Genetic Predisposition to Cancer

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: Identification of common genetic risk variants

Only 1% of neuroblastoma patients have a family history of the disease, while the remaining 99% appear to arise “sporadically”. Our lab has led the 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. This work has demonstrated a genetic basis for “sporadic” neuroblastoma. 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. This work has resulted in 21 peer reviewed research papers. Our laboratory has produced all computational pipelines, and discovered multiple NB susceptibility loci.

To date, GWAS studies in neuroblastoma have identified susceptibility loci associated with more than 10 different candidate genes and follow-up studies lend credence to their importance.  Many of these candidates have been validated as independent drivers of disease and play roles in both tumor initiation and aggressiveness.

With support through the NIH and Gabriella Miller Kids First (GMKF), in conjunction with the Children’s Brain Tumor Tissue Consortium, we are expanding these studies to a variety of pediatric brain tumors. We hope to further elucidate the genomics of cranial tumors in search of better treatments and cures.

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.