Topic Area and Military Health Focus Area: The focus of this application is to identify and characterize new genetic conditions that increase cancer risk in children. We will use a novel approach that combines assessing cancer risk in more than 1 million children with congenital anomalies (one of the strongest risk factors for developing childhood cancer), exploring the genes that might increase risk, and validating our findings by using existing genetic information in over 30,000 individuals. This research aligns with the Topic Area of “Cancer in Children, Adolescents, and Young Adults,” and based on our preliminary data will have impact on other Topic Areas including blood cancers, pediatric brain tumors, neuroblastoma, and rare cancers. Furthermore, this application addresses the important Military Health Focus Area of “gaps in cancer prevention, early detection/diagnosis, and prognosis that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public” by identifying new genetic conditions that increase cancer risk in children. This will ultimately lead to better cancer screening and outcomes for children and adolescents with congenital anomalies.
Scientific Objective and Rationale: Congenital anomalies are defined as disorders that affect a child during pregnancy and can be identified before or at birth, or sometimes later in life. In fact, 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 (like Down syndrome) and non-chromosomal birth defects (like congenital heart disease), as recently validated in our large multi-state epidemiologic study of over 10 million children. Specifically, by obtaining and linking information from various registries and hospitals on children in four states, we started the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study. In the GOBACK Study, we identified several new congenital anomaly-cancer patterns. After conducting genetic testing in a subset of these families, we identified genes that possibly underlie previously unreported genetic syndromes that increase cancer risk. Therefore, the objective of this application is to extend the GOBACK Study and identify new genetic syndromes that increase cancer risk in children, using both epidemiologic and genetic approaches. To accomplish this, we propose two aims: (1) identify new and confirm previously reported congenital anomaly-cancer patterns within an expanded multistate population-based cohort; and (2) discover and validate genetic variants underlying the overlap of congenital anomalies and pediatric cancers.
Near-Term Impact and Ultimate Applicability: This application will have a near-term impact on the Topic Area of “Cancer in Children, Adolescents, and Young Adults” by generating new insights into congenital anomalies and genetic conditions that increase cancer risk in children, adolescents, and young adults. This will accelerate improved diagnosis, surveillance, and detection of cancer in children with congenital anomalies. The ultimate clinical applications include: (1) novel cancer surveillance programs and genetic counseling strategies for children with congenital anomalies; and (2) the identification of new cancer susceptibility genes, which could lead to the discovery of novel therapeutic targets in both children and adults with cancer.
Relevance to Active Duty Service Members, Veterans, and Military Beneficiaries: Congenital anomalies are common, affecting about 3% of all livebirths in the United States, so their associations with cancer are relevant to many, both in the Armed Forces and the general population. Additionally, it has been estimated that 10% of childhood cancer cases could be due to congenital anomalies. Because half of the 1.4 million active duty Service members have children, and the largest group of children are those ages 5 years or younger, Service members and their beneficiaries bear especially heavy burdens from congenital anomalies and childhood cancer. In this study, we have the opportunity to improve cancer early detection and diagnosis, which would lead to better outcomes for Service members, their beneficiaries, and the general public. To ensure that our results are applicable to members of the Armed Forces, their family members, and Veterans, we will perform our research on a large cohort of children from nine states, including several with large military populations.