)(44)(45)(46)(47)(48)(49). In patients with RCC, MMP-9 is increased in tumors and plasma (50) and correlates with histological grade (51), poor prognosis, and lowered survival (52), metastasis, decreased time to progression, and poor response to sunitinib (53).…”

Emerging Variants of Castration-Resistant Prostate Cancer

“…For instance, the presence of nuclear AR expression and active AR signaling (“AR-mixed” CTCs and “AR-on” cells) despite treatment with ARPI therapies (ABI, ENZ) has demonstrated prognostic value [70, 71]. At the gene level, differential expression of 282 genes between samples with ≥5 CTCs versus <5 CTCs was demonstrated, with significant prognostic ability of a two-gene model [72]. Concordance of PTEN status between CTCs and fresh tumor tissue is promising of the ability of CTC profiling to reflect tumor mutational status [73].…”

Whole blood mRNA in prostate cancer reveals a four-gene androgen regulated panel

“…The majority of diagnostic biomarkers are identified through studies comparing benign and primary prostate cancer. All previous studies using PAXgene samples to determine circulating mRNA signatures in prostate cancer have examined primary indolent vs aggressive prostate cancer either using pre-selected genes of interest or by amplifying the mRNA that is known to introduce bias (Kitchen et al 2011, Olmos et al 2012, Ross et al 2012, Danila et al 2013, Marin-Aguilera et al 2015. In this study, we have described the identification of genes initially using a benign vs metastatic comparison using Illumina Human HT12 v4 expression arrays without amplification or use of haemoglobin reduction, which has been reported to improve data quality in PAXgene studies (Fan & Hegde 2005, Vartanian et al 2009).…”

“…It is hypothesised that the mRNA collected in PAXgene samples could be influenced by expression of specific genes in primary tumour tissue or be altered due to the immune response (Olmos et al 2012, Ross et al 2012, Marin-Aguilera et al 2015. As no tissue RNA was available from our discovery cohort, we examined gene expression of the four genes identified in a published independent cohort (Taylor et al 2010).…”

“…There have been a number of recent publications on prostate cancer, which utilise PAXgene samples for prognosis to identify those primary prostate cancers that are likely to be life limiting (indolent primary vs aggressive disease) (Liong et al 2012, Olmos et al 2012, Ross et al 2012, Danila et al 2013, Marin-Aguilera et al 2015. In back-to-back publications, Olmos et al and Ross et al showed different gene signatures, both capable of predicting shortened survival in patients with castration-resistant prostate cancer (Olmos et al 2012, Ross et al 2012.…”