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INTEGRATIVE META-ANALYSIS OF MICROARRAY DATA TO IDENTIFY PROFILES THAT PREDICT BLADDER CANCER OUTCOMES AND PROGRESSION
Vol. 179, No. 4, Supplement, Monday, May 19, 2008
THE JOURNAL OF UROLOGY®
267
,WLVK\SRWKHVL]HGWKDWWKHJHQHWLFSRO\PRUSKLVPVRIWKHVHPHWDEROLF HQ]\PHVKDYHDQHIIHFWRQWKHLQGLYLGXDOVXVFHSWLELOLW\WR8& METHODS: We studied the frequencies of the single QXFOHRWLGH SRO\PRUSKLVPV 613V RI WKHVH VHYHQ HQ]\PHV 8& included 108 bladder cancer patients and 112 controls were recruited by the Departments of urology, Tohoku University. All patients were Japanese. Information by structured interview was obtained on medical history, lifetime smoking history and the life-time occupational history. The effects of smoking exposure, and of the genetic polymorphisms on the risk of UC were estimated by odds ratios (ORs) and corresponding FRQ¿GHQFH LQWHUYDOV &, ZKLFK ZHUH GHULYHG IURP ORJLVWLF regression analysis using Statistical Package for the Social Science (SPSS). Based on the distribution on the data and known risk factors of UC, we adjusted for age, sex and smoking. RESULTS: CYP4B1 AT881-882del and GSTM1 null genotype were associated with an increased risk of UC (OR 1.73, 95%CI 1.00-3.01 and OR 2.11, 95%CI 1.24-3.58, respectively). CYP4B1 517C>T and NQO1 609C>T were tended to increase risk of UC (OR 1.39, 95%CI 0.78-2.49 and OR 1.50, 95%CI 0.87-2.60, respectively). CONCLUSIONS: These findings suggest that individual susceptibility to UC may be modulated by CYP4B1, GSTM1 and NQO1 polymorphisms. Source of Funding: None
766 GENE PROFILE EXPRESSION MAY PREDICT RECURRENCE IN HIGH RISK SUPERFICIAL BLADDER CANCER PATIENTS Paolo Puppo*, Ulrich Pfeffer, Valentina Mirisola, Patrizia Larghero, Rossana Andreatta, Angelo Naselli. Genoa, Italy. INTRODUCTION AND OBJECTIVE: High grade bladder OHVLRQVKDYHDULVNRISURJUHVVLRQXSWRDW¿YH\HDUV 6LOYHVWHU Eur Urol 2006). Nowadays, there is no clinical, pathological or molecular marker that can identify which patient exactly will progress and therefore ZRXOGEHQH¿WIURPDQHDUO\UDGLFDOWUHDWPHQW:HGHYHORSHGDJHQH SUR¿OH VLJQDWXUH WR SUHGLFW UHFXUUHQFH LQ KLJK ULVN VXSHU¿FLDO EODGGHU cancer, since recurrence is a pre-requisite for progression. METHODS: A real time PCR assays for 43 signature genes and 3 housekeeping genes was developed basing on a 45-gene signature implemented to predict progression (Dryskjot, Clin. Cancer Res, 2005). 131 consecutive pts were enrolled during 2005 and 2006. After transurethral resection (TUR), chips from tumor were collected at SWVKDGDKLJKJUDGHVXSHU¿FLDOEODGGHUFDQFHUDQGXQGHUZHQW re-TUR without evidence of residual disease. An induction BCG cycle followed by maintenance was always performed. Median follow up was 7 mo, range 3 to 25. 11 pts recurred (45%). No cases of disease progression occurred yet. RESULTS: Hierarchical clustering of the expression values IRUWKHJHQHVDIWHUQRUPDOL]DWLRQRQWKHDULWKPHWLFPHDQRIWKHWKUHH housekeeping genes yielded three main clusters that contained 20% (2 of 10), 70% (7 of 10) and 50% (2 of 4) of cases with relapse, respectively. 7KLV DQDO\VLV WKXV FRQ¿UPV WKDW WKH SURJQRVWLF JHQH VLJQDWXUH FDQ distinguish between cases with high and low risk of recurrence. Furthermore, a score to each gene by Cox regression analysis was attributed and a cumulative score obtained to distinguish between pts at low risk of recurrence (group A, 12 pts) or at high risk (group B, 12 pts). Graph 1 reports the Kaplan Meyer curves of group A and of group %/RJ5DQN7HVWUHVXOWHGVWDWLVWLFDOO\VLJQL¿FDQWWKHJURXS%KDYHD fold risk of developing a recurrence respect to group A (p 0.0003) CONCLUSIONS: Preliminary results suggest that the gene SUR¿OH VLJQDWXUH PD\ EH DEOH WR SUHGLFW UHFXUUHQFH LQ KLJK ULVN SWV Validation in other series of similar pts is needed before suggesting clinical use.
