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author:("Kan, donggui")
1.  External Validation of the Cancer of the Prostate Risk Assessment (CAPRA) Score in a Single-Surgeon Radical Prostatectomy Series 
Urologic oncology  2010;30(5):584-589.
Prostate cancer clinical staging has significant limitations in the ability to accurately risk-stratify patients for prompt treatment or expectant management. The University of California San Francisco Cancer of the Prostate Risk Assessment (UCSF CAPRA) was recently described as a straightforward staging system that uses clinical variables to generate a score ranging from 0 to 10. Our objective was to perform an external validation of the CAPRA score as a predictor of 5-year progression-free survival (PFS) in a single-surgeon radical retropubic prostatectomy (RRP) series.
Materials and Methods
We examined the performance characteristics of the preoperative CAPRA score (0–10) to predict biochemical progression-free survival (PFS) in 990 men who underwent RRP by a single surgeon from 2003 to 2009.
CAPRA scores were significantly associated with the risk of early biochemical progression in our series. For example, 5-year PFS was markedly different for scores at the extremes of 0 to 1 versus ≥7 (95% vs. 40%, respectively). The concordance index was 0.764 for the prediction of biochemical progression using CAPRA scores in this cohort, which compares favorably with the concordance index of 0.66 in the original CaPSURE dataset.
Our results validate the UCSF-CAPRA score as a significant predictor of 5-year PFS in a single surgeon series. The CAPRA score is a simple preoperative tool that can be readily applied in clinical practice to help risk-stratify prostate cancer patients.
PMCID: PMC3137684  PMID: 20822930
CAPRA; staging; prostate cancer; prostatectomy; biochemical recurrence
2.  Chromosomes 4 and 8 Implicated in a Genome Wide SNP Linkage Scan of 762 Prostate Cancer Families Collected by the ICPCG 
The Prostate  2011;72(4):410-426.
In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer remains largely incomplete. In a previous microsatellite-based linkage scan of 1233 prostate cancer (PC) families, we identified suggestive evidence for linkage (i.e. LOD≥1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members.
In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 ICPCG groups.
Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology.
These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.
PMCID: PMC3568777  PMID: 21748754
3.  Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility 
Nature genetics  2009;41(10):1122-1126.
We report a genome-wide association follow up study on prostate cancer. We identify four variants associated with the disease in European populations: rs10934853-A (OR = 1.12, P = 2.9×10−10) on 3q21.3, two moderately correlated (r2 = 0.07) variants on 8q24.21; rs16902094-G (OR = 1.21, P = 6.2×10−15) and rs445114-T (OR = 1.14, P = 4.7×10−10) and rs8102476-C (OR = 1.12, P = 1.6×10−11) on 19q13.2. We also refine a previous association signal on 11q13 with the SNP rs11228565-A (OR =1.23, P = 6.7 × 10−12). In a multi-variant analysis, using 22 prostate cancer risk variants typed in the Icelandic population, we estimate that carriers belonging to the top 1.3% of the risk distribution have a risk of developing the disease that is more than 2.5 times greater than the population average risk estimates.
PMCID: PMC3562712  PMID: 19767754
4.  Prostate-Specific Antigen Velocity Risk Count Improves the Specificity of Screening for Clinically Significant Prostate Cancer 
Bju International  2012;109(4):508-514.
Prostate-specific antigen (PSA)-based prostate cancer (CaP) screening has been shown to reduce CaP mortality at the expense of detecting some tumors that might never cause symptoms. PSA velocity (PSAV) has been shown to predict cancer-specific mortality after treatment. Our objective was to determine whether PSAV risk count (i.e. number of times PSAV exceeds a specific cutpoint) could increase the specificity of screening for biopsy-detectable CaP and potentially life-threatening tumors.
Patients and Methods
From 1989 to 2001, we calculated 2 serial PSAV measurements in 18,214 CaP screening study participants, of whom 1125 (6.2%) were diagnosed with CaP. PSAV risk count was determined as the number of PSAV measurements >0.4 ng/ml/year (0, 1, or 2). We used receiver operating characteristic and reclassification analyses to examine the ability of PSAV risk count to predict screen-detected CaP and high-grade CaP.
