Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle‐invasive bladder cancer. Issue 3 (22nd July 2014)

• Record Type: Journal Article
• Authors: Gurung, Pratik M.S.; Veerakumarasivam, Abhi; Williamson, Magali; Counsell, Nicholas; Douglas, James; Tan, Wei S.; Feber, Andrew; Crabb, Simon J.; Short, Susan C.; Freeman, Alex; Powles, Thomas; Hoskin, Peter J.; West, Catharine M.; Kelly, John D.
• Is Part Of: International journal of cancer. Volume 136:Issue 3(2015:Feb. 01)
• Page Start: 709
• Page End: 720
• Publication Date: 2014-07-22
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.29022
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The aim of this study was to test the utility of <italic>AIMP3</italic>, an upstream regulator of DNA damage response following genotoxic stress, as a clinical biomarker in muscle‐invasive bladder cancer (MIBC). <italic>AIMP3</italic> was identified from a meta‐analysis of a global gene‐expression dataset. AIMP3 protein expression was determined by immunohistochemistry on a customised bladder cancer tissue‐microarray (TMA). The mechanism of gene silencing was probed using methylation‐specific PCR. The association between <italic>AIMP3</italic> expression, <italic>Tp53</italic> transactivity and genomic stability was analysed. <italic>In vitro</italic> AIMP3 translocation to the nucleus in response to ionising radiation was demonstrated using immunofluorescence. Radiosensitisation effects of siRNA‐mediated <italic>AIMP3</italic>‐knockdown were measured using colony forming assays. TMAs derived from patients enrolled in BCON, a Phase III multicentre radiotherapy trial in bladder cancer (ISRCTN45938399) were used to evaluate the association between AIMP3 expression and survival. The prognostic value of AIMP3 expression was determined in a TMA derived from patients treated by radical cystectomy. Loss of AIMP3 expression was frequent in MIBC and associated with impaired Tp53 transactivity and genomic instability. <italic>AIMP3</italic>‐knockdown was associated with an increase in radioresistance. Loss of AIMP3 expression was associated with survival in MIBC patients following radiotherapy (HR = 0.53; 95% CI: 0.36 to 0.78, <italic>p =</italic> 0.002) but was not prognostic in the cystectomy set. In conclusion, AIMP3 expression is lost in a subset of bladder cancers and is significantly predictive of survival following radiotherapy in MIBC patients.</p> </abstract>