Population-based newborn screening (NBS) is one of the most successful public health programs in modern medicine. Over 60 actionable conditions are currently included in NBS using biologic samples from newborn "heel stick" dried blood spots (DBS). At this time, genetically-based detection of increased risk for early onset childhood cancer risk, such as heritable retinoblastoma, is not included in NBS. With state public health laboratories increasingly using DNA-based tests in NBS algorithms, primary sequencing-based NBS for the early identification of newborns at high risk for developing infant or early childhood cancers may be feasible.
We developed a novel tNGS-based panel, designated “PERC-Seq” (Pediatric Early Risk for Cancer-Sequencing), which includes 11 cancer predisposition syndrome genes. Pathogenic variants in these selected genes are associated with increased risk of specific early-onset childhood cancers whose outcomes could potentially be improved with early detection. We developed a simulation model to assess the impact of using this panel (and each gene individually) in NBS. The Childhood Cancer Predisposition Simulation Model suggests that identification and surveillance of at-risk infants would reduce overall childhood cancer deaths by ~8%, as well as reduce the percentage of survivors living with high risk of treatment-related mortality. We worked with the Michigan Cancer Surveillance Program and the Michigan Biobank to identify DBS from children born in Michigan who went on to develop with a malignancy in which the histologic tumor type was associated with variants in PERC-Seq panel genes. We identified 1803 such potential samples. The PERC-Seq Panel will be applied to the samples to estimate prevalence of pathogenic or likely pathogenic variants for each histologic subtype, and these data will be entered into the simulation model.
Modeling the impact of public health interventions in childhood cancer detection and prevention can be helpful in evaluating new interventions. Linkage of DBS specimens to childhood cancer cases is feasible and provides a new source of biologic materials for studying cancer etiology and risk.