Radical Prostatectomy Variants on Prostate-Specific Antigen

3068

Prognostic Significance of Prostate Cancer Susceptibility Variants on Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Shu-Pin Huang,1,2,3 Li-Chia Huang,4 Wen-Chien Ting,5 Lu-Min Chen,4 Ta-Yuan Chang,6 Te-Ling Lu,7 Yu-Hsuan Lan,7 Chia-Chu Liu,1 Wen-Hui Yang,8 Hong-Zin Lee,7 Chi-Jeng Hsieh,9,10 and Bo-Ying Bao7 1Department of Urology, Kaohsiung Medical University Hospital; 2Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital; 3Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Departments of 4Obstetrics and Gynecology and 5Colorectal Surgery, China Medical University Hospital; Departments of 6Occupational Safety and Health, 7Pharmacy, and 8Health Services Administration, China Medical University, Taichung, Taiwan; 9Department of Health Care Administration, Oriental Institute of Technology; and 10Graduate Institute of Health Care Organization Administration, College of Public Health, National Taiwan University, Taipei, Taiwan

Abstract

Recent genomewide association studies have identified were associated with prostate-specific antigen recur- several prostate cancer susceptibility variants. Howev- rence (P < 0.02). Of these, rs7920517 and rs10993994, er, the association between these variants and bio- which were in strong linkage disequilibrium (r2 = chemical failure in prostate cancer patients receiving 0.91), also showed significant associations with poor radical prostatectomy has not been determined. We prostate-specific antigen–free survival following radi- systematically evaluated 20prostate cancer –associated cal prostatectomy (log-rank test; P < 0.01). The associa- single-nucleotide polymorphisms in a cohort of 320lo- tions remained significant in our multivariate Cox calized prostate cancer patients receiving radical pros- proportional hazards analysis after adjusting for other tatectomy. Each single-nucleotide polymorphism found clinicopathologic risk covariates (P < 0.01). In conclu- to be associated with the recurrence of prostate-specific sion, loci associated with risk for prostate cancer, such antigen was further analyzed by Kaplan-Meier analy- as rs7920517 and rs10993994, might also be used to pre- sis and Cox regression model. Three prostate cancer dict the recurrence of prostate-specific antigen in pros- susceptibility single-nucleotide polymorphisms tate cancer patients receiving radical prostatectomy. (rs1447295 at 8q24, rs7920517 and rs10993994 at 10q11) (Cancer Epidemiol Biomarkers Prev 2009;18(11):3068–74)

Introduction

Prostate cancer is the most common cancer and the sec- Patients diagnosed with localized prostate cancer are ond leading cause of cancer deaths among American commonly treated with radical prostatectomy. Of these men (1). However, its etiology remains poorly under- patients, 15% to 46% experience recurrence of disease as stood. Incidence and mortality rates of prostate cancer detected by a relapse in prostate-specific antigen (10). Al- vary substantially worldwide, suggesting the importance though several clinicopathologic indicators, such as pros- of environmental/lifestyle risk factors and perhaps their tate-specific antigen level, Gleason score, pathologic combination with genetic variants across racial/ethnic stage, and surgical margin status, are currently used to populations. Recently, several genomewide association predict outcome following curative intended radical pros- studies have identified several genetic variants as being tatectomy for localized prostate cancer (11), there is a associated with risk for prostate cancer in men of Europe- need to find new biomarkers to improve the prediction an ancestry (2-9). Although these novel risk variants have of disease recurrence and selection of appropriate adju- been replicated in several study populations, little is vant therapy for high-risk patients. known about the associations of these risk variants with DNA-based genetic biomarkers have certain advan- non-European populations and with clinicopathologic tages over clinicopathologic indicators in that they can features of prostate cancer. be done preoperatively, can be conducted easily, and can be interpreted more objectively without individual bias. Despite some recent conducted studies showed a trend of prostate cancer susceptibility variants observed more frequently in prostate cancer patients with early age at di- Received 7/3/09; revised 8/28/09; accepted 9/8/09; published online 11/9/09. Grant support: National Science Council grants NSC-96-2321-B-039-005-MY2 and agnosis, higher Gleason score, or more aggressive disease NSC-96-2314-B-037-012-MY3, and China Medical University grant CMU97-183. (12-14), the prognostic roles of these risk variants on dis- Note: S-P. Huang and B-Y. Bao contributed equally to this work. ease progression remain undetermined. Thus, the aim of Requests for reprints: Bo-Ying Bao, Department of Pharmacy, China Medical this study was to investigate the prognostic significance University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan. Phone: 886-4-2205-3366 ext. 5126; Fax: 886-4-2203-1075. E-mail: [email protected] of the prostate cancer susceptibility variants and recur- Copyright © 2009 American Association for Cancer Research. rence of prostate-specific antigen in clinically localized doi:10.1158/1055-9965.EPI-09-0665 prostate cancer patients after radical prostatectomy.

