Abstract 950: Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort

Abstract The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon. Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care. The Gundersen Precision Oncology Cohort is a growing dataset of FFPE specimens and longitudinal clinical data from more than 750 patients who have had comprehensive cancer genome profiling using assays from a wide range of diagnostic companies. We use this resource for biomarker discovery and functional classification of many atypical cancer variants. Current subgroups include atypical point mutations in BRAF, ERBB2 and ERBB3, as well as fusions affecting BRAF, PIK3CA and ROS1. We present examples illustrating the value of this approach for classification of variants detected in a range of tumor types. Citation Format: Peter Feiszt, Paraic A. Kenny. Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 950.