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Abstract
Inflammation is emerging as a potential contributor to prostate cancer pathogenesis. Under the priori that there is an inherited susceptibility to prostate cancer, this study aims to identify germline variants within key inflammatory genes that may contribute to prostate cancer risk. Using a candidate gene / pathway driven approach, variants within and surrounding T helper (Th) influencing cytokine genes were selected to assess for association with prostate cancer risk using two large, Australian based epidemiological resources, namely the Risk Factors for Prostate Cancer Study (RFPCS; approximately 800 cases and 800 controls) and the Melbourne Collaborative Cohort Study (MCCS; approximately 800 cases and 1,800 controls). In addition, a range of genotyping methodologies applicable to a candidate gene / pathway driven study design were assessed.
Among the genotyping methodologies investigated this thesis presents a comprehensive assessment of one of the newer low-throughput genotyping / variant detection techniques, high resolution melt curve analysis and demonstrates some areas to be aware when using this technology. Furthermore, it describes the application of a novel, medium-throughput genotyping chemistry, Plexor, comparable to two of the most commonly used methods at the time, TaqMan and homogenous MassEXTEND (hME). Finally, it includes a report describing applications to improve and more efficiently interpret data generated using Illumina GoldenGate chemistry.
To investigate the genetic contribution to inflammatory mediated prostate cancer, this thesis targets two Th cytokine rich regions, at chromosomal positions 4q27 (including interleukin(IL)-2 and IL-21) and 5q31.1 (including IL-5, IL-13 and IL-4), as well as functionally relevant variants in the promoter of IL-6. Within the 4q27 region, rs13119723, most proximal to IL-21 is observed to be associated with familial prostate cancer risk on the RFPCS, lending this region as a target for investigating inherited susceptibility. Within the 5q31.1 locus, two IL-4 variants, rs2243250 and rss2227284 are shown to be associated with prostate cancer risk in the RFPCS only. rs2243250 (located in the promoter) demonstrates a trend towards suppressing IL-4 activity. Analysis of two functionally implicated IL-6 promoter variants, rs1800795 and rs10499563 (located -174 and -6331 bp from the transcription start site respectively) reveals evidence to suggest rs10499563 may be associated with prostate cancer risk in the RFPCS and further implicated in aggressive prostate cancer using the MCCS. This study also supports a functional role for rs10499563. Finally, this thesis illustrates the need for more comprehensive analysis of the inflammatory gene network by reporting 22 novel, ethnically unique variants within a recently described cytokine, IL-23A. This cytokine demonstrates a high level of genetic conservation, which may be attributed to a significant role within the immune pathways.
In conclusion, this study not only identifies a number of novel cytokine variants, but also significantly contributes to elucidating the genetic contribution to inflammatory mediated prostate cancer, by describing novel associations between a number of key cytokine variants with different clinicopathological characteristics of the disease.