Alterations Of BARF And Raf1Genes And Protein Expressions In Chinese Prostate Cancer

[objectives]Fusion genes involving the Raf family gene BRAF and Rafl, which are druggable, were recently identified in prostate cancer in the American population. As we previously found that loss of PTEN and the occurrence of TMPRSS2:ERG fusion are infrequent in Chinese prostate cancer, we investigated the BRAF and Rafl genomic rearrangements and their expression in prostate cancer in China and discussed their important clinical significance.[Methods](1)218cases of prostate cancer from2008to2011,in the affiliated hospital of Zhejiang University were collected continuously. A total of149cases were made into tissue microarrays.(2) Using the FISH signal split apart approach on prostate cancer samples to detect the frequency of BRAF and Rafl rearrangements as well as the copy numbers of these two genes.(3) The BRAF and Rafl protein expression were detected in184cases of formalin-fixed paraffin-embedded prostate cancer by immunohistological staining of the standard two-step En Vision.(4) SPSS16.0software were used for statistical analysis. Chi-square test assessed all datas. Statistical significance was defined as P<0.05.[Results]We found that BRAF was truncated in five (two split signals, two5’deletion and one3’deletion) of the200informative cases (2.5%) and Raf1was truncated in three (two3’deletions and one split signals) of204informative cases (1.47%). Genomic rearrangements of these genes were significantly correlated with Gleason Score (P<0.05) and have a trend to appear in high clinical stage disease. More than two copies of BRAF and Raf1signals were detected in53of183(29.0%) and28of186(15.1%) cancer cases respectively. BRAF copy number was significantly correlated with patient age (P<0.05), baseline PSA level, Gleason scores and clinical stages (P<0.01for the latter three). Raf1genomic copy number only significantly correlated with patient age (P<0.05) and high baseline PSA (P<0.05) but not Gleason score and clinical stage (both p>0.05).High level BRAFexpression was detected in69of180cases (38.33%).High level Raf1expression was detected in62of181cases (34.25%). High-level Raf1expression (3+) significantly correlated to high Gleason score cancers (P<0.05). High-level expression of BRAF was found in cancer cells compared with adjacent non-malignant epithelial cells, which was correlated with high BRAF copy number (P<0.05).3cases ductal adenocarcinomas were found in218prostate cases. Ductal cancers were more likely to present with advanced stage cancer and high Gleason score. High level BRAFexpression was detected in2of3cases, but none of Raf genomic rearrangements were found in all ductal cancers.[Conclusions]Rearrangements and potentially fusion of BRAF and Raf1occured in Chinese prostate cancer at a similar low frequency as found in the Western samples, but copy number gain and overexpression of BRAF are is frequent in Chinese prostate cancer and correlated with more advanced disease. Together with reported data, our finding suggests that the activation of Ras/Raf//MEK/ERK pathway is frequent in prostate cancer from Chinese and potentially other East Asian populations. There is potential to improve the treatment of this subset of prostate cancer patients by targeting Raf and downstream proteins.This study further supports our previous observations of different pathogenesis pathways in Western and Chinese prostate cancers.