Mensah, Nana Ekuntan; (2024) Molecular evolution in primary lesions and metastases from small intestinal neuroendocrine tumours and prostate cancers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancers arise through the expansion of clones with somatic mutations that increase their fitness under selective pressures. DNA sequencing has uncovered genomic drivers of cancer evolution, however, understanding the complexity of genetic and epigenetic routes to oncogenesis remains a priority in cancer research. To investigate the molecular correlates of cancer evolution, I analysed human cancer genomes and methylomes from three clinical cohorts. First, I assessed 35 small intestinal neuroendocrine tumours (SINETs) profiled by reduced representation bisulfite sequencing. This analysis combined a reference methylome for enterochromaffin cells, the SINET cell of origin, with in silico deconvolution using CAMDAC. I report novel candidate epigenetic driver events, including at promoters of CREB1, PTK6, HOXA9 and PRDM1. In the transition to metastasis, I identified the coevolution of genomic variation and hypomethylation, and reversion of promoter methylation at POU2AF1 and SLC26A1 within a single patient. Secondly, I investigated the genomic features of 827 primary prostate cancers from the Pan Prostate Cancer Group. I identified correlates of three evolutionary routes defined by aneuploid signals: early ETS fusions, early MYC amplifications with TP53 -associated WGD, and SPOP-driven tumours depleted for breakpoints at AR binding sites. Somatic mutation timing revealed preferentially early and late driver mutations and mutational signatures in prostate cancer evolution. Lastly, I adapted the CAMDAC algorithm to deconvolve whole genome bisulfite sequencing (WGBS) data and applied it to methylomes from 79 advanced metastatic castration-resistant prostate cancers (mCRPC). Bulk mCRPC methylomes were confounded by tumour purity and aneuploidy but succesfully purified by CAMDAC. I identified significant hypermethylation at promoters of genes involved in angiogenesis and NOTCH signalling and detected ubiquitous YY1AP1 hypomethylation, which may indicate an epigenetic component of AR sensitivity in mCRPC. These studies offer insights into the (epi)genomic evolution of SINETs, prostate cancers, and mCRPC, and lay a foundation for future research on driver epimutations and epigenomic variation in clonal evolution.

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