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Neoadjuvant hormonal therapies induce the expression of AR transcript variants
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
153
Neoadjuvant hormonal therapies induce the expression of AR transcript variants Eur Urol Suppl 2017; 16(3);e255
Tammela T.1, Kallio H.2, Annala M.2, Brofeldt A.2, Hieta R.2, Kivinummi K.2, Nykter M.2, Lilja H.2, Bova G.2, Visakorpi T.2 1
Tampere University Hospital, Dept. of Surgery, Tampere, Finland, 2University of Tampere, Biomeditech, Tampere, Finland INTRODUCTION & OBJECTIVES: Prostate cancer (PC) is the most common malignancy and third most common cause of cancer-related death among men in Europe. Although most PCs grow slowly, 20–25% of the patients believed to have organ-confined disease will experience biochemical recurrence already during 5-years of follow-up. The standard treatment against advanced PC is androgen deprivation (ADT). Unfortunately, androgen deprivation treatment eventually fails leading to the emergence of castration resistant PC (CRPC) that is lethal. However, also CRPCs are dependent on androgens. Owing to this understanding, several drugs have recently developed for the treatment of CRPC including enzalutamide and abiraterone, but approximately 20–40% of patients have no response to these agents. One explanation for this could be the expression of constitutively active androgen receptor splice variants (AR-Vs). The aim of our project is to interrogate all possible AR aberrations in PC and CRPC. MATERIAL & METHODS: Three patient cohorts were utilized in the study. Cohort 1 included samples from benign prostatic hyperplasia patients (n=12), prostate cancer patients (n=28) and CRPC patients whose cancer was locally recurred (n=13). Cohort 2 (n=25) included samples from patients treated with prostatectomy or neoadjuvant hormone therapy (goserelin or bicalutamide) prior to prostatectomy. Cohort 3 included CRPC metastases (mCRCP) collected at autopsy (n=31). Targeted sequencing of DNA and RNA was performed using SureSelectXT Target Enrichment systems (Agilent) and Illumina MiSeq (cohort 2 and 3 samples) for the analysis of AR locus. Whole genome sequencing and whole transcriptome sequencing was performed using Illumina HiSeq (cohort 1 samples).The expression levels of 5 AR-regulated genes (KLK3, FKBP5, TMPRSS2, ACPP and SLC45A3) was also measured along targeted RNA-seq assay. RESULTS: AR gene amplification was found in 22% and 38% of locally-recurrent CRPC and mCRPC, respectively. 1 (8%) locally-recurrent CRPC showed missense mutation in AR, whereas 5 (16%) of the mCRPCs were found to harbour mutation. Significant level of AR-Vs expression was detected only in neoadjuvant-treated tumors as well as in CRPCs. On the whole, the proportion of AR-Vs compared to full-length AR was less than 30% in these patients. The expression of AR-Vs was significantly associated with the levels of full-length AR. Expression of AR-Vs was not associated with the expression of AR target genes. CONCLUSIONS: Interestingly, not just CRPCs, but also neoadjuvant hormone treated tumors
Eur Urol Suppl 2017; 16(3);e255
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
153
Neoadjuvant hormonal therapies induce the expression of AR transcript variants Eur Urol Suppl 2017; 16(3);e256
expressed AR variants. Thus, it seems that neadjuvant treatment induces the expression of AR-Vs. The expression of AR-Vs was also associated with the levels of full-length AR suggesting that the high expression of the AR locus drives the expression of AR-Vs. The frequency of AR gene amplification and missense mutations in CRPCs was in the range that has previously been reported. Prostate cancers that have not been treated with hormonal therapy do not show aberrations in AR. These targeted panels may, in future, be useful predicting response to hormonal therapy.
Eur Urol Suppl 2017; 16(3);e256 Powered by TCPDF (www.tcpdf.org)
153
Neoadjuvant hormonal therapies induce the expression of AR transcript variants Eur Urol Suppl 2017; 16(3);e255
Tammela T.1, Kallio H.2, Annala M.2, Brofeldt A.2, Hieta R.2, Kivinummi K.2, Nykter M.2, Lilja H.2, Bova G.2, Visakorpi T.2 1
Tampere University Hospital, Dept. of Surgery, Tampere, Finland, 2University of Tampere, Biomeditech, Tampere, Finland INTRODUCTION & OBJECTIVES: Prostate cancer (PC) is the most common malignancy and third most common cause of cancer-related death among men in Europe. Although most PCs grow slowly, 20–25% of the patients believed to have organ-confined disease will experience biochemical recurrence already during 5-years of follow-up. The standard treatment against advanced PC is androgen deprivation (ADT). Unfortunately, androgen deprivation treatment eventually fails leading to the emergence of castration resistant PC (CRPC) that is lethal. However, also CRPCs are dependent on androgens. Owing to this understanding, several drugs have recently developed for the treatment of CRPC including enzalutamide and abiraterone, but approximately 20–40% of patients have no response to these agents. One explanation for this could be the expression of constitutively active androgen receptor splice variants (AR-Vs). The aim of our project is to interrogate all possible AR aberrations in PC and CRPC. MATERIAL & METHODS: Three patient cohorts were utilized in the study. Cohort 1 included samples from benign prostatic hyperplasia patients (n=12), prostate cancer patients (n=28) and CRPC patients whose cancer was locally recurred (n=13). Cohort 2 (n=25) included samples from patients treated with prostatectomy or neoadjuvant hormone therapy (goserelin or bicalutamide) prior to prostatectomy. Cohort 3 included CRPC metastases (mCRCP) collected at autopsy (n=31). Targeted sequencing of DNA and RNA was performed using SureSelectXT Target Enrichment systems (Agilent) and Illumina MiSeq (cohort 2 and 3 samples) for the analysis of AR locus. Whole genome sequencing and whole transcriptome sequencing was performed using Illumina HiSeq (cohort 1 samples).The expression levels of 5 AR-regulated genes (KLK3, FKBP5, TMPRSS2, ACPP and SLC45A3) was also measured along targeted RNA-seq assay. RESULTS: AR gene amplification was found in 22% and 38% of locally-recurrent CRPC and mCRPC, respectively. 1 (8%) locally-recurrent CRPC showed missense mutation in AR, whereas 5 (16%) of the mCRPCs were found to harbour mutation. Significant level of AR-Vs expression was detected only in neoadjuvant-treated tumors as well as in CRPCs. On the whole, the proportion of AR-Vs compared to full-length AR was less than 30% in these patients. The expression of AR-Vs was significantly associated with the levels of full-length AR. Expression of AR-Vs was not associated with the expression of AR target genes. CONCLUSIONS: Interestingly, not just CRPCs, but also neoadjuvant hormone treated tumors
Eur Urol Suppl 2017; 16(3);e255
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
153
Neoadjuvant hormonal therapies induce the expression of AR transcript variants Eur Urol Suppl 2017; 16(3);e256
expressed AR variants. Thus, it seems that neadjuvant treatment induces the expression of AR-Vs. The expression of AR-Vs was also associated with the levels of full-length AR suggesting that the high expression of the AR locus drives the expression of AR-Vs. The frequency of AR gene amplification and missense mutations in CRPCs was in the range that has previously been reported. Prostate cancers that have not been treated with hormonal therapy do not show aberrations in AR. These targeted panels may, in future, be useful predicting response to hormonal therapy.
Eur Urol Suppl 2017; 16(3);e256 Powered by TCPDF (www.tcpdf.org)