# Copy number variations contribute to malignant tumor development in children with serious birth defects

## TL;DR

Children with birth defects are more likely to develop cancer, and copy number variations may play a role in this increased risk.

## Contribution

This study is one of the first to explore the impact of copy number variations on cancer development in children with birth defects.

## Key findings

- CNVs are unevenly distributed and show strong heterogeneity among children with birth defects and cancer.
- Functional analysis reveals CNVs affecting pathways related to growth and cancer regulation, including non-coding RNA regulators.
- Deletions of neurological genes and duplications of immune response genes are associated with CNVs in these patients.

## Abstract

There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population‐based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new insights into the underlying mechanisms for pediatric tumor development. We performed whole‐genome sequencing (WGS) on blood‐derived DNA for 1556 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumor, 757 cancer‐free children with BDs, and 345 healthy individuals, focusing on copy number variation (CNV) analysis. Roughly half of the children with BD‐cancer have CNVs that are not identified in BD‐only/healthy individuals, and CNVs are not evenly distributed among these patients. Strong heterogeneity was observed, with a limited number of cancer predisposition genes containing CNVs in more than three patients. Moreover, functional enrichments of genes with CNVs showed that dozens of patients have variations related to the same biological pathways, such as deletions of genes with neurological functions and duplications of immune response genes. Phenotype clustering uncovered recurrences of patients with sarcoma: A notable enrichment was observed involving non‐coding RNA regulators, showing strong signals related to growth and cancer regulations in functional analysis. In conclusion, we conducted one of the first genomic studies exploring the impact of CNVs on cancer development in children with BDs, unveiling new insights into the underlying biological processes.

Children with birth defects are more likely to develop cancer. We observed strong heterogeneity and uneven distributions of copy number variations (CNVs) in 454 such children, with limited occurrence of cancer predisposition genes. However, consistency of the functional impact of CNVs on pathways, and enrichment of non‐coding RNA, was observed, showing strong signals related to growth and cancer regulation.