I conducted computational cancer genomics research at the Children’s Hospital of Philadelphia with Dr. John Maris. The Maris Laboratory is focused on understanding the underlying molecular and genetic mechanisms that contribute to the development and progression of pediatric neuroblastoma (NBL), and is dedicated to developing targeted cancer therapies to treat NBL.
NBL is an embryonal tumor that arises from the aberrant growth of neural crest progenitor cells during the development of the sympathetic nervous system. It is the most common solid tumor diagnosed in infants and is clinically heterogeneous. Based on assessment of clinical (e.g. stage, age) and tumor genomic factors (e.g. amplification of the MYCN oncogene), diagnoses can be classified as low-, mid-, or high-risk. Despite current combined therapies, 50-60% of the high-risk patients suffer disease relapse, which are largely incurable.
Telomere maintenance is a major hallmark of cancer; high-risk NBL has been associated with increased telomerase activity, which is often mediated through TERT activation. There are two known mechanisms that activate TERT in NBL in a mutually exclusive fashion: 1) TERT rearrangements (31% of high risk NBL), which result translocation of active enhancers, and 2) MYCN amplification (20%), which transcriptionally activates TERT.
To define how these abnormalities activate TERT in NBL, I analyzed the allelic specific expression of TERT in 162 NBL samples. I built a pipeline to align the RNA sequencing data, call heterozygous SNPs from whole genome and whole exome sequencing data, and perform TERT allelic specific expression analysis. I also examined MYCN activity of the NBL samples via single sample gene specific expression analysis, and it was observed that increased MYCN amplification and MYCN signature were associated with biallelic expression of TERT in NBL.
To extend the analysis to other pediatric cancers, I applied a similar pipeline to analyze TERT allelic specific expression in 476 acute lymphoblastic leukemia (ALL), 355 acute myeloid leukemia (AML), 61 osteosarcoma (OS), and 220 kidney tumor samples. It was observed that increased c-MYC signature was associated with biallelic expression of TERT in ALL and kidney tumors.
While MYC/N activity corresponded to biallelic activation of TERT for multiple histotypes, monoalellic activiation of TERT was rare except for ALL and NBL. Furthermore, TERT promoter mutations are often associated with monoallelic activation of TERT in adult cancers, but there were few TERT promoter mutations in pediatric cancers within this dataset.
Working in the Maris Laboratory was an incredible experience because I had the opportunity to apply my coursework in computational biology in the lab and at the clinics. I was extremely fortunate to work with leading professionals in this field and look forward to expanding my research in the future.