PSAV exceeded 0.4 ng/ml/year twice (risk count=2) in 40% of CaP cases compared to only 4% without cancer (p<0.0001). After adjusting for age and PSA, a PSAV risk count of 2 was associated with an 8.2-fold increased risk of CaP (95% CI, 7.0–9.6, p<0.0001) and 5.4-fold increased risk of Gleason score 8–10 CaP on biopsy. Compared to a model with age and PSA, the addition of PSAV risk count significantly improved discrimination (AUC 0.625 vs. 0.725, p=0.031) and reclassified individuals with respect to the risk of high-grade CaP (net reclassification, p≤0.0003).
Sustained rises in PSA indicate a significantly greater risk of CaP, particularly high-grade disease. Compared to men with a risk count ≤1, those with two PSAV measurements >0.4 ng/ml/year (risk count=2) had an 8-fold increased risk of CaP and 5.4-fold increased risk of Gleason 8–10 disease on biopsy, adjusting for age and PSA. Compared to PSA alone, PSAV risk count may be useful to reduce unnecessary biopsies and the diagnosis of low-risk CaP.
PMCID: PMC3338148  PMID: 22296334
prostate cancer; PSA velocity; risk count; screening; PSA
The Journal of urology  2010;183(4):1355-1359.
Due to the limited specificity of prostate-specific antigen (PSA) for prostate cancer (CaP) screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme PSA called [−2] proPSA (p2PSA) may enhance the specificity of PSA-based screening. The objective of our study was to examine the utility of p2PSA in a prospective CaP screening study.
Materials and Methods
From a population of 2034 men undergoing CaP screening, we examined the relationship between p2PSA and CaP detection. Specifically, we compared the utility of total PSA, the ratio of free PSA (fPSA) to total PSA (%fPSA), the ratio of p2PSA to fPSA (%p2PSA) and a formula combining PSA, fPSA and p2PSA (called Beckman Coulter prostate health index or phi®) to predict CaP among men from the study undergoing prostate biopsy with PSA levels of 2.5–10 ng/ml and non-suspicious digital rectal examination (DRE).
Despite similar total PSA levels (p=0.88), both %fPSA (p=0.02) and %p2PSA (p=0.0006) distinguished between positive and negative biopsy results. On receiver operating characteristic (ROC) analysis, %p2PSA (AUC 0.76) outperformed both PSA (AUC 0.50) and %fPSA (AUC 0.68) for differentiating between CaP and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity, positive and negative predictive values. The Beckman Coulter phi® (AUC 0.77) had the best overall performance characteristics.
This is the first prospective study to demonstrate that p2PSA provides improved discrimination between CaP and benign disease in screened men with PSA levels from 2.5 to 10 ng/ml and negative DRE.
PMCID: PMC3537165  PMID: 20171670
prostate-specific antigen; PSA; free PSA; PSA isoforms; proPSA
6.  Prostate Cancer Risk Alleles Significantly Improve Disease Detection and are Associated with Aggressive Features in Patients with a “Normal” Prostate Specific Antigen and Digital Rectal Exam 
The Prostate  2010;71(4):394-402.
Several reports suggest that a combination of risk alleles may be associated with prostate cancer (CaP) risk and tumor features. However, their ability to detect CaP and tumor characteristics in patients with a “normal” PSA (<4 ng/ml) and non-suspicious digital rectal examination (DRE) remains to be determined.
We examined 203 men of European ancestry with clinical stage T1c CaP diagnosed at a “normal” PSA and 611 healthy volunteer controls. The genotypes for 17 different risk alleles were compared between CaP cases and controls. Additional analyses were used to compare the pathologic features between carriers and non-carriers (defined using best-fit genetic model) of these variants.
All risk alleles were present at an increased frequency in cases with “normal” PSA values and DRE compared to controls. Amongst CaP patients, carriers of an increasing number of genetic risk factors (i.e., alleles and positive family history) were at a significantly increased risk of CaP (P-trend <0.001). Specifically, men with >10 genetic risk factors had an 11.2-fold risk (95% CI 4.3-29.2) of having the disease compared to men with ≤5 variants. There also was a higher frequency of many the variants amongst men with adverse pathologic features.
