Genetic Predisposition to Cancer
Childhood cancers are inherently malignancies arising during development, sometimes at very early stages. As a result, many pediatric cancers exhibit a relative paucity of recurrent somatic mutations in tumors compared to adult cancers. By studying germline variants – those present in DNA of “all” cells (not unique to cancer cells), we seek to identify genetic variants that predispose to cancer. These can include common single nucleotide variants (SNVs) and insertions/deletions (indels), rare SNVs/indels, and larger structural variants (SVs). They can be inherited from a parent, but can also arise de novo very early in development. We use a combination of large-scale genotyping and next generation sequencing (NGS) data to elucidate the genetic basis of neuroblastoma. We do this through a combination of genome-wide association studies (GWAS) to discovery common risk variants, and large next-generation sequencing (NGS) projects to identify rare variants with larger effect sizes. Experimental approaches are then applied to understand the biological relevance of newly discovered genetic risk factors. Collectively, this work has made lasting impacts on the field by defining the genetic basis of neuroblastoma and demonstrating that many of the genes targeted by neuroblastoma-associated variants not only influence tumor initiation by promoting malignant transformation, but are also required for maintenance of the malignant phenotype.
