Circulating NPTX2 methylation as a non-invasive biomarker for prognosis and monitoring of metastatic pancreatic cancer

Abstract

Background Pancreatic cancer is the most lethal cancer with a dismal prognosis mainly due to diagnosis at advanced stage and ineffective treatments. CA19-9 levels and computed tomography (CT) imaging are the main standard criteria for evaluating disease progression and treatment response. In this study we explored liquid biopsy-based epigenetic biomarkers for prognosis and monitoring disease in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods Plasma samples were collected from 44 mPDAC patients at the time of diagnosis, and in 15 of them, additional samples were obtained during follow-up of the disease. After cell-free DNA (cfDNA), isolation circulating levels of methylated NPTX2, SPARC, BMP3, SFRP1 and TFPI2 genes were measured using digital droplet PCR (ddPCR). BEAMing technique was performed for quantitation of RAS mutations in cfDNA, and CA19-9 was measured using standard techniques. Results NPTX2 was the most highly and frequently methylated gene in cfDNA samples from mPDAC patients. Higher circulating NPTX2 methylation levels at diagnosis were associated with poor prognosis and efficiently stratified patients for prediction of overall survival (6.06% cut-off, p = 0.0067). Dynamics of circulating NPTX2 methylation levels correlated with disease progression and response to therapy and predicted better than CA19-9 the evolution of disease in mPDAC patients. Remarkably, in many cases the disease progression detected by CT scan was anticipated by an increase in circulating NPTX2 methylation levels. Conclusions Our study supports circulating NPTX2 methylation levels as a promising liquid biopsy-based clinical tool for non-invasive prognosis, monitoring disease evolution and response to treatment in mPDAC patients.

Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer

“…However, post-therapy patients often show low methylation frequencies of RAS mutation and CA19-9, making them less ideal for tracking disease progression. In contrast, García-Ortiz et al found that NPTX2 exhibited the highest methylation frequency (87.5%) in cfDNA of mPDAC patients and maintained a higher level of methylation after treatment, starting from a baseline of 100% methylation frequency [85]. Additionally, higher plasma NPTX2 methylation levels were strongly correlated with shorter survival periods in these patients.…”

A secreted proteomic footprint for stem cell pluripotency

“…It is noteworthy that the expression of GRIA4 is also much higher in E8 than E6 (Supplementary RNAseq data) as for NPTX2, suggesting some as-yet unidentified function for this ligand-receptor pair in hPSCs. NPTX2 is also a circulating biomarker of pancreatic cancer [69]. In glioblastoma NPTX2 has been shown to inhibit AKT which in turn represses NFKB activity [70].…”

Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects

“…In a recent study by our group, NPTX2 methylation levels was analyzed in plasma from 44 metastatic PDAC patients using ddPCR to evaluate its utility for prognosis and monitoring disease progression. Significantly, we demonstrated that the circulating NPTX2 methylation levels not only serve as a valuable prognostic biomarker but also offer a practical tool for monitoring metastatic PDAC patients [ 90 ]. Thus, correlations were observed between changes in NPTX2 methylation levels and disease progression as well as response to therapy, surpassing CA19-9 in predicting disease evolution in mPDAC patients.…”

“…Thus, correlations were observed between changes in NPTX2 methylation levels and disease progression as well as response to therapy, surpassing CA19-9 in predicting disease evolution in mPDAC patients. Moreover, in many cases, an elevation in circulating NPTX2 methylation levels preceded the detection of disease progression by CT imaging [ 90 ].…”