Development of a comprehensive liquid biopsy-based genomics platform for pediatric solid tumors
The analysis of cell-free DNA (cfDNA) from liquid biopsies, such as blood or cerebrospinal fluid, is a rapidly growing area for clinical innovation. To date, most clinical assays have been developed for solid tumors in adults, which require large volumes of fluid that cannot be safely obtained from young children. Comprehensive cfDNA testing for pediatric patients with solid tumors has the potential to transform care by providing a less invasive yet highly effective alternative for identifying genetic changes in tumor DNA that can inform diagnosis, risk stratification, therapeutic options, and disease progression, especially compared to conventional radiographic imaging. We recently developed a liquid biopsy assay for patients with solid tumors, brain tumors and retinoblastoma based on whole genome sequencing of cfDNA from blood, cerebrospinal fluid, or the aqueous humor in the eye, respectively. This assay has been used to help make diagnoses and follow response to chemotherapy in young patients with solid tumors. The goal of the present study is to further develop our methods to capture additional changes that signify the presence of tumor DNA in these liquid biopsies. Validation of the platform in our clinical laboratory will have direct translational impact for children with solid tumors.
In this proposed study, we will design sensitive and specific means of interrogating DNA that is shed from solid tumors into the blood, cerebrospinal fluid or the eye that will form the basis for clinical tests that can be used to improve care for children with all types of solid tumors. We will analyze cell free DNA for alterations in 136 genes that contribute to pediatric cancer and analyze the DNA for modifications that alter the expression of genes in tumor as compared to normal cells. The introduction of this platform into our clinical test menu will provide physicians and their patients potential options to surgical biopsies when the tumors are not amenable to resection, as an adjunct to radiographic imaging for monitoring residual or recurrent disease, and ultimately, as a pathway to prospective screening for individuals who have a genetic risk for cancer.
2025 Update:
We developed a first-generation liquid biopsy assay for pediatric patients with solid tumors, brain tumors and eye tumors based on whole genome sequencing to identify tumor-associated chromosomal copy number alterations in cell free DNA (cfDNA) from blood, cerebrospinal fluid, or the aqueous humor in the eye, respectively. This clinical assay has been used to help inform the diagnosis, in some cases before the patients could have a surgical biopsy for standard pathologic evaluation. We have also used this assay to follow response to chemotherapy in children with brain tumors and retinoblastoma, in several patients demonstrating the persistence of residual disease in the liquid biopsy when radiographic imaging was negative. In the last year, we have employed a novel pediatric cancer focused assay to detect small changes (mutations) in the cfDNA to capture additional alterations that signify the presence of tumor. We expect to offer this as a clinical test for patients in early 2025.