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

Table 1. Demographic and clinicopathologic analyses were done on the whole specimens with step characteristics of prostate cancer patients who sections (2-3 mm), and the positive surgical margin was received radical prostatectomy defined as tumor cells present at the inked margin. This PSA No PSA P study was approved by the Institutional Review Board of recurrence* recurrence* Kaohsiung Medical University Hospital, and informed consent was obtained from each participant. No. of patients 113 207 Mean age (SD), y 65.8 (6.1) 65.6 (6.8) 0.821 2 Single-Nucleotide Polymorphism Selection and Gen- Body mass index (SD), kg/m 24.9 (2.9) 24.7 (2.8) 0.568 otyping. We selected 20 single-nucleotide polymorphisms PSA level (SD), ng/mL† 27.8 (31.9) 13.1 (12.6) <0.001 Pathologic stage , n (%) that were implicated in several genomewide association Localized 44 (40.7) 162 (78.6) <0.001 studies (2-9). They were highly significant single-nucleo- Locally advanced 64 (59.3) 44 (21.4) tide polymorphisms at 2q15 (rs721048; ref. 8), 3p12 n Gleason score, (%) (rs2660753; ref. 7), 6q25 (rs9364554; ref. 7), 7p15 2-7 82 (75.2) 189 (93.1) <0.001 8-10 27 (24.8) 14 (6.9) (rs10486567; ref. 9), 7q21 (rs6465657; ref. 7), 8q24 Surgical margin, n (%) (rs16901979, rs6983267, rs1447295, and 4242382; refs. 2, 4, Negative 49 (52.1) 147 (79.9) <0.001 6, 9), 9q33 (rs1571801; ref. 3), 10q11 (rs7920517 and Positive 45 (47.9) 37 (20.1) rs10993994; ref. 7), 10q26 (rs4962416; ref. 9), 11q13 Abbreviation: PSA, prostate-specific antigen. (rs7931342; ref. 7), 17q12 (rs4430796; ref. 5), 17q24 *With mean follow-up of 38.5 mo and median follow-up 30.8 mo. (rs1859962; ref. 5), 19q13 (rs266849 and rs2735839; ref. 7), † Tumor-node-metastasis staging by American Joint Committee on Cancer and Xp11 (rs5945572 and rs5945619; refs. 7, 8). in 1997: localized, T1/T2 N0 M0, and locally advanced, T3/T4 N1 M0. Genotyping was done using Sequenom iPLEX matrix- assisted laser desorption/ionization–time-of-flight mass spectrometry technology at the National Genotyping Cen- Materials and Methods ter, Academia Sinica, Taiwan. Briefly, primers for locus- Patient Recruitment and Data Collection. The study specific PCR and allele-specific extension were designed population was expanded from our hospital-based pros- by MassARRAY AssayDesign 3.0 software (Sequenom). tate cancer case-control study that has previously been de- The sample DNAs were amplified by primers flanking scribed (15-19). Briefly, patients with diagnosed and the targeted sequence, followed by dephosphorylation pathologically confirmed prostate cancer were actively re- and allele-specific primer extension. The extension pro- cruited from three medical centers in Taiwan: Kaohsiung ducts were purified, loaded into a 384-format Spectro- Chip, and subjected to matrix-assisted laser desorption/ Medical University Hospital, Kaohsiung Veterans General – Hospital, and National Taiwan University Hospital. Pa- ionization time-of-flight mass spectrometry. The resulting tients in this cohort were diagnosed with prostate biopsy data were analyzed by the Sequenom MassARRAY for elevated prostate-specific antigen levels or abnormal TYPER software. Quality control included genotyping of digital rectal examination during evaluation for benign 39 blind duplicate samples, revealing a 99.1% agreement prostatic hyperplasia–related lower urinary tract symp- on genotyping calls across all single-nucleotide poly- toms. Serum prostate-specific antigen levels and demo- morphisms we assayed. Each of the single-nucleotide polymorphisms in the autosomal chromosomes was in graphic information were available for all patients. A P subset of clinically localized prostate cancer patients who Hardy-Weinberg equilibrium ( > 0.05). underwent radical prostatectomy was followed prospec- Statistical Analysis. The association between demo- tively to investigate the potential role of genetic variants graphic and clinicopathologic characteristics with re- in the progression of prostate cancer (defined by the recur- currence of prostate-specific antigen was assessed by rence of prostate-specific antigen). Prostate-specific antigen Student's t test or χ2 test. Logistic regression analyses were recurrence was defined as two consecutive prostate-specif- done to compute odds ratios and the 95% confidence inter- ic antigen measurements of >0.2 ng/mL at an interval of >3 vals (95% CI) for estimating the associations of individual mo (20), and the prostate-specific antigen level of >0.2 ng/ single-nucleotide polymorphism alleles, as well as geno- mL at the first follow-up was considered the date of recur- types to the risk for prostate-specific antigen recurrence, rence. No prostate-specific antigen recurrence was defined while adjusting for age (age-adjusted odds ratio). The Ka- as prostate-specific antigen persistently <0.2 ng/mL during plan-Meier method was used to compare the influence of the postoperative follow-up period. For more precise anal- genotypes in the prostate-specific antigen–free survival in- ysis, the effect of disease recurrence after radical prostatec- terval, and significance was determined using the log-rank tomy, patients who received adjuvant hormone therapy or test. Univariate and multivariate analyses to determine the radiotherapy, and those without sufficient follow-up time interdependency of genotypes and the risk parameters, were excluded, thus leaving 320 cases into final analysis. such as age, preoperative prostate-specific antigen, Glea- Disease stage was determined by pathologic findings, son score, pathologic stage, and surgical margin, were car- pelvic computed tomography or magnetic resonance im- ried out using Cox proportional hazards regression. A two- aging, and radionucleotide bone scans, according to the sided P of < 0.05 was considered statistically significant. criteria outlined by the American Joint Committee on Because we were testing 20 single-nucleotide polymorph- Cancer tumor-node-metastasis classification system isms, false-discovery rates (q values) were calculated to de- (AJCC Cancer Staging Manual, 5th edition, 1997). Patho- termine the degree to which the tests for association were logic grade was recorded as Gleason scores and classified prone to false positives (22). q values were estimated using into two groups, one with Gleason scores 2 to 7 and the R q value package.11 other with Gleason scores 8 to 10, according to previous risk assessment models for prostate-specific antigen recurrence after radical prostatectomy (17, 21). Pathology 11 http://genomics.princeton.edu/storeylab/qvalue/

