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Bacon, Jack Victor Warren

University of British Columbia

Genomically-informed approaches to treatment selection, risk stratification, and disease prognostication are poised to transform clinical management of patients with cancer. Tissue biopsy and liquid biopsy each represent viable sources of genetic material for tumour assessment. Diagnostic tumour tissue is typically available for retrospective genomic analyses but limited in its ability to capture tumour heterogeneity. Plasma cell-free DNA from liquid biopsy enables convenient, minimally invasive genomic profiling but utility is affected by unpredictable levels of circulating tumour DNA (ctDNA) and presence of non-malignant clonal expansions. In this thesis, custom sequencing and bioinformatic approaches were used to profile blood and tumour tissue from patients with urologic malignancies. In high-risk non-muscle-invasive bladder cancer (NMIBC), patients are treated with bacillus Calmette-Guerin (BCG). Sequencing of tumour samples pre- and post-BCG revealed concordance among canonically early-arising events in chromatin-modifying genes and the TERT promoter. Receptor tyrosine kinase alterations were enriched pre-BCG, while TP53 alterations were enriched post-BCG; suggesting that archival tissue specimens may be ill-suited for assessing biomarker status in relapsed-disease. Pre-BCG ARID1A mutations and CCNE1 amplifications were associated with poor relapse-free survival. In metastatic renal cell carcinoma (mRCC), there are few molecular biomarkers for disease prognostication. Presence of ctDNA is associated with worse prognosis in several malignancies, but previously underexplored in mRCC. We detected ctDNA in a minority of patients with mRCC (33%) at lower levels than other urologic malignancies profiled using the same methodology. However, mRCC-derived ctDNA was prognostic for poor overall survival and progression-free survival. Non-cancer somatic alterations were frequently detected via liquid biopsy and attributed to clonal hematopoiesis (CH). CH features and clinical relevance in mRCC were explored further using a high-depth custom-targeted sequencing approach applied to a larger mRCC cohort. CH variants were detected in 68% of patients at VAF > 0.25% and 32% at VAF > 2%. Most alterations were detected in hematologic malignancy-associated genes, though several are also recurrent in solid tumours (i.e. TP53). Presence of CH >2% was associated with modestly reduced overall survival. This work affirms the relevance of genomic alterations in urologic malignancies and establishes frameworks for nuanced interpretation of genomic data from blood and tissue.

Text

2023-12-12

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86945

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/