Abstract:
DESCRIPTION (provided by applicant):
Children diagnosed with high-risk neuroblastoma receive intensive multi-modal therapy, yet 40-50% die of their primary cancer, and those who survive experience substantial treatment-related morbidities. There is no reliable way to identify those at greatest risk of treatment failure (death) or late effects, and only a nascent understanding of underlying genetic determinants. Our long term goal is to improve neuroblastoma outcomes by first characterizing the events driving tumorigenesis and treatment response so that evidence-based and less toxic therapies can be developed. We hypothesize that comprehensive whole genome sequencing (WGS) of high- risk neuroblastoma subjects treated with modern therapy and annotated with late effect phenotypes will identify genetic determinants of survival and treatment-related morbidities. Through an existing Gabriella Miller Kids First (GMKF) project, we performed WGS of neuroblastoma patient-parent triads/dyads (n=556) together with matched tumor DNA (n=336) and RNA-sequencing (n=207). These data have defined the heritable fraction of rare pathogenic variants in cancer predisposition genes and suggest carriers have worse survival. However, only a subset of cases (n=178) sequenced are high-risk and none include phenotyping of late effects. Here, we will build on existing GMKF profiling to generate germline WGS for 1,100 total children (n=922 new) who received modern high-risk neuroblastoma therapy, along with additional WGS of matched tumor DNA (n=553 new) and RNA-sequencing (n=461 new). All subjects participated in the Children’s Oncology Group (COG) neuroblastoma biology study (ANBL00B1). The entire cohort is annotated with demographic (age, sex, race, ethnicity), clinical (e.g. age at diagnosis, stage, risk group, survival), and tumor biological (e.g. MYCN status) co-variates. A subset (n=367) are 5+ year survivors enrolled in the COG ALTE15N2: Late Effects After High-Risk Neuroblastoma (LEAHRN) study and have undergone extensive clinical assessments, with excellent characterization of late toxicities. We will test our hypothesis through two Specific Aims: 1) Identify germline and somatic variants associated with high-risk neuroblastoma treatment failure. Using a phased approach, we will identify coding and non-coding germline variation, somatic alterations, and transcriptomic profiles predicting refractory disease and survival. 2) Discover genetic risk factors associated with late effects after high-risk neuroblastoma therapy. We will define the spectrum, prevalence, and association of rare pathogenic variants with respect to hearing loss, cardiomyopathy, growth impairment and primary gonadal failure in the LEAHRN subjects. Data from NCI- TARGET (n=1,108), our genome-wide association study (GWAS; n=6,202), and phenotyping in recent high-risk trials will be integrated to validate genetic associations with treatment outcomes. Sequencing of this unique and extensively phenotyped high-risk neuroblastoma cohort will provide an unparalleled opportunity to discover germline and somatic alterations that can be used to identify patients at risk for treatment failure and late effects. This will serve as rationale for the design of future trials aimed at improved survival and reduction in late effects.
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