Abstract A03: Prevalence and spectrum of germline mutations in children with high-risk cancer
Authors: Barahona Paulette , Sherstyuk Alexandra , Cowley Mark , Ekert Paul , Kirk Judy , Khuong-Quang Dong-Anh , Kumar Amit , Lau Loretta , Mayoh Chelsea , Marshall Glenn , Moud Emily , O’Brien Tracey , Pinese Mark , Thomas David , Tyrell Vanessa , Ziegler David , Haber Michelle , Tucker Katherine , Fuentes-Bolanos Noemi Auxiliadora , Warby Meera 
Published: August 2020

Abstract
Introduction: Zero Childhood Cancer’s National Precision Medicine for Children with Cancer Study (PRISM) utilizes novel technologies to guide individualized management of children with high-risk cancer (expected overall survival less than 30%). Germline DNA is utilized to distinguish cancer-specific somatic variants from constitutional variants or polymorphisms, allowing identification of clinically relevant germline mutations. The prevalence of cancer predisposition syndromes in pediatric cancer may range from 8.5% to as high as 33%. Method PRISM combines molecular genomic analysis (WGS and RNASeq) with in vitro high-throughput drug screening and patient-derived xenograft drug efficacy testing. A Molecular Tumour Board (MTB) of Oncology and Genetics professionals convenes to determine the significance of genomic analysis as curated by bioinformaticians, molecular scientists, and clinicians.
Results: Between September 2017 and June 2019, 218 children aged under 21 years have been recruited in PRISM (37% with central nervous system tumors, 47% with non-CNS solid tumors, and 16% with hematologic malignancies), and results are available for 208 after discussion at MTB meeting. Forty-two reportable germline variants were detected in 35 participants (detection rate: 16.8%), comprising 28 pathogenic and 14 likely pathogenic variants, across 22 cancer predisposition genes. The most frequently affected gene was CHEK2 (n=7), followed by SMARCB1 (n=5) and BRCA2 (n=3) and NF1 (3). In one out of three participants with germline mutations, somatic analysis revealed a double hit in the same gene altered in the germline. Distributions of participants with germline mutation per group were 16% of patients with CNS tumors (12/77), 19% of patients with non-CNS solid tumors (18/96), and 15% of patients with hematologic malignancies (5/34).
Conclusion: Germline mutation detection rate in cancer predisposition genes was higher than expected, 16.8%; however, it may result from selection bias (i.e., cohort of high-risk cancers). Although genomic sequencing has expanded our understanding of pediatric cancer predisposition and presented opportunities for genetics-mediated care, identifying underlying germline mutations with potential clinical implications remains a clinical challenge for pediatric oncologists.
Citation Format: Paulette Barahona, Alexandra Sherstyuk, Mark Cowley, Paul Ekert, Judy Kirk, Dong-Anh Khuong-Quang, Amit Kumar, Loretta Lau, Chelsea Mayoh, Glenn Marshall, Emily Moud, Tracey O’Brien, Mark Pinese, David Thomas, Vanessa Tyrell, David Ziegler, Michelle Haber, Katherine Tucker, Noemi Auxiliadora Fuentes-Bolanos, Meera Warby. Prevalence and spectrum of germline mutations in children with high-risk cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A03.