Liquid biopsies in pediatric oncology: opportunities and obstacles

Abstract

Purpose of review: Liquid biopsies have emerged as a noninvasive alternative to tissue biopsy with potential applications during all stages of pediatric oncology care. The purpose of this review is to provide a survey of pediatric cell-free DNA (cfDNA) studies, illustrate their potential applications in pediatric oncology, and to discuss technological challenges and approaches to overcome these hurdles.

Recent findings: Recent literature has demonstrated liquid biopsies' ability to inform treatment selection at diagnosis, monitor clonal evolution during treatment, sensitively detect minimum residual disease following local control, and provide sensitive posttherapy surveillance. Advantages include reduced procedural anesthesia, molecular profiling unbiased by tissue heterogeneity, and ability to track clonal evolution. Challenges to wider implementation in pediatric oncology, however, include blood volume restrictions and relatively low mutational burden in childhood cancers. Multiomic approaches address challenges presented by low-mutational burden, and novel bioinformatic analyses allow a single assay to yield increasing amounts of information, reducing blood volume requirements.

Summary: Liquid biopsies hold tremendous promise in pediatric oncology, enabling noninvasive serial surveillance with adaptive care. Already integrated into adult care, recent advances in technologies and bioinformatics have improved applicability to the pediatric cancer landscape.

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FIGURE 1

Clinical applications of liquid biopsy in pediatric oncology. Liquid biopsies capture genetic material shed throughout the body, enabling noninvasive molecular profiling without the confounding variable of tumor heterogeneity. Liquid biopsies can, therefore, inform care and treatment selection at diagnosis, monitor clonal evolution during treatment, sensitively detect minimum residual disease following local control and provide sensitive posttherapy surveillance. Multiple studies have demonstrated that liquid biopsies have the potential to detect relapsed disease before radiographically evident.

FIGURE 2

Moderate depth whole genome sequencing improve detection by enabling multiomic integration from a single assay. Recent studies have demonstrated that, with advanced bioinformatic analysis, WGS to depths of 12x–35x is sufficient for detection of copy number alterations, indels, translocations and fusions, assessment of chromatin accessibility and fragmentomics [^▪▪,^▪▪]. In addition to detecting the most common genomic alterations in childhood cancer, therefore, integration of these output also infers epigenetic and transcriptomic signatures. Combinatorial approaches, previously requiring multiple assays, enhance detection of early stage cancers.