BIRTH DEFECTS AND CHILDHOOD CANCER: A SHARED BIOLOGICAL PATHWAY FOR
HIRSCHSPRUNG DISEASE AND HEPATOBLASTOMA DEVELOPMENT?
Background: The association of birth defects and developmental
alterations with pediatric cancer is a recognized long-standing global
observation, although very few syndromes confer a high risk of
hepatoblastoma development. Procedures: Here we describe the results of
germline exome analysis of two syndromic patients with Hirschsprung
disease who developed hepatoblastoma. Results: Germline variants of
uncertain clinical significance (VUS) were disclosed in 28 genes that
might be related to patients’ phenotypes. More importantly, germline VUS
were detected in eight known cancer predisposition genes (APC, BRCA1,
ERBB2, ERCC2, HRAS, ODC1, SERPINA6, and MCC). Additionally, our data
disclosed two candidate genes with germline variants potentially
contributing to the phenotype of these patients, namely, CEP164 and
CYP1A1. The last one was the only gene presenting variants of uncertain
significance in both patients. This gene encodes the most important
xenobiotic-metabolizing enzyme of the placenta for which relevant
inducible activity has been demonstrated throughout pregnancy.
Conclusion: our data pointed out a set of genes that are enriched for
pathways already related to cancer and developmental biology, suggesting
they could have a broader role in cancer and congenital abnormalities.
These results can help future studies to understand the biology of
Hirschsprung disease and its association with hepatoblastoma.