Understanding prostate cancer from a Tasmanian perspective
Creators: name: Foley, Georgea
Publisher: name: University of Tasmania
Year: 2024

description: Prostate cancer (PrCa) is the most frequently diagnosed form of non-cutaneous cancer and the second-leading cause of male cancer deaths in Australia. It is highly heritable, with a family history of PrCa being one of the strongest risk factors for disease development and twin studies indicating that up to 58% of risk is due to inherited factors. Currently, an explanation has been elucidated for little more than a third of this risk, despite the identification of over 250 common genetic variants associated with PrCa. It is suggested that up to 42% of the remaining heritability may be attributed to rare genetic variants. <br>The founder population of Tasmania, an island state of Australia, is ideally suited to genetic research. This is especially relevant with regard to rare variants, which are likely to be enriched in the presence of reduced genetic complexity. The studies presented in this thesis take advantage of multiple valuable resources from the Tasmanian population: The Prostate Cancer Outcomes Registry – Tasmania (PCOR-TAS), a population-based registry with extensive clinical data; the Tasmanian Familial Prostate Cancer Study, a collection of genetic material from 76 large families with densely aggregated PrCa; and the Tasmanian Sporadic Prostate Cancer Study, a population-based, case-control genetic resource. A second, independent, hereditary PrCa resource, the <i>PROGRESS</i> cohort from the Fred Hutchinson Cancer Center, was also utilised. <br>This study firstly aimed to develop a broader understanding of the factors that influence the landscape of PrCa in Tasmania, contextualising and improving our knowledge of patterns of incidence and outcomes across the state. This aim specifically focussed on investigating disparities in diagnosis and treatment using the PCOR-TAS. Comparison of rural PrCa patients with their urban counterparts revealed that men from regional and remote areas of the state were significantly more likely to be diagnosed with PrCa at a later age and with more clinically advanced disease. These individuals were also more likely to reside in areas of greater socio-economic disadvantage, took longer to commence active PrCa treatment post?diagnosis, and travelled further in order to receive medical care. There were no differences in diagnostic or treatment methodology observed between the two populations. This study establishes the need for continued investigation into regional disparities to improve and optimise patient outcomes and clinical practice in outer regional and remote populations in Australia and across the globe. <br>A second study, utilising an updated PCOR-TAS dataset, aimed to compare clinical characteristics and treatment pathways of Tasmanian men treated in the public and private healthcare systems. This study revealed that a greater proportion of publicly treated patients underwent an active form of treatment, whereas privately treated patients were most likely to manage their disease with active surveillance (46.5%). Despite an overall higher rate of active surveillance amongst private patients, a higher proportion of privately treated men with low-risk disease underwent active treatment compared with public patients (33% vs. 19%). Of these, the majority were treated surgically, with radical prostatectomy. This remained the most common treatment for the privately treated intermediate- and high-risk groups, whereas publicly treated patients were most likely to receive radiotherapy for low- and intermediate?risk disease, and radiotherapy concurrent with androgen deprivation therapy for high-risk disease. These results reveal significantly disparate treatment pathways for PrCa patients being treated in the Tasmanian public and private healthcare sectors and emphasise the importance of such studies to accurately inform healthcare policy and improve equity and access to treatment across the state. <br>In order to investigate the genetic basis of PrCa in Tasmania, this study also aimed to identify rare genetic variants associated with disease risk in the population. This aim was first pursued through an agnostic approach, wherein WGS data from a Tasmanian pedigree underwent a filtering and prioritisation process to identify candidate risk variants. A rare, germline, missense mutation in <i>RAD51C</i> (rs61758784) was identified as segregating with disease and predicted to be highly deleterious. Analysis of Tasmanian familial and case-control PrCa datasets found this variant was significantly associated with PrCa risk (OR = 2.46; p = 4.13 × 10-3 ). The variant was also observed to partially segregate in four families from the North American <i>PROGRESS</i> dataset, and further analysis revealed a 1.3Mb risk haplotype shared between cases in the Tasmanian discovery family and two affected brothers in one North American family. The <i>RAD51C</i> gene plays a key role in DNA damage repair (DDR), and variation in the gene poses a potential therapeutic target, highlighting the importance of identifying and understanding the role of rare disease-associated variants. <br>Other rare, inherited variants in DDR genes have been recognised as playing a role in PrCa susceptibility, and these genes are also proving to be therapeutically targetable. With the aim of addressing the current lack of identified DDR risk variants, two independent, familial PrCa datasets were interrogated utilising a candidate gene approach. Next-generation sequencing data from Australian and North American familial PrCa datasets were interrogated, and segregating, high-risk, likely pathogenic DDR genetic variants were identified and subsequently genotyped in the full Tasmanian familial and case-control cohorts. Rare variants significantly associated with PrCa risk were identified in <i>ERCC3</i> (rs145201970, p = 2.57 × 10-4 ) and <i>BRIP1</i> (rs4988345, p = 0.025) in the combined Australian and North American datasets. A <i>PARP2</i> variant (rs200603922, p = 0.028) in the Australian dataset and a <i>MUTYH</i> variant (rs36053993, p = 0.031) in the North American dataset were also associated with PrCa risk. Evaluation of clinicopathological characteristics of risk variant carriers provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, demonstrating a need to expand genetic screening eligibility to capture and identify a greater proportion of DDR variant carriers who may be eligible for targeted, gene-based treatments. <br>The final approach utilised here involved the examination of a rare genetic mutation in the <i>BRCA2</i> gene. This truncating variant (rs80358561) was self-reported to the Tasmanian Familial Prostate Cancer Study by a family member with breast cancer, and interrogation of the pedigree revealed a significant association with PrCa risk in the Tasmanian cohorts (p = 1.39 × 10-11). The variant was not present in any additional individuals outside of the proband’s family and was observed to partially segregate with both PrCa and breast cancer within this branch of the kindred, emphasising the power of families with a dense aggregation of disease for rare variant discovery. <br>These studies have identified disparities in PrCa diagnosis and treatment in Tasmania for the first time and identified novel associations between rare genetic variants and disease risk in this population. Expanding our understanding of the inherited component of PrCa and associated genes will ultimately allow for advances in screening, diagnostic, prognostic, and therapeutic strategies, improving outcomes and quality of life for PrCa patients in Tasmania and across the globe. The comprehensive characterisation of DDR genetic risk variants in PrCa will have clear implications for germline screening and clinical management of this disease, and continued investigation into such factors is essential for the continued advancement and progression of PrCa care.