detection-monitoring-tumor-associated-circulating-dna-patient

Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids

Complications associated with upfront and repeat surgical tissue sampling present the need for minimally invasive platforms capable of molecular ...

Children's National Health System

The George Washington University School of Medicine and Health Sciences

Universitats-Kinderspital Zurich

Central nervous system (CNS) tumors are the most common solid tumors in children, and the leading cause of cancer-related death. Over the past decade, molecular profiling has been incorporated into treatment for pediatric CNS tumors, allowing for a more personalized approach to therapy. Through the identification of tumor-specific changes, it is now possible to diagnose, assign a prognostic subgroup, and develop targeted chemotherapeutic treatment plans for many cancer types. The successful incorporation of informative liquid biopsies, where the liquid biome is interrogated for tumor-associated molecular clues, has the potential to greatly complement the precision-based approach to treatment, and ultimately, to improve clinical outcomes for children with CNS tumors. In this article, the current application of liquid biopsy in cancer therapy will be reviewed, as will its potential for the diagnosis and therapeutic monitoring of pediatric CNS tumors.

Liquid biopsy for pediatric central nervous system tumors.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

Diffuse intrinsic pontine gliomas (DIPGs) are deadly tumors comprising 10%-15% of all childhood CNS cancers. Standard treatment is considered palliative and prognosis is near universal mortality. DIPGs have been classified into genomic subtypes based on histone variants with the lysine to methionine mutation on position 27 of histone tails (K27M). Given the increasing promise of immunotherapy, there have been ongoing efforts to identify tumor-specific antigens to serve as immunologic targets. We evaluated a large cohort of CNS specimens for Wilms' tumor protein (WT1) expression. These specimens include primary pediatric CNS tumors (n = 38 midline gliomas and n = 3 non-midline gliomas; n = 23 DIPG, n = 10 low-grade gliomas, n = 8 high-grade gliomas), and DIPG primary cells. Here, we report the validation of WT1 as a tumor-associated antigen in DIPGs. We further report that WT1 expression is significantly correlated with specific oncohistone variants, with the highest expression detected in the H3.3K27M subgroup. WT1 expression was absent in all control specimens (n = 21). Western blot assays using DIPG primary cells (n = 6) showed a trend of higher WT1 expression in H3.3K27M cells when compared with H3.1 K27M cells and H3 wildtype cells. Our data are the first indication of the association between WT1 and DIPG, with specific upregulation in those harboring oncohistone H3.3K27M.

Article	Year
Liquid biopsy for pediatric central nervous system tumors. NPJ precision oncology\| PubMed ID: 30588509	2018
A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium. International journal of cancer\| PubMed ID: 30861105	2019
Differential Expression of Wilms' Tumor Protein in Diffuse Intrinsic Pontine Glioma. Journal of neuropathology and experimental neurology\| PubMed ID: 30990879	2019

Javad Nazarian

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