Abstract

A compound heterozygous (CH) variant is a type of germline variant that occurs when each parent donates one alternate allele and these alleles are located at different loci within the same gene. Pathogenic germline variants have been identified for some pediatric cancer types but in most studies, CH variants are overlooked. Thus, the prevalence of pathogenic CH variants in most pediatric cancer types is unknown. We identified 26 studies (published between 1999 and 2019) that identified a CH variant in at least one pediatric cancer patient. These studies encompass 21 cancer types and have collectively identified 25 different genes in which a CH variant occurred. However, the sequencing methods used and the number of patients and genes evaluated in each study were highly variable across the studies. In addition, methods for assessing pathogenicity of CH variants varied widely and were often not reported. In this review, we discuss technologies and methods for identifying CH variants, provide an overview of studies that have identified CH variants in pediatric cancer patients, provide insights into future directions in the field, and give a summary of publicly available pediatric cancer sequencing data. Although considerable insights have been gained over the last 20 years, much has yet to be learned about the involvement of CH variants in pediatric cancers. In future studies, larger sample sizes, more pediatric cancer types, and better pathogenicity assessment and filtering methods will be needed to move this field forward.

Highlights

  • Each year worldwide, ∼300,000 children under the age of 14 are diagnosed with cancer (SweetCordero and Biegel, 2019)

  • We focus on compound heterozygous (CH) variants, a type of germline variant that has been understudied in pediatric cancers

  • acute lymphoblastic leukemia” (ALL) and non-Hodgkin’s lymphoma are both bloodbased cancers, while medulloblastoma is a type of brain tumor (Sandlund et al, 1996; Hunger and Mullighan, 2015; Kumar et al, 2015)

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Summary

Introduction

Each year worldwide, ∼300,000 children under the age of 14 are diagnosed with cancer (SweetCordero and Biegel, 2019). Since the 1970s, 5-year survival rates for pediatric cancer patients have steadily increased and are presently over 80% (Phillips et al, 2015). Despite improvements in treatments and survival rates, the causes of most pediatric cancers are still relatively unknown (American Cancer Society). Recent large-scale studies have helped elucidate the involvement of germline mutations in pediatric cancer development. A 2015 study analyzed mutations across 565 known, cancer-associated genes for 1,120 pediatric cancer patients and found that 8.5% of the patients had an identifiable, pathogenic germline mutation in at least one of these genes (Zhang et al, 2015). A 2016 study identified 10% of pediatric cancer patients as having

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