Source of Funding: None
767 INTEGRATIVE META-ANALYSIS OF MICROARRAY DATA TO IDENTIFY PROFILES THAT PREDICT BLADDER CANCER OUTCOMES AND PROGRESSION David S Morris*, Scott A Tomlins, Daniel R Rhodes, Rou Wang, Robert J Lonigro, Cheryl T Lee, Alon Z Weizer, Arul M Chinnaiyan. Ann Arbor, MI. INTRODUCTION AND OBJECTIVE: While genetic and molecular variations enable prediction of outcomes and response to therapy in a variety of tumors, prediction of bladder cancer tumor characteristics has been limited by sample numbers and population KHWHURJHQHLW\\LHOGLQJPROHFXODUVLJQDWXUHVZLWKRXWVLJQL¿FDQWRYHUODS In order to overcome these limitations, we applied an accepted method RIPHWDSUR¿OLQJPLFURDUUD\GDWDWRGHYHORSJHQHVLJQDWXUHVWRSUHGLFW bladder cancer aggressiveness. METHODS: Gene expression data from 9 separate bladder FDQFHUSUR¿OLQJVWXGLHVDQGPXOWLFDQFHUSUR¿OLQJVWXGLHVWRWDOLQJ samples measuring between 1,168 and 59,619 genes were uploaded into Oncomine, an online platform for advanced expression analysis. Meta-signatures were developed to predict grade, stage, progression, recurrence, and death from bladder cancer. Furthermore, a meta-signature for predicting aggressive from indolent bladder cancer was developed by combining genes present in multiple meta-signatures. The expression of a selection of the meta-signature genes, 12 underexpressed and 42 overexpressed in high risk tumors, were evaluated by qPCR in 48 WXPRU VDPSOHV ZLWK VXI¿FLHQW FOLQLFDO LQIRUPDWLRQ WR GHWHUPLQH GLVHDVH outcome. RESULTS: Meta-signatures had minimal overlap with signatures reported from individual studies (range 3/174 (2%) to 7/41 (17%)). The PHWDVLJQDWXUHLQFOXGHGQRYHOJHQHVVLJQL¿FDQWO\RYHUH[SUHVVHGDQG associated with aggressive tumor characteristics from 48 tumor samples (all p<0.01). Conversely, 4 of the 12 genes predicted to be underexpressed LQ DJJUHVVLYH FDQFHUV ZHUH DOVR VLJQL¿FDQWO\ DVVRFLDWHG ZLWK ORZ ULVN WXPRUV DOOS 2IWKHVLJQL¿FDQWO\DVVRFLDWHGJHQHV JHQHVZHUH QRWLGHQWL¿HGGXULQJSUHYLRXVSUR¿OLQJVWXGLHV CONCLUSIONS: Meta-profiling based on multiple study populations may increase the validity and applicability of gene signatures. 0HWDVLJQDWXUHVZLOOOLNHO\LPSURYHULVNVWUDWL¿FDWLRQSULRUWRWKHUDS\DQG enable tailored treatment recommendations based on risk of disease recurrence and progression. Clinical application of these meta-signatures will rely on ongoing validation from retrospective and prospective trials. Source of Funding: None
THE JOURNAL OF UROLOGY®
267
,WLVK\SRWKHVL]HGWKDWWKHJHQHWLFSRO\PRUSKLVPVRIWKHVHPHWDEROLF HQ]\PHVKDYHDQHIIHFWRQWKHLQGLYLGXDOVXVFHSWLELOLW\WR8& METHODS: We studied the frequencies of the single QXFOHRWLGH SRO\PRUSKLVPV 613V RI WKHVH VHYHQ HQ]\PHV 8& included 108 bladder cancer patients and 112 controls were recruited by the Departments of urology, Tohoku University. All patients were Japanese. Information by structured interview was obtained on medical history, lifetime smoking history and the life-time occupational history. The effects of smoking exposure, and of the genetic polymorphisms