Date of Award
8-16-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cancer is a genetic disease stemming from a combination of inherited and acquired mutations. In my thesis, we sought to characterize how germline genetic variation affects acquired clonal expansions in normal tissues and its progression to malignancy. In Chapter 2, we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 novel CH predisposition genes, most of which predispose to CH driven by specific mutational events. CH predisposition genes contribute to unique somatic landscapes reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic-germline interactions influence the risk of CH progression to hematologic malignancies. In Chapter 3, we generated a murine model of germline TP53 mutations and longitudinally characterized how cancer treatment affects the progression of CH to hematologic cancer. We observed evidence of synergistic effect between cytotoxic exposure and germline background on promoting hematologic disorder, but further experiments with longer follow-up and better model are warranted. In Chapter 4, we comprehensively characterized the associations between pathogenic germline variants and the full spectrum of solid tumor types in 640,888 individuals. We identified 20 new associations and provided more accurate population-based risk estimates for 52 known germline-solid tumor associations. Findings will provide unique biological insights into the genetic determinants of tumorigenesis and inform the development of novel prevention and early intervention strategies.
Language
English (en)
Chair and Committee
Kelly Bolton
Committee Members
Christopher Maher; Daniel Link; Matthew Walter; Nathan Stitziel
Recommended Citation
Liu, Jie, "Germline Genetic Determinates of Cancer and Pre-Malignant Conditions" (2024). Arts & Sciences Electronic Theses and Dissertations. 3308.
https://openscholarship.wustl.edu/art_sci_etds/3308