UBC Theses and Dissertations

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UBC Theses and Dissertations

Molecular characterization and genetic diagnosis of cancer predisposition syndromes using genome and transcriptome sequencing Dixon, Katherine


Genetic variation makes important and often uncharacterized contributions to both rare syndromes and more common complex diseases. Around 8% of all cancers are caused by high- and moderate-penetrance deleterious germline variants that are present in an individual from birth and predispose to specific cancer types throughout life. Such cancer predisposition genes associated with moderate to high lifetime cancer risks, conventionally defined as greater than twofold and fivefold increases, respectively, are involved in various biological pathways required for regulating cellular proliferation, maintaining genome integrity, and mediating inter- and intracellular signaling. Clinical use of multigene next-generation sequencing panels has improved molecular diagnosis of cancer predisposition syndromes, demonstrating both genetic heterogeneity and phenotypic variability amongst carriers. However, many individuals with a strong personal or family cancer history receive uninformative results from clinical genetic testing that may lead to increased health anxiety and missed opportunities for increased cancer screening, cancer prevention or use of targeted therapies. Therefore, the main objective of my dissertation was to characterize the biological significance, functional impact, and heterogeneity of genetic variation underlying high-penetrance cancer predisposition syndromes to improve rates of genetic diagnosis. Using genome and transcriptome sequencing, I explored molecular characteristics associated with inactivation of high-penetrance cancer predisposition genes across advanced cancers and in an organoid model system. Tissue-specific molecular signatures provided insights into the aetiology of site-specific tumour development in carriers, allowing opportunities for carrier ascertainment and differential genetic diagnosis of suspected hereditary cancer families. Based on findings that structural variants account for 10% of causal variants, I investigated the utility of long-read sequencing in the clinical interpretation of germline structural variants that were undetected or unresolved through next-generation sequencing. Short- and long-read genome sequencing improved genetic diagnosis in known and suspected carriers for autosomal dominant cancer syndromes, demonstrating incomplete penetrance and phenotypic heterogeneity in population-based and disease-specific cancer cohorts. The research presented here thus supports a broader understanding of the contributions of germline variation to cancer susceptibility and disease progression, ultimately informing guidelines for screening, variant interpretation, and clinical management.

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