ABSTRACT In the United States, cancer remains the leading cause of death by disease in those <20 years of age, and approximately 80% of survivors have at least one chronic health condition by 45 years of age. One of the strongest risk factors for cancer in children and adolescents is being born with a congenital anomaly—this is true both for chromosomal abnormalities (e.g., Down syndrome) and non-chromosomal birth defects (e.g., non- syndromic congenital heart defects), as recently validated in our registry linkage study of over 10 million live births. By linking data from population-based birth defects and cancer registries in four states included in the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study, we identified multiple novel congenital anomaly-cancer associations that are not part of known cancer predisposition syndromes, including choanal atresia-acute leukemia (HR=9.2, 95% CI: 3.8-22.1) and CHD-neuroblastoma (HR=3.4, 95%: 2.6-4.5). Furthermore, consistent with our epidemiologic findings, our genomic assessments have led to the identification of a novel leukemia predisposition disorder characterized by multiple congenital anomalies (including choanal atresia) and pathogenic germline variants in USP9X. In this application, we propose to expand our integrated epidemiologic and genomic approach to address our central hypothesis that pleiotropic genetic variation generates specific congenital anomaly-pediatric cancer (CA-PC) patterns with increased risk conferred to each co-occurring phenotype. Our overall objective is to elucidate the overlap between congenital anomalies and pediatric cancer by leveraging and integrating existing datasets, including 1) the Gabriella Miller Kids First Pediatric Research Program with 44 congenital anomaly and pediatric cancer cohorts, representing 20,000 patients and 48,000 genomes; 2) the All of Us Research Program with WGS data on >90,000 individuals; and 3) the GOBACK Registry Linkage Birth Cohort, which includes population-based data on >25 million live births. In Aim 1, we will analyze an expanded population- based cohort of >25 million children to identify new CA-PC patterns and confirm previously reported patterns. In Aim 2, we will analyze germline whole-genome sequencing (WGS) data from 2,000 children with both congenital anomalies and pediatric cancer and over 20,000 children with either congenital anomalies or pediatric cancer to identify novel pleiotropic genes harboring rare, pathogenic variants responsible for specific CA-PC patterns. In Aim 3, we will describe the landscape of somatic alterations in pediatric cancers that result from pathogenic CA-PC variants through the analysis of tumor-normal WGS and RNA-Seq data in 2,000 children. This work will generate novel insights into cancer predisposition and subsequently lead to improved care for children with congenital anomalies, who comprise 120,000 births every year in the United States. In addition, insights into cancer development among at-risk populations could provide clinical utility (e.g., genetic counseling or therapeutic targets) for children and adults with cancer in the general population.

NARRATIVE In our prior work, we have identified multiple novel congenital anomaly-cancer associations by linking data from population-based birth-defects and cancer registries from four states. Here, we propose to expand this study to seven additional states to analyze a cohort representing >25 million live births and approximately 35% of the US population. We will also search for genetic mechanisms driving these associations through the analysis of whole-genome sequencing data in 20,000 children with congenital anomalies or pediatric cancer, including 2000 sequenced tumors.