The genomic landscape of pediatric cancers: Implications for diagnosis and treatment

Abstract

The past decade has witnessed a major increase in our understanding of the genetic underpinnings of childhood cancer. Genomic sequencing studies have highlighted key differences between pediatric and adult cancers. Whereas many adult cancers are characterized by a high number of somatic mutations, pediatric cancers typically have few somatic mutations but a higher prevalence of germline alterations in cancer predisposition genes. Also noteworthy is the remarkable heterogeneity in the types of genetic alterations that likely drive the growth of pediatric cancers, including copy number alterations, gene fusions, enhancer hijacking events, and chromoplexy. Because most studies have genetically profiled pediatric cancers only at diagnosis, the mechanisms underlying tumor progression, therapy resistance, and metastasis remain poorly understood. We discuss evidence that points to a need for more integrative approaches aimed at identifying driver events in pediatric cancers at both diagnosis and relapse. We also provide an overview of key aspects of germline predisposition for cancer in this age group.

Fig. 1.. Model for integrative genomic analysis of pediatric cancers in clinical practice.

Comprehensive cytogenomic and molecular assays are performed at diagnosis to determine genomic or epigenetic alterations in the tumor. Pathogenic germline variants, as well as DNA variants that reflect ancestry and influence drug metabolism (pharmacogenomics), are determined by analysis of normal tissues, typically blood or fibroblasts. Results from these assays are integrated to refine diagnosis and select therapy. Focused gene-specific assays are performed for a subset of patients to determine whether pathogenic germline variants are de novo or inherited from a parent. Carriers should be counseled regarding recurrence risk and enrolled in a surveillance program (imaging, blood work) for early detection of cancer. In the relapse setting, focused assays may be used to determine whether the same genetic events that were detected at diagnosis are present. In addition, comprehensive cytogenomic and molecular assays should be used to identify novel genetic alterations that would dictate the need for alternative therapy.