The different genetic alterations between Western and Chinese prostate cancers indicate the aetiology
Session type: Poster / e-Poster / Silent Theatre session
Prostate cancer is the most common male cancer in Western countries, but much less frequent in Asian countries. We systematically investigated genomic changes in prostate cancers from UK and China to determine genetic similarity and difference and the underlying mechanisms of prostate carcinogenesis.
We analysed genome-wide genomic alterations using Affymetrix SNP array 6.0, and evaluated data using fluorescence in situ hybridisation and immunohistochemistry on tissue microarrays (TMAs). Microsatellite analysis were used for AR polymorphism and an in vitro system was used to induce TMPRSS2:ERG fusion by androgen and investigate the associated mechanisms.
Genome-wide analysis of 32 UK and 39 Chinese samples revealed that losses of 21q22 (leading to TMPRSS2:ERG fusion) and 10q23.3 (PTEN), which are common genomic alterations in Western prostate cancer, were rarely detected in the Chinese samples. From TMAs of 160 UK and 143 Chinese samples, PTEN deletion and ERG rearrangements were found at a significantly higher frequency in samples from UK than China (P<0.001 for both). Both PTEN and ERG protein were also differentially expressed (p<0.001), including different cellular locations of ERG. Interestingly, we found that the differences of PTEN deletion/inactivation and ERG rearrangements/overexpression occur at the high-grade prostatic intraepithelial neoplasia (HGPIN) stage. Consequently, we found that AR CAG repeat lengths are significantly shorter in the UK than Chinese patients (P<0.05). Most importantly, we induced TMPRSS2:ERG fusion in prostate epithelial cells following exposure to androgen. We associated the induced fusion with androgen-stimulated TMPRSS2 and ERG gene proximity and low expression of PIWIL1, which acts as a double-strand break protector.
In conclusion, we revealed genomic differences in prostate cancer in Western (high-risk) and Chinese (low-risk) populations, commencing at pre-invasive, HGPIN stage. Based on the different frequency of TMPRSS2:ERG fusion, we associated TMPRSS2:ERG fusion with AR activity and demonstrated that this fusion is inducible by androgen.