| dc.description.abstract | Prostate cancer is the most common male cancer in Western countries. The genetic
mechanism underlying its initiation and progression is still unclear. The aim of this
project was to identify novel genomic changes in prostate cancer and the underlying
genetic mechanisms of prostate carcinogenesis using a high-resolution genome-wide
analysis approach.
Firstly, three prostate cancer cell lines, thirty-two UK and thirty-nine Chinese prostate
cancer clinical samples were analysed using Affymetrix’s SNP microarrays (500K and
array 6.0). Most of the common genomic changes observed in these samples are the
same as those found in previous studies. Among the common genomic alterations, ERG
rearrangements were also detected in 6/10 circulating tumour cell samples by
flouroscence in situ hybridisation (FISH). Interestingly, loss of 21q22 and PTEN deletion,
which were commonly found in Western prostate cancer, were rarely detected in the
Chinese samples. This was further evaluated and comfirmed by FISH and
immunohistochemistry analyses on UK and Chinese prostate cancer tissue microarrays
and reverse transcript polymerase chain reaction (RT-PCR) analysis of TMPRSS2:ERG
fusion transcripts in 48 UK and 66 Chinese fresh frozen cases (p<0.001). Subsequently, I
identified a difference in the AR CAG repeat length polymorphism between UK and
Chinese samples. This genetic disparity indicates differential distribution of
causative/protective factors in these two populations.
To study chromosome rearrangements and fusion genes, I developed a high-resolution
karyotype approach to fully karyotype three cell lines, and identified five potential
genomic fusions. Genomic fusion sequence of MAMDC1:SCL25A21 was identified, but
the expected fusion transcript could not be detected by RT-PCR. As metaphase spreads
are difficult to make in prostate cancer clinical samples, I used a common breakpoint
identification approach and identified many frequently truncated genes.
During this study, I observed extensive intratumour heterogeneity, which reflects
genomic instability in prostate cancer. Therefore, I investigated the involvement of
genomic instability in human cancers through genomic analysis of four 2N cancer cell
lines. | |
