Vainauskas, Osvaldas; (2025) Spatial and temporal resolution of genomic heterogeneity in lethal prostate cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite advances in treatment, metastatic castration-resistant prostate cancer (mCRPCa) remains invariably lethal, with tumour heterogeneity contributing to therapeutic failure. Here, I investigated the genomic and phenotypic diversity underlying treatment resistance and lethality in mCRPCa using an integrated analysis of samples from patients co-enrolled in the PEACE (Posthumous Evaluation of Advanced Cancer Environment) and TRAILS (Treatment Resistance Aberrations Identified by Longitudinal Sampling) tissue collection programmes at UCL/UCLH. This cohort comprised 15 lethal prostate cancers with 316 specimens, including post-mortem tumours (n = 197), longitudinal plasma samples (n = 106), and archival biopsies (n = 13). Using a bespoke targeted sequencing approach, I characterised haplotype-allelespecific copy number (hasCN) profiles and small variants. Unsupervised clustering of post-mortem tumours revealed a finite number of patient-specific clusters defined by truncal and sample-restricted alterations, frequently shaped by parallel evolution. Cluster “entropy” (variance unexplained by k-means clustering) was significantly associated with overall survival (low entropy: 129.8 months vs high entropy: 45.73 months; P = 0.0079). Patient entropy correlated with phylogenetically inferred clonal diversity using MEDICC2 (low entropy: 0.625 clones vs high entropy: 1.05 clones; P = 0.016). Longitudinal plasma analyses revealed dynamic clonal shifts, with therapy-sensitive populations regressing and being replaced by newly emergent, spatially distinct alterations at death i.e. emerging CCND1 amplification. In some cases, regressing clones (e.g. clones responding to treatment) were detected post-mortem despite being undetectable after treatment in plasma. Matched whole-transcriptome sequencing of 134 post-mortem samples uncovered widespread morphological and phenotypic heterogeneity, with nearly all patients harbouring at least one phenotypically distinct metastasis. Notably, one tumour exhibited triple concomitant differentiation – adenocarcinoma, neuroendocrine carcinoma, and squamous cell carcinoma. In several cases, phenotypic variation aligned with specific genomic k-means clusters, linking mutational landscapes to phenotypic evolution. Whole-genome sequencing of 64 samples (45 post-mortem, 19 plasma) further resolved focal lesion landscapes in these patients. In two cases, treatment resistance was associated with extra-chromosomal DNA (ecDNA), suggesting potential novel mechanism of resistance in these patients. Collectively, this study provides a multi-modal characterisation of lethal mCRPC, revealing patient-specific evolutionary trajectories, dynamic clonal architecture, and novel ecDNA-associated resistance.

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