Epigenetic regulation of prostate cancer metastasis to the bone

Wilkinson EJ1,2, Malley R1, Dickinson JL2 and Holloway AF1

  1. School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia, 7000.
  2. Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia, 7000.

Prostate cancer is the most commonly diagnosed cancer in Australian males with a reported five-year survival rate of 95%. Prostate cancers, however, primarily metastasise to the bone with a decreased five-year survival rate of 3%. Current diagnostic tools are unable to distinguish indolent disease from that with a propensity to become metastatic. We have taken complimentary single-gene and genome-wide approaches to identifying key genes that contribute to prostate cancer metastasis. Integrins, a group of adhesion receptors, are known to facilitate metastasis to the bone, however the pathway(s) through which this occurs are incompletely understood. Integrins, which act as receptors for the bone constituents laminin and collagen, are aberrantly expressed in prostate cancer. We have shown that methylation changes and associated expression changes are observed in several key integrins, including ITGB4, in cell lines representative of different stages of prostate tumour disease progression. Formalin-fixed paraffin tissue derived from matched localised and metastatic prostate tumours were examined to determine whether these changes are also observed in patient samples. We also performed genome-wide methylation analysis using the Infinium® MethylationEPIC array in matched normal and primary tumour samples, and matched tumour and metastasis samples to identify changes associated with disease progression. Preliminary analysis has revealed 10 significantly differentially methylated regions between matched normal and primary tumour samples, and over 2,300 significantly differentially methylated regions between matched tumour and metastasis samples. These data indicate that changes in methylation occur throughout disease progression, and suggest that wide-spread epigenetic changes accompany tumour metastasis.