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

Results rs7920517, and rs10993994 at 10q11 in patients with recur- ring prostate-specific antigen to be significantly different As can be seen in Table 1, which summarizes the demo- from those without recurrence. The rare alleles of these graphic characteristics of our study population, prostate- three single-nucleotide polymorphisms were associated specific antigen recurred in 113 (35.3%) of 320 prostate with increased risk for prostate-specific antigen re- cancer patients who had received radical prostatectomy currence [age-adjusted odds ratios of 1.59 (95% CI, 1.08-2.35) during the mean and median follow-up of 38.5 and 30.8 for rs1447295, 1.59 (95% CI, 1.14-2.21) for rs7920517, and months (range, 1-96 months), respectively. All clinico- 1.66 (95% CI, 1.19-2.31) for rs10993994], and all had a pathologic features were significantly associated with q value < 0.127. In addition, the rare homozygous geno- the recurrence of prostate-specific antigen (P < 0.001), ex- type carriers of these three single-nucleotide polymorph- cept for age (P = 0.821) and body mass index (P = 0.568). isms were also found to be at greater relative risk for Allele and genotype analyses for the associations of 20 prostate-specific antigen recurrence than in common ho- prostate cancer susceptibility single-nucleotide poly- mozygous carriers [age-adjusted odds ratios of 3.50 morphisms with prostate-specific antigen recurrence (95% CI, 1.10-11.2) for rs1447295, 2.50 (95% CI, 1.27- after radical prostatectomy are shown in Table 2. We 4.89) for rs7920517, and 2.71 (95% CI, 1.39-5.29) for found the allelic frequency of rs1447295 at 8q24, rs10993994], and all had a q value < 0.170.

Table 2. Association between 20 prostate cancer risk single-nucleotide polymorphisms and prostate-specific antigen recurrence after radical prostatectomy