on the risk of UC were estimated by odds ratios (ORs) and corresponding FRQ¿GHQFH LQWHUYDOV &, ZKLFK ZHUH GHULYHG IURP ORJLVWLF regression analysis using Statistical Package for the Social Science (SPSS). Based on the distribution on the data and known risk factors of UC, we adjusted for age, sex and smoking. RESULTS: CYP4B1 AT881-882del and GSTM1 null genotype were associated with an increased risk of UC (OR 1.73, 95%CI 1.00-3.01 and OR 2.11, 95%CI 1.24-3.58, respectively). CYP4B1 517C>T and NQO1 609C>T were tended to increase risk of UC (OR 1.39, 95%CI 0.78-2.49 and OR 1.50, 95%CI 0.87-2.60, respectively). CONCLUSIONS: These findings suggest that individual susceptibility to UC may be modulated by CYP4B1, GSTM1 and NQO1 polymorphisms. Source of Funding: None
766 GENE PROFILE EXPRESSION MAY PREDICT RECURRENCE IN HIGH RISK SUPERFICIAL BLADDER CANCER PATIENTS Paolo Puppo*, Ulrich Pfeffer, Valentina Mirisola, Patrizia Larghero, Rossana Andreatta, Angelo Naselli. Genoa, Italy. INTRODUCTION AND OBJECTIVE: High grade bladder OHVLRQVKDYHDULVNRISURJUHVVLRQXSWRDW¿YH\HDUV 6LOYHVWHU Eur Urol 2006). Nowadays, there is no clinical, pathological or molecular marker that can identify which patient exactly will progress and therefore ZRXOGEHQH¿WIURPDQHDUO\UDGLFDOWUHDWPHQW:HGHYHORSHGDJHQH SUR¿OH VLJQDWXUH WR SUHGLFW UHFXUUHQFH LQ KLJK ULVN VXSHU¿FLDO EODGGHU cancer, since recurrence is a pre-requisite for progression. METHODS: A real time PCR assays for 43 signature genes and 3 housekeeping genes was developed basing on a 45-gene signature implemented to predict progression (Dryskjot, Clin. Cancer Res, 2005). 131 consecutive pts were enrolled during 2005 and 2006. After transurethral resection (TUR), chips from tumor were collected at SWVKDGDKLJKJUDGHVXSHU¿FLDOEODGGHUFDQFHUDQGXQGHUZHQW re-TUR without evidence of residual disease. An induction BCG cycle followed by maintenance was always performed. Median follow up was 7 mo, range 3 to 25. 11 pts recurred (45%). No cases of disease progression occurred yet. RESULTS: Hierarchical clustering of the expression values IRUWKHJHQHVDIWHUQRUPDOL]DWLRQRQWKHDULWKPHWLFPHDQRIWKHWKUHH housekeeping genes yielded three main clusters that contained 20% (2 of 10), 70% (7 of 10) and 50% (2 of 4) of cases with relapse, respectively. 7KLV DQDO\VLV WKXV FRQ¿UPV WKDW WKH SURJQRVWLF JHQH VLJQDWXUH FDQ distinguish between cases with high and low risk of recurrence. Furthermore, a score to each gene by Cox regression analysis was attributed and a cumulative score obtained to distinguish between pts at low risk of recurrence (group A, 12 pts) or at high risk (group B, 12 pts). Graph 1 reports the Kaplan Meyer curves of group A and of group %/RJ5DQN7HVWUHVXOWHGVWDWLVWLFDOO\VLJQL¿FDQWWKHJURXS%KDYHD fold risk of developing a recurrence respect to group A (p 0.0003) CONCLUSIONS: Preliminary results suggest that the gene SUR¿OH VLJQDWXUH PD\ EH DEOH WR SUHGLFW UHFXUUHQFH LQ KLJK ULVN SWV Validation in other series of similar pts is needed before suggesting clinical use.
