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There is increasing evidence that multiple chromosomal rearrangements occur in prostate cancer. PTEN loss is considered to be a key event in prostate carcinogenesis but the mechanisms of loss remain to be fully elucidated. We hypothesised that gross rearrangements may exist that cause disruption of the PTEN gene in the absence of genomic deletion. We therefore designed a novel fluorescence in situ hybridisation (FISH) assay with probes overlying regions 3 0 and 5 0 of PTEN and a third probe overlying the gene. We aimed to identify both genomic deletions and gross rearrangements of PTEN that would be overlooked by previously reported singleprobe FISH assays. We proceeded to evaluate a tissue microarray with radical prostatectomy and trans-urethral resection of the prostate specimens from 187 patients. We identified PTEN genomic loss in 45/150 (30%) radical prostatectomy patients and 16/37 (43%) trans-urethral resection of the prostate patients. Importantly, our assay detected novel chromosomal alterations in the PTEN gene (characterised by splitting of FISH signals) in 13 tumours (6.9% of all prostate cancers; 21% of PTEN-lost cancers). All PTEN-rearranged tumours had genomic loss at the other allele and had no expression of PTEN by immunohistochemistry. PTEN-rearranged tumours were significantly more likely to have an underlying ERG rearrangement. Our assay differentiated loss of the probe overlying PTEN in isolation or in combination with either one of or both the probes overlying the 3 0 and 5 0 regions. This gave an indication of the size of genomic loss and we observed considerable inter-tumoural heterogeneity in the extent of genomic loss in PTEN-lost tumours. In summary, gross rearrangements of the PTEN locus occur in prostate cancer and can be detected by a 'break-apart' FISH assay. This observation could explain the absence of PTEN protein expression in a subgroup of tumours previously classified as having heterozygous genomic loss using single-probe traditional FISH assays. Modern Pathology (2012) 25, 902-910;

We recently found that TMPRSS2:ERG fusion genes and PTEN loss, which are common in Western prostate cancers are infrequent in Chinese cases. As previous studies indicated a higher frequency of RAS and BRAF mutation rates in Eastern Asian than in Western prostate cancers and fusion genes involving the RAF family genes BRAF and RAF1 were recently identified in prostate cancer in the American population, we investigated BRAF and RAF1 alterations in Chinese prostate cancer. Using fluorescence in situ hybridization, we found that BRAF was truncated in five of 200 informative Chinese cases (2.5%) and that RAF1 was truncated in three of 204 informative cases (1.5%) and genomic rearrangements of these genes were significantly correlated with high Gleason scores (>7; P < 0.01) and have a trend to appear in high clinical stage disease. A high frequency of BRAF and RAF1 copy number gain was found (29 and 15%, respectively). BRAF copy number gain in Chinese cancers was significantly higher than in UK cases (9.2%)(P < 0.001) and correlated with a number of clinical parameters. High-level expression of BRAF was found by immunohistochemistry in Chinese cancer samples compared with adjacent nonmalignant epithelial cells, which was correlated with high BRAF copy number. We also identified KRAS codon 12 mutations in three of 96 Chinese cases, no BRAF V600E mutations were observed. Our finding suggests that the activation of the RAS/RAF/MEK/ERK pathway may be frequent in Chinese prostate cancer, with RAF gene copy number gain potentially being the main contributor.

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