Abstract IA026: Charting genotype to phenotype maps of tumorigenesis

Abstract

Abstract Cancers often arise from a mutated cell that undergoes premalignant clonal expansion, all the while accruing additional mutations. These somatic mutations accumulate and spread in phenotypically normal tissues prior to apparent morphological changes, with aneuploidy and driver gene mutations often preceding cancer diagnosis by years. Identifying the causes of malignant transformation requires characterization of abnormal molecular phenotypes that precede this event in a tissue-specific manner. However, repeated sampling of healthy tissue or pre-neoplasia is not practical. Critically, neither the order of somatic alterations nor the clonal dynamics that precede malignant transformation can be reliably inferred from genomic sequencing of established tumors. New approaches are therefore needed to characterize pre-neoplastic clonal evolution. Here we model this occult process via CRISPR/dCas9 engineering of human epithelial organoids, followed by multi-year experimental evolution. Through longitudinal genome sequencing, transcriptional profiling and lineage tracing, we define causal relationships between common initiating genetic lesions and resulting phenotypes. The resultant data illuminate evolutionary constraints and barriers to malignant transformation with implications for early detection and risk stratification. Citation Format: Christina Curtis. Charting genotype to phenotype maps of tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA026.