Blood-Based Detection of BRAF V600E in Gliomas and Brain Tumor Metastasis.

Anudeep Yekula,Leonora Balaj,Zachary S Rosh,Julia L Small,Pamela S Jones,Keiko M Kang,Bob S Carter,Koushik Muralidharan

doi:10.3390/cancers13061227

Blood-Based Detection of BRAF V600E in Gliomas and Brain Tumor Metastasis.

Anudeep Yekula, Leonora Balaj + Show 6 more

Open Access

https://doi.org/10.3390/cancers13061227

Copy DOI

Abstract

Simple SummaryThe BRAF V600E mutation has been identified as a key driver in brain tumors and brain tumor metastasis. The ability to detect this mutation in a minimally invasive plasma assay offers advantages over traditional tissue-based biopsy for the disease diagnosis and monitoring. The aim of this study was to develop an assay for the detection of BRAF V600E in the plasma of patients with brain tumors and brain tumor metastasis. We demonstrate BRAF V600E detection using a novel plasma-based ddPCR assay. We detect the mutation in circulating nucleic acids in 4/5 patients with mutant gliomas and metastatic melanoma. We also show correlation between plasma BRAF V600E and clinical status. This proof of principle study is important in the context of application of liquid biopsy in plasma to the neuro-oncologic field. The assay may be useful as a diagnostic adjunct, prognostication tool, and method for monitoring of disease and treatment response.Liquid biopsy provides a minimally invasive platform for the detection of tumor-derived information, including hotspot mutations, such as BRAF V600E. In this study, we provide evidence of the technical development of a ddPCR assay for the detection of BRAF V600E mutations in the plasma of patients with glioma or brain metastasis. In a small patient cohort (n = 9, n = 5 BRAF V600E, n = 4 BRAF WT, n = 4 healthy control), we were able to detect the BRAF V600E mutation in the plasma of 4/5 patients with BRAF V600E-tissue confirmed mutant tumors, and none of the BRAF WT tumors. We also provide evidence in two metastatic patients with longitudinal monitoring, where the plasma-based BRAF V600E mutation correlated with clinical disease status. This proof of principle study demonstrates the potential of this assay to serve as an adjunctive tool for the detection, monitoring, and molecular characterization of BRAF mutant gliomas and brain metastasis.

Highlights

Brain tumors, most commonly metastasis and gliomas, are a highly heterogeneous disease group with poor prognosis despite invasive and intensive multimodal treatment [1,2,3]
We focus on the technical development of the BRAF V600E hotspot mutations in gliomas and central nervous system (CNS) metastases
We have developed a ddPCR assay to detect the BRAF V600E mutation in circulating plasma-derived cell free DNA and EV RNA

Summary

Introduction

Most commonly metastasis and gliomas, are a highly heterogeneous disease group with poor prognosis despite invasive and intensive multimodal treatment [1,2,3]. Diagnosis often involves imaging and tissue-based biopsy, and longitudinal disease monitoring currently relies on serial magnetic resonance imaging to assess treatment response, progression, or recurrence. Imaging is limited in its detection of molecular heterogeneity and tumor evolution and obtaining tissue for histologic and molecular analysis is not always feasible due to the highly invasive nature of the surgery [4]. Liquid biopsy-based strategies provide the ability to diagnose intracranial disease based on specific biomarkers, monitor response to treatment and disease progression, and provide real-time information on the molecular characteristics of the tumor [5,6,7,8]. In patients with primary cancers outside the CNS, liquid biopsy assays have been developed for the diagnosis and monitoring of several cancers, including malignant melanoma, colorectal cancer and prostate cancer [8,14,15,16]

Objectives

Methods

Results

Discussion

Conclusion