Potential Genetic Variants Linked to Increased Cancer Risk in Children

Children with non-chromosomal birth defects have been shown to be 2.5x more likely to be diagnosed with cancer than children without congenital disabilities and have an increased risk of developing cancer either during adolescence or later in adulthood. The underlying causes of non-chromosomal birth defects remain poorly understood, so researchers at the Center for Applied Genomics (CAG) wanted to determine what molecular mechanisms were at play in these patients, as well as potentially identify any clues that could lead to early cancer identification.

“We assembled one of the largest pediatric oncology and birth defects projects in children as part of the Gabriella Miller Kids First program project, which helps to uncover new insights into childhood cancer and structural birth defects,” explains senior author Hakon Hakonarson, MD, PhD, director of the CAG at CHOP. “With this partnership, we sought to identify functional molecular pathways based on mutations we identified as part of this study.”

The study, published in Biomarker Research, began by utilizing the Kids First Data Resource Center to obtain whole genome sequencing data from blood samples of 1,653 individuals without chromosomal abnormalities. The samples included 541 birth defect probands (i.e., the first person in a family to receive genetic counseling or testing for hereditary risk of disease) with at least one type of malignant tumor, 767 birth defect probands without malignant tumors, and 345 healthy family members who are parents or siblings of the probands. Once the variants were identified, whole genome sequencing data from 40 birth defect probands from outside the data resource center, including 25 patients with at least one type of cancer, were used to further validate the study.

The findings revealed thousands of variants of interest, including 119 genes with at least two variants in coding regions or regions of the gene that will be transcribed and translated into proteins. The team also found 478 genes with at least 20 variants in non-coding regions. AXIN2, BMP1, CR1, ERBB2, and RYR1 were all genes associated with birth defects and increased risk of cancer.

Additionally, the researchers built a deep learning model to assess the variants of interest identified in the Kids First cohort with 40 other validation samples, ultimately finding that they had achieved ~75% accuracy, with even greater accuracy for variants associated with non-coding regions.

Further analysis identified genes and non-coding mutations that not only result in congenital disabilities but also identify which types of cancer the individuals are more prone to and whether the risk is more pronounced in childhood or adulthood.

 “While more research is needed to delve into the variants of interest we identified, this study represents a critical step toward the earlier detection of cancer children with non-chromosomal birth defects,” says Hakonarson.