SNP ID Chromosome position Allele Recurrence/no recurrence MAF Allele analysis Rare allelic aOR (95% CI) Pq rs721048 2: 62985235 G→A 0.044/0.042 1.07 (0.48-2.37) 0.873 0.887 rs2660753 3: 87193364 C→T 0.290/0.309 0.91 (0.64-1.31) 0.620 0.887 rs9364554 6:160753654 C→T 0.286/0.290 0.96 (0.67-1.39) 0.844 0.887 rs10486567 7: 27943088 A→G 0.161/0.162 1.04 (0.66-1.63) 0.869 0.887 rs6465657 7: 97654263 C→T 0.183/0.137 1.46 (0.93-2.28) 0.099 0.396 rs16901979 8:128194098 C→A 0.321/0.332 0.98 (0.69-1.39) 0.887 0.887 rs6983267 8:128482487 G→T 0.504/0.480 1.11 (0.80-1.55) 0.521 0.887 rs1447295* 8:128554220 C→A 0.265/0.192 1.59 (1.08-2.35) 0.019 0.127 rs4242382* 8:128586755 G→A 0.279/0.220 1.41 (0.97-2.05) 0.075 0.375 rs1571801 9:123467194 G→T 0.059/0.050 1.20 (0.58-2.46) 0.620 0.887 rs7920517* 10: 51202627 G→A 0.554/0.443 1.59 (1.14-2.21) 0.006 0.060 rs10993994* 10: 51219502 T→C 0.562/0.445 1.66 (1.19-2.31) 0.003 0.060 rs4962416 10:126686862 T→C 0.009/0.005 1.83 (0.26-13.1) 0.548 0.887 rs7931342 11: 68751073 T→G 0.283/0.262 1.03 (0.71-1.49) 0.873 0.887 rs4430796 17: 33172153 A→G 0.208/0.180 1.23 (0.82-1.86) 0.324 0.887 rs1859962 17: 66620348 T→G 0.420/0.418 1.04 (0.74-1.45) 0.829 0.887 rs266849 19: 56040902 A→G 0.388/0.336 1.24 (0.87-1.79) 0.240 0.800 rs2735839 19: 56056435 G→A 0.424/0.386 1.13 (0.81-1.58) 0.470 0.887 rs5945572* X: 51246423 G→A 0.097/0.080 1.26 (0.56-2.82) 0.576 0.887 rs5945619* X: 51258412 T→C 0.097/0.090 1.11 (0.50-2.44) 0.803 0.887 Genotype analysis SNP ID Heterozygous aOR (95% CI) PqRare homozygous aOR (95% CI) Pq rs721048 1.22 (0.53-2.82) 0.641 0.888 — rs2660753 0.75 (0.45-1.24) 0.259 0.583 1.04 (0.48-2.24) 0.928 0.971 rs9364554 0.82 (0.50-1.33) 0.411 0.822 1.25 (0.50-3.16) 0.636 0.954 rs10486567 1.05 (0.61-1.80) 0.871 0.972 1.05 (0.30-3.68) 0.946 0.971 rs6465657 1.19 (0.70-2.05) 0.523 0.888 3.87 (0.94-15.9) 0.061 0.229 rs16901979 0.91 (0.55-1.50) 0.704 0.905 1.04 (0.48-2.14) 0.971 0.971 rs6983267 1.67 (0.93-3.00) 0.088 0.317 1.25 (0.62-2.52) 0.529 0.882 rs1447295* 1.48 (0.90-2.42) 0.119 0.357 3.50 (1.10-11.2) 0.034 0.170 rs4242382* 1.39 (0.86-2.25) 0.181 0.465 2.48 (0.80-7.74) 0.117 0.351 rs1571801 1.01 (0.47-2.21) 0.971 0.972 — rs7920517* 1.81 (1.00-3.29) 0.050 0.317 2.50 (1.27-4.89) 0.008 0.060 rs10993994* 1.76 (0.97-3.19) 0.063 0.317 2.71 (1.39-5.29) 0.004 0.060 rs4962416 1.84 (0.25-13.3) 0.547 0.888 — rs7931342 1.57 (0.96-2.57) 0.071 0.317 0.56 (0.21-1.46) 0.235 0.504 rs4430796 1.58 (0.94-2.66) 0.084 0.317 0.85 (0.29-2.51) 0.771 0.971 rs1859962 0.99 (0.59-1.67) 0.972 0.972 1.09 (0.56-2.14) 0.798 0.971 rs266849 1.08 (0.63-1.87) 0.771 0.925 1.58 (0.77-3.25) 0.217 0.504 rs2735839 1.14 (0.68-1.92) 0.622 0.888 1.29 (0.64-2.60) 0.482 0.882 rs5945572* — — rs5945619* — —

NOTE: For allele analysis, the category of reference is the common allele (age-adjusted odds ratio, 1); For genotype analysis, the category of reference is the common homozygous (age-adjusted odds ratio, 1). P ≤ 0.05 is in boldface. Em dashes are age-adjusted odds ratio that were not calculated because of the lack of this genotype in patients or nondiploid genotypes. Abbreviations: MAF, minor allele frequency; aOR, age-adjusted odds ratio; SNP, single-nucleotide polymorphism. *rs4242382 is in strong linkage disequilibrium with rs1447295 (r2 = 0.72). rs7920517 is in strong linkage disequilibrium with rs10993994 (r2 = 0.91). rs5945619 is in strong linkage disequilibrium with rs5945572 (r2 = 0.96).

