CCDI-COG molecular characterization initiative: The expanding data on childhood cancer.

Abstract

10013 Background: The Molecular Characterization Initiative (MCI), a collaboration between the Children's Oncology Group (COG) and the NCIs Childhood Cancer Data Initiative (CCDI) which is intended to define a standardized genomic characterization of pediatric cancer, provides rapid, clinical sequencing for newly diagnosed central nervous system (CNS) tumors, rare tumors, soft tissue sarcomas (STS), or advanced stage neuroblastoma (NB) to guide diagnosis and treatment for these children. Methods: Patients enrolled on APEC14B1-MCI who are ≤25 years of age with an eligible tumor type treated at national or international COG sites with available snap frozen or FFPE tissue and paired germline samples undergo RNA/DNA extraction. Whole exome sequencing (paired tumor and germline), targeted RNA fusion (excluding NB) and methylation array (CNS clinical / STS, NB and rare tumor research only) analyses are performed, with clinical results returned in 2-3 weeks. Results: Between 3/31/22 and 11/1/24, MCI provided results for 3,972 patients, including 2,666 with CNS tumors, 781 with STS, 372 with rare tumors and 153 with NB, across 188 institutions. 89% of the > 10,000 individual tests resulted within 2 weeks of receiving nucleic acids for sequencing. Tier I/II germline single nucleotide (SNV) or copy number (CNV) variants were identified in 528 (14.1%) patients [10.4% (NB) to 25.1% (rare tumors)]. The most common germline alterations included SNVs in TP53 (n = 52,1.4%), CHEK2 (n = 50,1.3%), DICER1 (n = 35,0.93%), NF1 (n = 29,0.78%) and ATM (n = 24, 0.64%). Somatic SNVs or CNVs were identified in 85% of samples overall. Somatic SNVs most commonly involved TP53 (n = 309,8.3%), BRAF (n = 222,6.9%), or CTNNB1 (n = 166,4.4%). Targeted RNA sequencing identified gene fusions in 30% overall (23% rare, 27% CNS, 40% STS). Methylation array resulted in positive subclassification of CNS tumors in 90% of patients, including 522 patients with medulloblastoma. Additional characterization of residual nucleic acid samples is planned, with data available through the database of Genotypes and Phenotypes (dbGaP). Follow up data has been collected for 1236 patients (NCI-CCDI Hub), including frontline treatment (chemotherapy and/or radiation), response to therapy, and vital status. Additionally, 749 reported on the utility of MCI testing six months following enrollment. MCI results were used for: enrollment on a clinical trial (n = 86,11.5%), treatment with a targeted therapy (n = 8,10.7%), and/or refining the pathologic diagnosis (n = 223,29.5%). Conclusions: The MCI has resulted > 10,000 sequencing assays from 3,972 children with cancer in 31 months. This has directly impacted the diagnosis and/or management of patients with newly diagnosed tumors, providing access to timely molecular testing (including methylation in CNS tumors and fusion testing in STS), and guiding therapy and clinical trial enrollment for many patients.