Whole genome sequencing and inheritance-based variant filtering as a tool for unraveling missing heritability in pediatric cancer

Abstract

Survival rates for pediatric cancer have significantly increased the past decades, now exceeding 70–80% for most cancer types. The cause of cancer in children and adolescents remains largely unknown and a genetic susceptibility is considered in up to 10% of the cases, but most likely this is an underestimation. Families with multiple pediatric cancer patients are rare and strongly suggestive for an underlying predisposition to cancer. The absence of identifiable mutations in known cancer predisposing genes in such families could indicate undiscovered heritability. To discover candidate susceptibility variants, whole genome sequencing was performed on germline DNA of a family with two children affected by Burkitt lymphoma. Using an inheritance-based filtering approach, 18 correctly segregating coding variants were prioritized without a biased focus on specific genes or variants. Two variants in FAT4 and DCHS2 were highlighted, both involved in the Hippo signaling pathway, which controls tissue growth and stem cell activity. Similarly, a set of nine non-coding variants was prioritized, which might contribute, in differing degrees, to the increased cancer risk within this family. In conclusion, inheritance-based whole genome sequencing in selected families or cases is a valuable approach to prioritize variants and, thus, to further unravel genetic predisposition in childhood cancer.

Keywords:

• Familial
• germline predisposition
• missing heritability
• pediatric cancer
• whole genome sequencing

Disclosure statement

The authors report there are no competing interests to declare.

Data availability statement

The data presented in this study are available in Supplementary materials. Raw WGS call-sets are not publicly available due to privacy concerns.

Additional information

Funding

This research was funded by the Belgian Foundation against Cancer, grant number 2016–126 (grant to GL), Wardie’s Way (grant to TL), and vzw Kinderkankerfonds, a non-profit childhood cancer foundation under Belgian law (grant to TL).