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

The associations between genotypes of these three prostate cancer in two independent genomewide associ- single-nucleotide polymorphisms and time to disease ation studies (7, 9). The MSMB gene encodes prostatic recurrence were presented in Fig. 1. Kaplan-Meier sur- secretory protein 94, which is synthesized by prostate vival analysis and log-rank test revealed a significant epithelial cells and then secreted into the seminal fluid association between rs7920517 and rs10993994 genotypes and prostate-specific antigen–free survival. The median estimated cumulative survivals were significant- lylowerinrarehomozygouscarriersthaninthose common homozygous carriers (32 versus >96 months, P = 0.005, and q = 0.097 for rs7920517; 29 versus >96 months, P = 0.002, and q = 0.076 for rs10993994), show- ing an earlier recurrence of prostate cancer after radical prostatectomy. To confirm the predictive effects of rs1447295, rs7920517, and rs10993994 on prostate-specific antigen recurrence after radical prostatectomy, various clinicopathologic parameters, including age at diagnosis, preoperative prostate- specific antigen, Gleason score, pathologic stage, and surgical margin, were evaluated together with each of these three single-nucleotide polymorphisms, using Cox proportional hazards analysis (Table 3). Our univariate analyses found that high preoperative prostate-specific antigen level, Gleason score 8 to 10, advanced pathologic stage, positive surgical margin, and rare homozygous genotypes of rs7920517 and rs10993994 significantly in- fluenced post–radical prostatectomy prostate-specific antigen–free survival time. After adjusting for all clinicopathologic risk factors in the multivariate analyses, the rare homozygous genotypes of rs1447295, rs7920517, and rs10993994 were further identified as independent prognostic factors for the recurrence of prostate-specific antigen in patients receiving radical prostatectomy (P < 0.01).

Discussion

Biochemical failure (prostate-specific antigen recurrence) is an important indicator of disease recurrence after radical prostatectomy, and many prostate-specific antigen recurrent patients are prone to develop metastatic lesions accompanied by increased risk for mortality (21). There- fore, finding new biomarkers that could predict the recurrence of prostate-specific antigen may make it possible to detect disease recurrence earlier, select treat- ment strategies, and possibly uncover the underlying mechanism behind the recurrence of the disease. In our investigation on the relationship between 20 single-nucleotide polymorphisms recently highlighted by several genomewide association studies and prostate-specific antigen recurrence, we found that rs7920517 and rs10993994, which were in strong linkage disequilibrium (r2 = 0.91), at 10q11 showed significant association with poor prostate-specific antigen–free survival in Kaplan-Meier survival analysis and in multivariate Cox proportional hazards analysis after considering other clinicopathologic risk covariates (Fig. 1 and Table 3). To the best of our knowledge, this study may be the first report of an association between the 10q11 single-nucleotide polymorphisms and prostate-specific antigen recurrence after radical prostatectomy. Recently, rs10993994, located at 57 bp upstream of Figure 1. Kaplan-Meier analysis of time to prostate-specific the transcription start site of the β-microseminoprotein antigen recurrence after radical prostatectomy, stratified by gen- (MSMB) gene, has been associated with the risk for otypes at rs1447295 (A); rs7920517 (B); and rs10993994 (C).

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

Table 3. Cox proportional hazards analysis of factors associated with prostate-specific antigen recurrence after radical prostatectomy

Variables Univariate analysis Multivariate analysis* HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P Age (y) 0.99 (0.97-1.02) 0.589 0.99 (0.96-1.02) 0.508 0.99 (0.96-1.03) 0.654 0.99 (0.96-1.03) 0.711 Preoperative PSA, ng/mL 1.02 (1.01-1.03) <0.001 1.03 (1.02-1.04) <0.001 1.03 (1.02-1.04) <0.001 1.03 (1.01-1.04) <0.001 Gleason score 2-7 1.00 1.00 1.00 1.00 8-10 3.74 (2.38-5.89) <0.001 2.68 (1.57-4.57) <0.001 2.64 (1.54-4.52) <0.001 2.63 (1.53-4.53) <0.001 Pathologic stage Localized 1.00 1.00 1.00 1.00 Locally advanced 3.56 (2.42-5.24) <0.001 2.09 (1.27-3.42) 0.004 2.19 (1.33-3.61) 0.002 2.21 (1.33-3.66) 0.002 Surgical margin Negative 1.00 1.00 1.00 1.00 Positive 2.80 (1.86-4.22) <0.001 1.38 (0.84-2.26) 0.206 1.54 (0.93-2.55) 0.097 1.58 (0.95-2.64) 0.078 rs1447295 CC 1.00 1.00 CA 1.34 (0.91-1.98) 0.138 1.12 (0.70-1.79) 0.636 AA 2.05 (0.98-4.29) 0.058 3.07 (1.36-6.96) 0.007 rs7920517 GG 1.00 1.00 GA 1.50 (0.91-2.47) 0.115 1.16 (0.65-2.09) 0.617 AA 2.21 (1.28-3.83) 0.005 2.45 (1.30-4.62) 0.006 rs10993994 TT 1.00 1.00 TC1.46 (0.88-2.41) 0.140 0.92 (0.51-1.66) 0.788 CC 2.34 (1.36-4.02) 0.002 2.32 (1.25-4.30) 0.008

NOTE: P ≤ 0.05 is in boldface. Abbreviation: HR, hazard ratio. *Age, preoperative prostate-specific antigen, Gleason score, pathologic stage, surgical margin, and each genotype were included in the multivariate analysis.

