Understanding the molecular landscape of rare tumors through the CCDI-COG Molecular Characterization Initiative.

Abstract

10012 Background: Through collaboration with the National Cancer Institute as part of the Childhood Cancer Data Initiative, the Children’s Oncology Group offers prompt paired tissue and germline sequencing for newly diagnosed rare tumor subtypes. Methods: Individuals are eligible for paired germline and somatic blood/tissue sequencing if they are age 25 or younger, have been diagnosed with a rare tumor in the past 6 months and have both germline and tissue samples available. The paired samples undergo DNA and RNA extraction, followed by whole exome sequencing (paired tumor and germline) of cancer associated genes and RNA targeted fusion analysis. Results are returned to the primary institution within 2-3 weeks of receipt of both samples. Results: Between 09/12/2022 and 11/01/2024, 490 individuals from 123 institutions were enrolled with a total of 98 distinct diagnoses reported. The most common diagnosis groups were thyroid carcinoma (n = 120), neuroendocrine tumors (n = 53), sex cord stromal tumors (n = 41), and other carcinomas (n = 83). Of the 490 patients enrolled, 438 had submitted samples with successful return of exome results in 351/438 (80.1%) and fusion results in 302/438 (69.1%) by the data cut. Tier I/II germline single nucleotide (SNV) or copy number (CNV) variants were identified in 88 (25.1%) of patients that completed sequencing. The most prevalent germline alterations included SNVs in DICER1 (n = 20, 5.7%), TP53 (n = 7, 2.0%), RB1 (n = 7, 2.0%), CHEK2 (n = 6, 17%), SDHB (n = 5, 1.4%) and VHL (n = 5, 1.4%). 98% of samples demonstrated a Tier I/II somatic variant across 26 genes, most commonly found in DICER1 (n = 39, 11.1%), BRAF (n = 30, 8.5%), TP53 (n = 22, 6.3%) and CTNNB1 (n = 14, 4.0%). RNA fusion analysis identified positive results in 22.8% of samples. Testing identified over 33 distinct fusions. Fusions were most commonly associated with thyroid cancer; RET in 16 and NTRK in 12, or desmoplastic small round cell tumor; EWSR1::WT1 in 8. In 16.5% (n = 58) of the samples, the final diagnosis was refined based on the results of the molecular testing and 6.8% (n = 24) of the centers reported using a commercially available treatment targeting an identified molecular alternation. Conclusions: The MCI has enabled access to genetic sequencing to patients across the Children’s Oncology Group across a wide range of rare tumor diagnoses. Information about the available data can be accessed through the CCDI Hub Explore. Germline cancer predisposition was identified in a quarter of these samples, highlighting the importance of tumor-normal profiling to allow genetic counselling in these patients and appropriate surveillance. These results have the potential for lasting impact on understanding and treating individuals with rare cancers and the development of targeted future clinical trials.