Kasmintan Schrader

The popularity of genetic testing and counselling for hereditary cancer syndromes has increased rapidly in the past decade due to a decrease in genetic sequencing costs, increase in public interest, and increase in medically actionable results. As the demand for genetic testing services has increased, the wait times for patients to receive genetic testing and counselling has also increased. In order to increase patient access to genetic testing and counselling, genetics services must examine new genetic counselling models and ensure that historically under-served patient populations are receiving equitable health outcomes. In this thesis I have examined the impact of a new model of genetic counselling termed oncology clinic-based genetic counselling, examined patient demographics at the Hereditary Cancer Program (HCP) in British Columbia Canada, and assessed patient reported outcome measures (PROMs) from patients receiving genetic testing and counselling. I found that oncology clinic-based genetic testing and counselling significantly reduced patient wait times from referral to return of genetic testing results compared to traditional genetic counselling (403 vs 198 days; p
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Genomic sequencing technology provides insight into cancer pathogenesis and tumoural mechanisms. Tumour RNA sequencing can be used to assess the functionality of genes by allowing for gene expression quantification and transcriptome analysis. Mutational signatures are somatic patterns of mutations arising from specific mutagenic processes such as exogenous and endogenous exposures, defective DNA repair mechanisms or DNA enzymatic editing. Such signatures are “genomic scars” informing on the underlying biological processes that led to cancer. Whole genome sequencing (WGS) of tumour DNA and matched blood DNA as well as whole transcriptome sequencing (WTS) of tumour RNA was performed in advanced cancers of diverse types as part of the Personalized OncoGenomics project. Germline single nucleotide variants (SNVs), copy number variants (CNVs) and structural variants (SVs) in 98 hereditary cancer genes were analyzed from germline WGS data. Somatic SNVs, CNVs and SVs were analyzed from tumour WGS and WTS data. Somatic SNVs profiles were used for mutational signature modelling. Gene expression was obtained from WTS. Transcriptome targeted assembly was performed for transcript splicing analysis. We present specific examples demonstrating the usefulness of combined genomic and bioinformatic approaches for understanding clinically unusual cases of cancer and their molecular mechanisms. We used somatic mutational signature profiling to determine the functional impact of germline and somatic variants in MUTYH, a base excision repair gene, on the overall mutational landscape. In Chapter 2, we present a case series of patients with germline MUTYH variants and diverse cancers. We identified two MUTYH variants for which the previous classification in public databases are inconsistent and we show that these variants cause aberrant splicing and base excision repair deficiency signatures enriched for C:G>A:T transversion mutations. Our results support the pathogenicity of these variants. In Chapter 3, we present the example of comprehensive genomic profiling of a rare and uncharacterized tumour, the eccrine porocarcinoma, in which CDKN2A was identified as a potential novel driver. In both chapters, we used transcriptome targeted assembly to detect and characterize aberrant splicing due to selected germline and somatic variants of interest.

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