and blood (23). Prostatic secretory protein 94 and pros- against prostate cancer. There are several possible expla- tate-specific antigen, two of the most abundant proteins nations for this inconsistency. First, prostate cancer sus- secreted from the prostate, are thought to be possible ceptibility loci have not been confirmed in multiple markers for prostate cancer (24). More recently, prostatic populations, including people of Han Chinese origin. secretory protein 94 has been found to circulate in If rs10993994 is a prostate cancer risk single-nucleotide blood with low–(free prostatic secretory protein 94) polymorphism in men of Han Chinese ancestry, it is and high (bound to prostatic secretory protein 94– possible that this risk single-nucleotide polymorphism binding protein)–molecular weight forms (25). In the might also influence other genes besides MSMB and ac- prostate cancer patients who have undergone radical count for the disparate effects. The rs10993994 is also prostatectomy, the bound/free prostatic secretory protein located at 23 kb upstream of an interesting prostate 94 ratio was positively associated with the risk for cancer candidate gene, nuclear receptor coactivator 4, recurrence after adjusting for prostate-specific antigen, providing another biological relevance for this genetic Gleason score, and margin status (26). Furthermore, association. Nuclear receptor coactivator 4, also known MSMB is thought to be a tumor suppressor (27) possi- as the androgen receptor coactivator ARA70, is an an- bly capable of impeding prostate cancer growth, pro- drogen receptor–associated protein and enhances the moting apoptosis, inhibiting the secretion of matrix transcriptional activity of androgen receptor in human metalloproteinase implicated in tumor metastasis, and prostate cancer cells in a ligand-dependent manner decreasing vascular endothelial growth factor-mediated (31). ARA70-induced androgen receptor transactivation vascularization. could result in the decreased apoptosis, increased cell In addition to the previous genomewide association proliferation, promoted cell invasion, and facilitated tu- studies association results, the prostate cancer risk allele mor progression in prostate cancer cells (32, 33). Thus, T of rs10993994 has been reported to greatly reduce the genetic variation at rs10993994 might influence onco- tumor suppressor MSMB promoter activity in the fol- gene and tumor suppressor in a context-dependent low-up functional analyses (28-30). Replacing the T al- manner. If rs10993994 is not a prostate cancer risk sin- lele with the C allele destroys the binding site of gle-nucleotide polymorphism in men of Han Chinese cAMP response element binding protein, and the mean ancestry, it is possible that Han Chinese and European mRNA expression level of MSMB with the T allele is men do in fact share a true prostate cancer risk variant significantly lower than that with the C allele (30). at 10q11. However, the true prostate cancer risk variant These findings suggest that rs10993994 is functionally is in the strong linkage disequilibrium with rs10993994 important and might partially account for the observed in European men but not in Han Chinese. Fine map- association with prostate cancer susceptibility. In con- ping of 10q11 has suggested a recombination hotspot trast, we estimate that men with two rare allele C at immediately telomeric of the rs10993994 (29), indicating rs10993994 are 2.5 times more likely to experience dis- the possibility of the separation of disease risk and re- ease recurrence than those with no rare alleles in our currence risk loci. Second, results on associations of study population (Tables 2 and 3). Our findings are rs10993994 with clinicopathologic features of prostate not consistent with the notion that C alleles protect cancer were inconsistent. Although some studies have