Source of Funding: None
767 INTEGRATIVE META-ANALYSIS OF MICROARRAY DATA TO IDENTIFY PROFILES THAT PREDICT BLADDER CANCER OUTCOMES AND PROGRESSION David S Morris*, Scott A Tomlins, Daniel R Rhodes, Rou Wang, Robert J Lonigro, Cheryl T Lee, Alon Z Weizer, Arul M Chinnaiyan. Ann Arbor, MI. INTRODUCTION AND OBJECTIVE: While genetic and molecular variations enable prediction of outcomes and response to therapy in a variety of tumors, prediction of bladder cancer tumor characteristics has been limited by sample numbers and population KHWHURJHQHLW\\LHOGLQJPROHFXODUVLJQDWXUHVZLWKRXWVLJQL¿FDQWRYHUODS In order to overcome these limitations, we applied an accepted method RIPHWDSUR¿OLQJPLFURDUUD\GDWDWRGHYHORSJHQHVLJQDWXUHVWRSUHGLFW bladder cancer aggressiveness. METHODS: Gene expression data from 9 separate bladder FDQFHUSUR¿OLQJVWXGLHVDQGPXOWLFDQFHUSUR¿OLQJVWXGLHVWRWDOLQJ samples measuring between 1,168 and 59,619 genes were uploaded into Oncomine, an online platform for advanced expression analysis. Meta-signatures were developed to predict grade, stage, progression, recurrence, and death from bladder cancer. Furthermore, a meta-signature for predicting aggressive from indolent bladder cancer was developed by combining genes present in multiple meta-signatures. The expression of a selection of the meta-signature genes, 12 underexpressed and 42 overexpressed in high risk tumors, were evaluated by qPCR in 48 WXPRU VDPSOHV ZLWK VXI¿FLHQW FOLQLFDO LQIRUPDWLRQ WR GHWHUPLQH GLVHDVH outcome. RESULTS: Meta-signatures had minimal overlap with signatures reported from individual studies (range 3/174 (2%) to 7/41 (17%)). The PHWDVLJQDWXUHLQFOXGHGQRYHOJHQHVVLJQL¿FDQWO\RYHUH[SUHVVHGDQG associated with aggressive tumor characteristics from 48 tumor samples (all p<0.01). Conversely, 4 of the 12 genes predicted to be underexpressed LQ DJJUHVVLYH FDQFHUV ZHUH DOVR VLJQL¿FDQWO\ DVVRFLDWHG ZLWK ORZ ULVN WXPRUV DOOS 2IWKHVLJQL¿FDQWO\DVVRFLDWHGJHQHV JHQHVZHUH QRWLGHQWL¿HGGXULQJSUHYLRXVSUR¿OLQJVWXGLHV CONCLUSIONS: Meta-profiling based on multiple study populations may increase the validity and applicability of gene signatures. 0HWDVLJQDWXUHVZLOOOLNHO\LPSURYHULVNVWUDWL¿FDWLRQSULRUWRWKHUDS\DQG enable tailored treatment recommendations based on risk of disease recurrence and progression. Clinical application of these meta-signatures will rely on ongoing validation from retrospective and prospective trials. Source of Funding: None