TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/26429/
A1  - Körber, Verena
N2  - Somatic mutations accumulate in tissues primarily through cell divisions. This observation opens the opportunity to use somatic mutations as clonal markers for inferring the past dynamics of cell turnover during tissue growth and homeostasis. In this thesis, I develop mathematical approaches to the inference problems that are stimulated by deep genome sequencing data of malignant growth and physiological tissue turnover. 
In the first part of this thesis I reconstruct the evolutionary history of adult glioblastoma, a highly aggressive brain cancer, prior to and after standard therapy. To this end, I develop a likelihood-based multinomial model that jointly infers genetic subclones and their phylogenetic relationships from whole genome sequencing data. Applied to 21 sample pairs from primary and recurrent glioblastomas, the model infers a common path of early tumorigenesis characterized by three pervasive copy number changes on chromosome 7 (gain), chromosome 9p (loss) and chromosome 10 (loss). TERT promoter mutations are subclonal in one third of the tumor pairs and are thus placed at a later stage of tumorigenesis. Our data indicate that recurrent tumors typically re-grow from multiple subclones of the primary tumor with no evidence for a 'resistance genotype' induced by therapy. Combining the results from phylogenetic inference with population dynamics models of tumor growth, I estimate that glioblastomas originate several years prior to initial diagnosis but reach detectable sizes only after TERT promoter mutations stabilized cellular survival. This project provides new insights into the evolutionary history of glioblastoma that may ultimately aid early diagnosis.
In the second part I analyze the mutation frequency distribution in normal tissues. To this end, I extend existing theory on mutation accumulation in exponentially growing tissues to a two-stage situation of initial embryonic expansion and subsequent homeostasis during adulthood. Based on stochastic simulations I show that the theoretical framework recovers the average mutation frequency spectrum in stem cell populations. Whole genome sequencing data from murine granulocytes and human leukocytes from subjects of different ages without diagnosed leukemia confirm the model prediction in the majority of cases but reveal an unexpectedly high mutational burden in a smaller subgroup. These cases were associated with one or several leukemic driver mutations, suggesting that perturbed hematopoiesis or pre-leukemic expansions caused the deviation of the mutation frequency spectrum from neutrality. The comprehensive analysis of the mutation frequency spectra in normal and perturbed hematopoiesis may aid the understanding of tumor initiation in vivo.
ID  - heidok26429
Y1  - 2019///
TI  - Somatic mutations and tissue turnover in glioblastoma and hematopoiesis
AV  - public
ER  -