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

found a higher frequency of the prostate cancer risk al- chromosome 17 confer prostate cancer risk, and the one in TCF2 pro- T tects against type 2 diabetes. Nat Genet 2007;39:977–83. lele in patients with more aggressive prostate cancer 6. Yeager M, Orr N, Hayes RB, et al. Genome-wide association study of (9, 34), others have not (14, 35). Third, rs10993994 has prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007; not been significantly associated with other clinicopath- 39:645–9. ologic characteristics of prostate cancer, such as age at 7. Eeles RA, Kote-Jarai Z, Giles GG, et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 2008; diagnosis, Gleason score, pathologic stage, or prostate – – 40:316 21. cancer specific survival (13, 14, 34-36). Finally, although 8. Gudmundsson J, Sulem P, Rafnar T, et al. Common sequence variants it has been suggested that MSMB/prostatic secretory on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat protein 94 is a tumor suppressor, increased intratumoral Genet 2008;40:281–3. 9. Thomas G, Jacobs KB, Yeager M, et al. Multiple loci identified in a expression of prostatic secretory protein 94 also seems to genome-wide association study of prostate cancer. Nat Genet 2008; be associated with worse survival outcomes (37, 38). 40:310–5. Therefore, further investigation is needed to determine 10. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term bio- the role of rs10993994, MSMB/prostatic secretory pro- chemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experi- tein 94, and ARA70 in the etiology of prostate cancer. – A ence. Urol Clin North Am 2001;28:555 65. The rare allele of rs1447295 at 8q24, also the reported 11. Humphrey PA. Gleason grading and prognostic factors in carcinoma risk allele, is associated with a significantly increased risk of the prostate. Mod Pathol 2004;17:292–306. for prostate-specific antigen recurrence in logistic regression 12. Levin AM, Machiela MJ, Zuhlke KA, Ray AM, Cooney KA, Douglas JA. Chromosome 17q12 variants contribute to risk of early-onset pros- and multivariate Cox proportional hazards models (Tables 2 tate cancer. Cancer Res 2008;68:6492–5. and 3). However, this result should be consider with caution 13. Wiklund FE, Adami HO, Zheng SL, et al. Established prostate cancer because our study only had a limited number of rs1447295 susceptibility variants are not associated with disease outcome. Can- rare homozygous carriers (n = 14). Chromosome 8q24 has cer Epidemiol Biomarkers Prev 2009;18:1659–62. 14. Xu J, Isaacs SD, Sun J, et al. Association of prostate cancer risk variants been found to contain several single-nucleotide polymorph- with clinicopathologic characteristics of the disease. Clin Cancer Res isms associated with risk for prostate (2), colorectal (39), 2008;14:5819–24. breast (40), ovarian (41), and bladder (42) cancers, but no 15. Huang SP, Chou YH, Chang WS, et al. Androgen receptor gene poly- genes have been identified in the region of interest to date. morphism and prostate cancer in Taiwan. J Formos Med Assoc 2003; 102:680–6. Therefore, further fine mapping of 8q24 in multiethnic sam- 16. Huang SP, Chou YH, Wayne Chang WS, et al. Association between ples might help in the identification of the strongest markers vitamin D receptor polymorphisms and prostate cancer risk in a Tai- in each population and possibly add to our understanding wanese population. Cancer Lett 2004;207:69–77. of the contribution of 8q24 single-nucleotide polymorph- 17. Huang SP, Huang CY, Wang JS, et al. Prognostic significance of p53 and X-ray repair cross-complementing group 1 polymorphisms on isms to prostate cancer progression. prostate-specific antigen recurrence in prostate cancer post radical In conclusion, systematically evaluating 20 recently prostatectomy. Clin Cancer Res 2007;13:6632–8. highlighted prostate cancer susceptibility single-nucleo- 18. Huang SP, Huang CY, Wu WJ, et al. Association of vitamin D receptor tide polymorphisms, we provided the first evidence for FokI polymorphism with prostate cancer risk, clinicopathological features and recurrence of prostate specific antigen after radical prosta- the association of these variants and recurrence of the dis- tectomy. Int J Cancer 2006;119:1902–7. ease. However, this study is limited by sample size in 19. Huang SP, Wu WJ, Chang WS, et al. p53 Codon 72 and p21 codon 31 analyses of outcomes and in subset analyses. In addition, polymorphisms in prostate cancer. Cancer Epidemiol Biomarkers Prev our homogeneous Chinese Han population may make 2004;13:2217–24. 20. Freedland SJ, Sutter ME, Dorey F, Aronson WJ. Defining the ideal cut- our findings less generalizable to other ethnic groups. point for determining PSA recurrence after radical prostatectomy. Thus, further functional analyses and large independent Prostate-specific antigen. Urology 2003;61:365–9. studies in other ethnic populations are required to vali- 21. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate can- date the relevance of the observed associations to the pro- cer-specific mortality following biochemical recurrence after radical – gression of prostate cancer after radical prostatectomy. prostatectomy. JAMA 2005;294:433 9. 22. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 2003;100:9440–5. Disclosure of Potential Conflicts of Interest 23. Mbikay M, Nolet S, Fournier S, et al. Molecular cloning and sequence No potential conflicts of interest were disclosed. of the cDNA for a 94-amino-acid seminal plasma protein secreted by the human prostate. DNA 1987;6:23–9. 24. Maeda N, Kamada M, Daitoh T, et al. Immunoglobulin binding factor: Acknowledgments a new tumor marker for prostatic tumors. Prostate 1994;24:125–30. The costs of publication of this article were defrayed in part 25. Reeves JR, Xuan JW, Arfanis K, et al. Identification, purification and by the payment of page charges. This article must therefore be characterization of a novel human blood protein with binding affinity advertisement for prostate secretory protein of 94 amino acids. Biochem J 2005;385: hereby marked in accordance with 18 U.S.C. 105–14. Section 1734 solely to indicate this fact. 26. Reeves JR, Dulude H, Panchal C, Daigneault L, Ramnani DM. Prog- We thank the National Genotyping Center of National nostic value of prostate secretory protein of 94 amino acids and its Research Program for Genomic Medicine, National Science binding protein after radical prostatectomy. Clin Cancer Res 2006;12: Council, Taiwan, for their technical support. 6018–22. 27. Beke L, Nuytten M, Van Eynde A, Beullens M, Bollen M. The gene encoding the prostatic tumor suppressor PSP94 is a target for repres- References sion by the Polycomb group protein EZH2. Oncogene 2007;26:4590–5. 1. Crawford ED. Epidemiology of prostate cancer. Urology 2003;62:3–12. 28. Buckland PR, Hoogendoorn B, Coleman SL, Guy CA, Smith SK, 2. Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant O'Donovan MC. Strong bias in the location of functional promoter associated with prostate cancer in European and African populations. polymorphisms. Hum Mutat 2005;26:214–23. Nat Genet 2006;38:652–8. 29. Chang BL, Cramer SD, Wiklund F, et al. Fine mapping association 3. Duggan D, Zheng SL, Knowlton M, et al. Two genome-wide associa- study and functional analysis implicate a SNP in MSMB at 10q11 as tion studies of aggressive prostate cancer implicate putative prostate a causal variant for prostate cancer risk. Hum Mol Genet 2009;18: tumor suppressor gene DAB2IP. J Natl Cancer Inst 2007;99:1836–44. 1368–75. 4. Gudmundsson J, Sulem P, Manolescu A, et al. Genome-wide associa- 30. Lou H, Yeager M, Li H, et al. Fine mapping and functional analysis tion study identifies a second prostate cancer susceptibility variant at of a common variant in MSMB on chromosome 10q11.2 associated 8q24. Nat Genet 2007;39:631–7. with prostate cancer susceptibility. Proc Natl Acad Sci U S A 2009; 5. Gudmundsson J, Sulem P, Steinthorsdottir V, et al. Two variants on 106:7933–8.

