Oral Presentation 29th Lorne Cancer Conference 2017

Identifying the origins and drivers of castration resistant prostate cancer. (#31)

Natalie J Kurganovs 1 2 3 4 , Marek Cmero 1 3 4 5 , Nicholas Howard 2 , Pat Bugeja 2 3 , Michael Kerger 2 , David Clarke 3 , Phil Dundee 2 3 , Jeremy Grummet 6 7 , Justin Peters 1 3 , John Pederson 7 8 , Andrew Ryan 8 , Anthony Costello 2 , Paul Ruliancich 9 , Phillip Parante 7 9 , Christopher M Hovens 1 2 3 4 , Niall M Corcoran 2 3 4
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia
  3. Department of Surgery, Division of Urology, The Royal Melbourne Hospital, Parkville, VIC, Australia
  4. Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
  5. Walter and Eliza Hall Institute , Parkville, Vic, Australia
  6. Alfred Hospital, Prahran, VIC, Australia
  7. Monash University, Clayton, VIC, Australia
  8. TissuPath Specialist Pathology Services, Mt Waverly, VIC, Australia
  9. Eastern Health and Epworth Eastern, Box Hill, VIC, Australia

Objective: To identify the genomic drivers of castration resistant prostate cancer.

Methods:A neo adjuvant trial consisting of a "super-castration" treatment with bicalutamide, abiraterone and degarelix treatment for a period of 6 months prior to radical prostactomy was conducted. DNA from 7 pre (formalin fixed paraffin bedded (FFPE)), 20 post (11 FFPE, 9 fresh frozen) and 14 germline (whole blood) samples were used for whole genome sequencing (WGS). Tissue was sequenced at 30X and blood at 15X depth on the Illumina HiTenX. RNA from 6 fresh frozen post treatment samples, and 8 matched hormone naïve samples were used to construct a RNA-Seq library and sequenced at a length of 150bp using paired end chemistry on an Illumina HiSeq.

Results: Although we have found through WGS that there is an increase in single nucleotide variants (SNVs), and copy number variations (CNVs) in post treatment samples as compared to germline and pre treatment samples in some patients, this increase is not observed in other patients with a similar response to treatment. In addition to this, the clonality of the patient's tumours remained the same between pre and post treated samples, indicating that there is not a selection for a resistant subclone. Preliminary RNA-Seq data has shown a decrease in expression of androgen dependent genes, has detected both novel and already identified gene fusions, and identified key signatures which may be driving the treatment resistance such as an epithelial to mesenchymal transition and stem cell signatures.

Conclusions: Our results indicate that the development of castration resistant prostate cancer may be due to epigenetic changes which occur as a result of treatment.