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.
Rare Variant Analysis
Rare germline variants, those with minor allele frequency under 1% in the general population, may contribute to disease progression more significantly through a higher effect size than GWAS identified polymorphisms. GWAS studies have revealed oncogenic vulnerabilities but these often have modest effect size and it is only through combinatorial effect that disease threshold is crossed.
Contrasting the results of GWAS, analysis of germline sequencing from the NCI-TARGET project is working to identify rare variants in the germline of neuroblastoma patients.
Genetic basis of neuroblastoma
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 Genomcis (CAG) at CHOP. This work has demonstrated a genetic basis for “sporadic” neuroblastoma. We have genotyped blood-derived 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. Further, we have shown that genes targeted by these neuroblastoma-associated germline variants can also drive tumor aggressiveness, a finding not initially expected. We are analysis germline sequencing from the NCI-TARGET project to identify rare variants in the germline of neuroblastoma patients. Through support from the NIH and Gabriella Miller Kids Fist (GMKF), our lab is also leading the analysis of a large cohort of neuroblastoma patient-parent trios with matched tumor DNA and RNA sequencing. This will allow us to assess, for the first time whether mutations observed in patients were inherited or acquired de novo, with important implications for genetic counseling.
