Ravinarayana Chakravarthy, A; (2017) The Molecular Landscape of HPV-driven Tumourigenesis. Doctoral thesis , UCL (University College London).

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Abstract

Human Papillomaviruses (HPV) contribute significantly to the global cancer burden, causing nearly all cervical cancers and varying proportions of head and neck, and other anogenital cancers. Previous studies, limited to small sample sizes or single tissue sites in studies, have suggested that HPV+ tumours can exhibit distinct molecular profiles. Initially, a comprehensive transcriptional signature was established for HPV-driven tumourigenesis and culminated in the confirmation of a driver role for HPV outside the Oropharynx in Head and Neck cancer and the discovery of prognostically relevant differences in the immune microenvironment with implications for patient management. Analysis of exomes for mutagenesis by APOBEC3B, found upregulated in HPV+ tumours, identified it as a key driver of genomic evolution in these tumours, and broadly as a determinant of hotspot specificity in PIK3CA mutations across cancers. Establishment of HPV-associated DNA methylation signatures, useful for classification, also highlighted novel HPV-related transcriptional changes and putative heterogeneity in cell-of-origin associated with HPV types and tissue sites. Analyses of transcriptional and epigenetic heterogeneity in Cervical Cancer, where multiple HPV types are causal, identified HPV45-associated molecular signatures indicative of increased invasiveness and inflammation with putative applications in patient stratification. Finally, Support Vector Regression approaches developed to perform deep deconvolution of the cellular composition of tumours facilitated integrative analysis of immune cell infiltration patterns, the prognostic patterns discovered in the thesis and molecular variation, offering insights into the role of the immune microenvironment in shaping the evolution of these tumours.

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