The Gleason Score (GS) is a powerful predictor of outcome among prostate cancer patients. Patients with tumours graded with a GS of 2 to 6 have a much greater chance of survival compared to those with a GS of 8 to 10. A significant proportion (~40%) of men present with early stage GS 7 tumours (indicating intermediate risk) for whom prognosis is highly variable. Three gene signatures were derived from publicly available gene expression profiles of prostate cancers from the Swedish Watchful Waiting cohort: 1) The Genomic Grade Index consisted of the top 24 genes discriminating between high (8, 9 & 10) and low (≤ 6) GS tumours, 2) The Lethal Gene Score consisted of the top 24 genes discriminating between lethal and indolent disease within GS 7 tumours only, and 3) The network-based gene signature consisted of 88 genes. When these gene signatures were tested in silico on the gene expression profiles of GS 7 patients in both the SWW and the Mayo cohort, patients were stratified into high and low risk for recurrence. These results demonstrate that gene signatures are capable of differentiating low risk and high risk patients within GS 7 tumours. The prognostic capacity of our gene signature will be tested prospectively in a retrospective collection of archived prostate cancer tissue blocks from a phase 3 clinical trial, and it is hypothesized that the patients can be stratified into good and poor outcome groups. NanoString Technology will be used to quantify mRNA values for the signature genes on selected paraffin blocks. Expression values of candidate genes will be correlated with patients’ long-term follow-up information to derive a clinically meaningful signature. Outcome will be defined as biochemical recurrence or metastatic event. The goal of this study is to identify multiple genes whose expression could be formulated into a clinically applicable assay, the implementation of which could serve to better stratify intermediate risk prostate cancer patients for appropriate treatment. / Thesis / Master of Science (MSc) / The over-treatment of prostate cancer patients is a significant concern, as recent clinical trials has shown that it can lead to significant patient morbidity. Although the Gleason Scoring system is a powerful predictor of lethal or indolent disease, a significant proportion of men who present with early stage Gleason Score 7 tumours experience poorer prognosis than expected. The goal of this study is to develop and optimize a gene signature that can be utilized on Gleason Score 7, intermediate risk prostate cancer patients to differentiate them into good and poor outcome groups. We hypothesize that this signature will be able to accurately predict outcome in a separate retrospective cohort of prostate cancer patients. In short, our study hopes to provide proof-of-principle that through the use of gene signatures, it is possible to better differentiate prostate cancer patients into different outcome groups so that they may receive more appropriate treatment specific to their disease type.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/20576 |
| Date | January 2016 |
| Creators | Li, Brian |
| Contributors | Bane, Anita, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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