Abstract B031: Evaluating the consequence of homologous recombination deficiency in models of pediatric solid tumor

Abstract

Abstract Homologous recombination deficiency (HRD) has been extensively studied in adult cancers where its association with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitor sensitivity is well established. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and tumors often exhibit characteristic genomic scars such as elevated HRD.sum score and specific mutational signatures derived from single nucleotide variants, insertions and deletions, and structural variants. Despite its clinical relevance, the therapeutic predictive value of HRD has not been systematically studied in pediatric cancers. Consequently, our team devised a strategy to identify and validate targetable deficiencies in DNA damage response (DDR) genes and assess genomic scars in pediatric tumors. Here, we report evaluation of HRD in a cohort of >200 patient-derived orthotopic xenograft models from the Childhood Solid Tumor Network (CSTN), a freely sharing resource established by our institution to accelerate the development of therapies for children with cancer. We provide an overview of our pipeline and discuss the landscape of genomic scars within our cohort. We profiled somatic and germline variants from over 500 DNA damage response genes and identified TP53 as the most frequently mutated gene with biallelic loss, whereas bi-allelic loss of BRCA1/2 was not found. Overall, our study suggests that HRD exists within solid tumors, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in adult cancers where HRD is common. Importantly, the CSTN contains models of pediatric solid tumors that are amenable to in vitro and in vivo interrogation, and therefore, will facilitate examination of the functional consequences of inactivated DDR genes, characterization of the unique genomic scar profiles underlying these inactivation events, and evaluation of novel therapeutic strategies. Citation Format: Evan Savage, Ke Xu, Jason Myer, Evadnie Rampersaud, Yawei Hui, Ti-Cheng Chang, Gang Wu, Christopher Tinkle, Anang Shelat. Evaluating the consequence of homologous recombination deficiency in models of pediatric solid tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B031.