Genetic pleiotropy across pediatric cancers, and cancer-related outcomes

ABSTRACT More than 15,000 children are newly diagnosed with cancer each year in the US. Although breakthroughs in treatments have improved the survival rate to over 85%, cancer remains the leading disease-related cause of death among children while survivors face significant lifelong health-related morbidity and mortality. Studies of

cancer predisposition genes and genome-wide association studies (GWAS) have increased our knowledge of the genetic etiology of pediatric cancers. However, this knowledge base has been built almost exclusively from investigations of individual cancer types. Given emerging evidence that heterogeneous cancer types also have

a significant shared genetic component, we propose to conduct the first large-scale investigation of pediatric cancer pleiotropy. To accomplish this goal, we will combine existing genetic datasets to perform pan-cancer analyses with up to 43,000 pediatric cancer cases representing >25 cancer subtypes from studies including St.

Jude Cloud-hosted research initiatives such as the Pediatric Cancer Genome Project, Real-Time Clinical Genomics, Genomes 4 Kids, Childhood Cancer Survivor Study, and St. Jude Lifetime Cohort Study; the NIH Common Fund Kids First Pediatric Research Consortium studies; and ZERO Childhood Cancer Program. As a

notable data harmonization effort, we will organize existing datasets to construct the largest uniformly processed whole-genome/-exome sequencing (WGS/WES) data resource to date with >20,000 pediatric cancer cases. With these resources, we will conduct a systematic and comprehensive search for common variants and genes

harboring rare cancer predisposition variants (CPVs) that contribute to risks across multiple pediatric cancer types (Aim 1). This search for specific pleiotropic risk loci will be complemented with cross-pediatric cancer evaluations of polygenic risk, genetic correlation, and shared heritability to elucidate global patterns of genetic

pleiotropy between cancer subtypes (Aim 2). Lastly, we will characterize the clinical impacts of pleiotropic genetic susceptibility with CPVs, rare variant burden and polygenic risk scores (PRS) on risks for pediatric cancers and adverse cancer-related outcomes, including relapse, early mortality, subsequent malignant neoplasms (SMNs),

and SMN-related mortality (Aim 3). To assess genome-wide significant findings, we will perform replication studies with independent data from NCI TARGET (Therapeutically Applicable Research to Generate Effective Treatments) and St. Jude clinical genomics programs (Real-Time Clinical Genomics and Genomes 4 Kids), and

evaluate the biological and functional relevance of pleiotropic variants, including for specific cancer types. Altogether, this proposed project represents a unique approach to leverage existing genetic/genomic resources to detect novel risk loci contributing to the development of distinct pediatric cancers and facilitate the generation

of new hypotheses about common carcinogenic mechanisms. Completion of these aims will also potentially support the development of new algorithms for precision medicine, with enhanced genetic risk profiles to better predict who may develop pediatric cancer or experience cancer-related adverse outcomes during survivorship.