A substantial proportion of biopsy-detectable CaP occurs in men with “normal” PSA levels and negative DRE. In this population, CaP risk alleles and family history are significantly associated with CaP risk and may help predict aggressive disease. Future studies are warranted to determine the utility of incorporating these variants into CaP screening programs.
PMCID: PMC3089434  PMID: 20860009
Cumulative; adverse features; prostate cancer detection
7.  Number of prostate cancer risk alleles may identify possibly ‘insignificant’ disease 
BJU international  2010;106(11):1602-1606.
To determine whether the cumulative effects of five prostate cancer risk alleles (three single-nucleotide polymorphisms [SNPs] on chromosome 8Q24 and two SNPs on chromosome 17a) could help to identify possibly ‘insignificant’ disease.
We genotyped 629 men of European ancestry who underwent radical prostatectomy at our institution between 2002 and 2007. Possibly ‘insignificant’ CaP was defined using the Ohori criteria (organ-confined, tumour volume <0.5 mL, Gleason pattern ≤4). Statistical analysis was used to compare patients with ‘insignificant’ and all other ‘significant’ cancer based upon genotype. Carrier status for the 5 SNPs were compared between patients with ‘insignificant’ disease and a separate population of 801 controls without CaP.
Overall, 38 (6.0%) patients with CaP met the Ohori criteria for ‘insignificant’ disease. Men with ‘significant’ cancer had a greater frequency of any of the five risk alleles than either patients with ‘insignificant’ disease or controls. None of the individual alleles genotyped on chromosomes 8 or 17 distinguished between ‘significant’ and ‘insignificant’ CaP. However, carriers of two or more risk alleles were more likely to have ‘significant’ disease.
Although no single risk allele distinguished ‘insignificant’ CaP, ‘insignificant’ disease was nearly three times as likely among carriers of ≤ one risk allele. Future studies are needed to further elucidate the cumulative relationship between CaP risk alleles and CaP aggressiveness.
PMCID: PMC3072834  PMID: 20590552
8q24; 17q; genetics; Ohori criteria; insignificant prostate cancer
8.  Correlation between Serum PSA and Cancer Volume in Prostate Glands of Different Sizes 
Urology  2010;76(5):1072-1076.
Although early studies showed a strong correlation between PSA and tumor volume, it has been suggested that PSA is no longer a valid marker for PCa and only correlates with prostate size. The objective of this study was to further evaluate the relationship of PSA with prostate size and tumor volume in a contemporary surgical series.
From 2003 to 2009, 1234 men with data on prostate weight and total tumor volume underwent radical prostatectomy by a single surgeon. Prostate size was classified into tertiles: small (≤41.2 grams), medium (41.3–54.5 grams) and large (≥54.6 grams). Pearson correlation coefficients were used to examine the relationship of PSA with prostate size and tumor volume across different prostate sizes.
Median preoperative PSA was 4.9 ng/ml (SD ± 4.6), mean prostate size was 51.7 grams, and mean tumor volume was 5.6 cc. PSA had a significant correlation with prostate size only at a prostate weight ≥54.6 gm (p=0.01). Regardless of prostate size, PSA had a more robust significant correlation with tumor volume than with prostate size (all p<0.0001).
PSA was significantly correlated with prostate size only in the largest prostate glands, but was significantly associated with tumor volume in small, medium, or large prostates. Thus, PSA continues to be a better marker for tumor volume than for prostate size.
PMCID: PMC2975771  PMID: 20846711
prostate cancer; prostate-specific antigen; PSA; tumor volume; pathology
9.  Does diabetes mellitus modify the association between 17q12 risk variant and prostate cancer aggressiveness? 
BJU international  2009;104(9):1200-1203.
