Clonal dynamics of somatic evolution and gene therapy in cancer predisposition syndromes

Abstract

Preventing cancer before malignancy is established requires identifying which early somaticevents drive cancer progression. This problem is especially important in inherited cancer predisposition syndromes, where germline pathogenic variants put individuals at elevated cancer risks compared to the general population. In this dissertation, I first investigate how an inherited TP53 pathogenic variant alters the somatic evolutionary dynamics across normal tissues in a family with Li-Fraumeni syndrome, a cancer predisposition syndrome associated with high cancer penetrance and early onset. Using ultra-deep duplex sequenc- ing, I show that a germline TP53 variant is associated with parallel evolution of a second- hit TP53 hotspot mutation across organ sites and with elevated mutagenesis in regions of the genome that evolve neutrally in the general population. Then, I investigate whether in situ gene correction reduces cancer risk in Fanconi Anemia, a bone marrow failure and cancer predisposition syndrome, using a computational agent-based model of the oral mu- cosa. I show that cellular competition between gene corrected and uncorrected cells in an epithelial tissue context is a central determinant of therapeutic success and that gene ther- apy has the potential to suppress the accumulation of pro-tumorigenic mutations in a can- cer predisposed context. Together, this work advances understanding of how germline vari- ation shapes pre-malignant somatic evolution across tissue contexts and provides a quanti- tative framework for therapeutic prevention in individuals with inherited cancer risk.