Huebner, Ariana Melanie Ivana; (2023) Characterizing cancer genome evolution in metastasis. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text 20230111_Thesis_ArianaHuebner.pdf - Other Download (14MB) | Preview

Abstract

Metastatic disease is responsible for the majority of cancer related deaths. Exploring metastatic patterns in an evolutionary framework is crucial to predicting and treating metastases. However, previous studies have mainly relied on archival tissue obtained from early-stage disease and less commonly included samples from recurrent or metastatic disease. In this thesis, genomics data is used to elucidate the tumor’s evolutionary trajectory and to better understand the processes involved in metastatic development. To better understand the phylogenetic relationships between primary and metastatic samples, especially in extensively sampled multi-region cohorts, a novel method to perform mutation clustering and phylogenetic reconstruction was developed. Using paired primary metastatic data, the genomic features characterizing clones seeding metastases are explored. Definitions for patterns of metastatic dissemination from the primary tumor are presented and explored within the cohort. Additionally, selection patterns are explored in the seeding clone within the primary tumor compared with selection in other primary specific clones as well as with non-metastasizing tumors. The relative timing of metastatic divergence is defined and explored in paired primary metastatic data. The importance of extensive sampling of the primary tumor to correctly classify timing of divergence is highlighted. Additionally, a cohort of extensively sampled metastases is presented and leveraged to further characterize the metastatic process. Furthermore, by applying a method to infer migration histories, instances of metastasis-to-metastasis seeding are highlighted. To understand the process of metastatic evolution in late-stage disease, a cohort of 24 patients with pancreatic ductal adenocarcinoma was processed and analyzed. Using whole exome sequencing of cfDNA samples, the evolution of tumor progression and dynamics of mutations and copy number alterations over time are investigated. Understanding the processes involved in metastatic dissemination can guide therapeutic management of metastatic tumors as well as lead to the identification of new potential targets for therapy.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item