Integrated genomics in prostate cancer: defining the lethal phenotype

© 2014 Dr. Matthew Kok-Hao HongProstate cancer is the second leading cause of cancer death in Australian men. However, it has a wide spectrum of biological aggressiveness from those that lead indolent courses to cases with rapidly lethal propensity. The inability to confidently identify cases with lethal disposition at an early clinical stage has led to widespread overtreatment and an urgent need for more discriminating biomarkers. Recent advances in genomics techniques have presented powerful new tools with which to study cancer. Simultaneous analysis can be undertaken of millions of genetic markers and even entire cancer cell genomes and this has transformed the landscape for molecular discovery. Methods in computational biology have similarly evolved to meet the challenges of deriving meaningful conclusions from the huge quantities of data produced in genomics experiments. This thesis aimed to combine genomics and the question of lethality in prostate cancer. Prostate cancer lethality is intertwined with the development of metastasis, which usually heralds the onset of a trajectory towards prostate cancer-specific death, and it is around this central theme that the majority of the work is based. As the acquisition of clinical tissue samples for prostate cancer research has previously been based on radical prostatectomy programs for primary cancer samples and rapid autopsy studies for metastases, a significant gap exists along the spectrum from localised disease to end-stage treatment-resistant metastatic disease. I therefore developed a program to obtain metastatic prostate cancer tissue from live patients, and demonstrated the feasibility of percutaneous image-guided biopsy of osseous prostate cancer metastasis in a way that yields nucleic acids suitable for genomics applications. The remaining work follows lethality along the clinical spectrum of disease from distant metastatic disease to locoregional lymph node metastases to localised disease, and finally to the biopsy setting. Samples of primary and metastatic prostate cancer from two patients were interrogated through genomic sequencing, with observation of the subclonal origin of metastases and the dynamic shift in subclonal populations within a metastasis in response to therapy. The relationships between lymph node metastases to different primary cancer foci within the prostate gland were then explored in three patients with high-risk prostate cancer. The final two chapters demonstrate an approach towards clinically relevant biomarker discovery by using integrated genomics to characterise molecular differences between high-risk prostate cancer and indolent disease based on both primary cancer tissue and surrounding benign tissue. Biomarkers discovered based on patient cohorts selected on clinical outcome may be exploited for therapy or clinically relevant prognostic tools. For genomics research in prostate cancer, one requires precision in clinical informatics and patient selection, careful tissue preparation and integrated use of genomic platforms. In this thesis I show how this might be achieved in different patient groups representing different aspects of the disease spectrum, and how this can be used to unravel the molecular underpinnings of lethality in prostate cancer