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

31. Yeh S, Chang C. Cloning and characterization of a specific coactivator, 37. Girvan AR, Chang P, van Huizen I, et al. Increased intratumoral ex- ARA70, for the androgen receptor in human prostate cells. Proc Natl pression of prostate secretory protein of 94 amino acids predicts for Acad Sci U S A 1996;93:5517–21. worse disease recurrence and progression after radical prostatectomy 32. Niu Y, Yeh S, Miyamoto H, et al. Tissue prostate-specific antigen facil- in patients with prostate cancer. Urology 2005;65:719–23. itates refractory prostate tumor progression via enhancing ARA70-reg- 38. Sakai H, Tsurusaki T, Kanda S, Koji T, Xuan JW, Saito Y. Prognostic ulated androgen receptor transactivation. Cancer Res 2008;68:7110–9. significance of β-microseminoprotein mRNA expression in prostate 33. Peng Y, Li CX, Chen F, et al. Stimulation of prostate cancer cellular cancer. Prostate 1999;38:278–84. proliferation and invasion by the androgen receptor co-activator 39. Tomlinson I, Webb E, Carvajal-Carmona L, et al. A genome-wide as- ARA70. Am J Pathol 2008;172:225–35. sociation scan of tag SNPs identifies a susceptibility variant for colo- 34. Kader AK, Sun J, Isaacs SD, et al. Individual and cumulative effect of rectal cancer at 8q24.21. Nat Genet 2007;39:984–8. prostate cancer risk-associated variants on clinicopathologic variables 40. Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association in 5,895 prostate cancer patients. Prostate 2009. study identifies novel breast cancer susceptibility loci. Nature 2007; 35. Waters KM, Le Marchand L, Kolonel LN, et al. Generalizability of as- 447:1087–93. sociations from prostate cancer genome-wide association studies in 41. Ghoussaini M, Song H, Koessler T, et al. Multiple loci with different multiple populations. Cancer Epidemiol Biomarkers Prev 2009;18: cancer specificities within the 8q24 gene desert. J Natl Cancer Inst 1285–9. 2008;100:962–6. 36. Kote-Jarai Z, Easton DF, Stanford JL, et al. Multiple novel prostate can- 42. Kiemeney LA, Thorlacius S, Sulem P, et al. Sequence variant on 8q24 cer predisposition loci confirmed by an international study: the PRAC- confers susceptibility to urinary bladder cancer. Nat Genet 2008;40: TICAL Consortium. Cancer Epidemiol Biomarkers Prev 2008;17:2052–61. 1307–12.

Cancer Epidemiol Biomarkers Prev 2009;18(11). November 2009

Downloaded from cebp.aacrjournals.org on October 1, 2021. © 2009 American Association for Cancer Research. Prognostic Significance of Prostate Cancer Susceptibility Variants on Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Shu-Pin Huang, Li-Chia Huang, Wen-Chien Ting, et al.

Cancer Epidemiol Biomarkers Prev 2009;18:3068-3074.

Updated version Access the most recent version of this article at: http://cebp.aacrjournals.org/content/18/11/3068

Cited articles This article cites 41 articles, 12 of which you can access for free at: http://cebp.aacrjournals.org/content/18/11/3068.full#ref-list-1

Citing articles This article has been cited by 5 HighWire-hosted articles. Access the articles at: http://cebp.aacrjournals.org/content/18/11/3068.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cebp.aacrjournals.org/content/18/11/3068. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.