Genetic Predisposition to Childhood Cancers

Examining germline differences that may lead to susceptibility, both Common Variants through GWAS and Rare Variants through Next-Gen Sequencing efforts, as well as Copy Number Alternations, we seek to elucidate the differences which may contribute to a predisposition to developing cancer.

genetic susceptibility chart

Genome-wide association study (GWAS) in neuroblastoma

Only 1% of neuroblastoma patients have a family history of the disease, while the remaining 99% appear to arise “sporadically”, without a family history. Our lab has developed the computational pipelines and led data analyses in a large genome-wide association study (GWAS) of neuroblastoma in collaboration with Dr. John Maris, the Children’s Oncology Group (COG), and the Center for Applied Genomics (CAG) at CHOP.  We have genotyped blood-derived (germline) DNA from over 6,000 children diagnosed with neuroblastoma, and the CAG has provided genotypes for over 30,000 children as controls. To date, over a dozen susceptibility loci have been identified, demonstrating a clear genetic basis for “sporadic” neuroblastoma.  In addition, we have shown that common variants at several of these susceptibility loci target key oncogenes and tumor suppressor genes in neuroblastoma, thereby influencing both disease initiation and maintenance of the malignant phenotype.

Germline structural variation (SV) in neuroblastoma

Our lab has a long-standing interest in the role of structural variation in childhood cancers, and neuroblastoma in particular.  Structural variation (SV), as the name implies, represents variation in the structure of an organism’s chromosome or chromosomes. This variation can take the form of DNA deletions, duplications, inversions, or translocations.  Multiple methods exist to detect SVs, including genotyping arrays and next generating sequencing (NGS) approaches.  We are utilizing a combination of array-based genotyping data from the neuroblastoma GWAS and whole genome sequencing (WGS) data to assess the role of SVs detected in  the germline (blood-derived lymphocyte DNA) of children diagnosed with neuroblastoma. In a recent study of over 5,500 neuroblastoma cases and 25,000 children without cancer, we identified a rare 550-kb microdeletion on chromosome 16p11.2 that predisposes to neuroblastoma with a much larger effect size than seen for common variants identified by GWAS.  The causal gene(s) at the locus remain to be identified. The microdeletion is very rare, but corresponds to an established microdeletion syndrome associated with diverse phenotypes, predominantly related to neurodevelopment.

Defining the landscape of rare genetic variants in childhood cancers

Our lab has a long-standing interest in the role of structural variation in childhood cancers, and neuroblastoma in particular.  Structural variation (SV), as the name implies, represents variation in the structure of an organism’s chromosome or chromosomes. This variation can take the form of DNA deletions, duplications, inversions, or translocations.  Multiple methods exist to detect SVs, including genotyping arrays and next generating sequencing (NGS) approaches.  We are utilizing a combination of array-based genotyping data from the neuroblastoma GWAS and whole genome sequencing (WGS) data to assess the role of SVs detected in  the germline (blood-derived lymphocyte DNA) of children diagnosed with neuroblastoma. In a recent study of over 5,500 neuroblastoma cases and 25,000 children without cancer, we identified a rare 550-kb microdeletion on chromosome 16p11.2 that predisposes to neuroblastoma with a much larger effect size than seen for common variants identified by GWAS.  The causal gene(s) at the locus remain to be identified. The microdeletion is very rare, but corresponds to an established microdeletion syndrome associated with diverse phenotypes, predominantly related to neurodevelopment.