To examine further the relationship between diabetes mellitus (DM), genotype and prostate cancer aggressiveness. Specifically, we sought to evaluate for effect modification between DM, a newly discovered prostate cancer susceptibility locus on chromosome 17q12 (single nucleotide polymorphism rs4430796) and prostate cancer features.
Patients and methods
In 593 genotyped men treated with radical prostatectomy (RP), we examined RP features stratified by DM and rs4430796 carrier status.
Despite a significantly higher body mass index among patients with DM, individual pathological features were similar between men with and without DM. Using a dominant model, 17q12 carriers were less likely to have DM and more likely to have a RP Gleason score of ≥ 7. However, the presence or absence of DM did not modify the relationship between 17q12 susceptibility alleles and pathological features.
Among 17q12 risk allele carriers, there was no significant relationship between DM and adverse tumour features. However, there were relatively few men with DM (7%) in our RP cohort, particularly compared with its 21% prevalence in the USA population aged > 60 years. It is unclear whether this reflects selection bias, genetic protection from prostate cancer among patients with DM, or both. Despite these limitations, the present data suggest that DM alone does not appear to modify any association between 17q12 risk alleles with prostate cancer features.
PMCID: PMC3168555  PMID: 19627283
17q12; single nucleotide polymorphism; diabetes; prostate cancer; aggressiveness
10.  Genetic Prostate Cancer Risk Assessment: Common Variants in 9 Genomic Regions are Associated with Cumulative Risk 
The Journal of urology  2010;184(2):501-505.
Five genetic variants along chromosomes 8q24 and 17q were previously shown to have a cumulative association with prostate cancer (CaP) risk. Our research group has previously demonstrated an association between these variants and clincopathologic characteristics. More recently, 4 additional CaP susceptibility variants were identified on chromosomes 2p15, 10q11, 11q13 and Xp11. Our objectives were to examine a cumulative risk assessment incorporating all 9 genetic variants, and to determine the relationship of the new variants with clincopathologic tumor features.
The genotype for all 9 variants was determined in 687 men of European ancestry who underwent radical prostatectomy (2002-2008) and 777 healthy volunteer controls. We compared the frequencies of these variants between CaP cases and controls and examined a cumulative model. In addition, we determined the relationship between carrier status for the 4 new variants and clinical and pathology tumor features.
CaP cases had an increased frequency of all 9 risk variants compared to controls. A cumulative model that included the 9 SNPs provided greater CaP risk stratification than a model restricted to the original 5 SNPs described. Specifically, men with ≥6 variants had a >6-fold increased risk of CaP. Although 2p15 and 11q13 carriers were more likely to have aggressive features, other clinical-pathology features were similar between carriers and non-carriers.
Genetic variants located in 9 regions have a cumulative association with CaP risk. The identification of an increasing number of SNPs may provide a greater understanding of their combined relationship with CaP risk and disease aggressiveness.
PMCID: PMC3164535  PMID: 20620408
11.  Characteristics of Prostate Cancers Detected at Prostate-Specific Antigen Levels Less than 2.5 ng/ml 
The Journal of urology  2009;181(6):2515-2519.
The Prostate Cancer Prevention Trial (PCPT) reported that 15% of men with a PSA value < 4 ng/ml and a normal digital rectal examination (DRE) have biopsy-detectable prostate cancer (PCa). However, limited published data describe the tumor features of PCa detected at very low PSA levels (< 2.5 ng/ml).
A total of 934 men underwent radical retropubic prostatectomy (RRP) by one surgeon between 2003 and 2007. Herein, we describe the clinico-pathological features of 77 patients with a preoperative PSA < 2.5 ng/ml.
Of the men with a low-PSA (<2.5 ng/ml) tumor, 51 (66%) had findings suspicious for PCa on DRE. Indications for prostate biopsy in the remainder included an elevated PSA velocity, hematospermia, and abnormal transrectal ultrasound findings. PCa was detected at transurethral resection of the prostate (TURP) in the remaining 8%. Despite their low PSA at diagnosis, 8 (10.4%) and 20 (26%), respectively, had a biopsy and RRP Gleason grade ≥7, while 7 (9%) and 6 (7.8%) had extracapsular tumor extension or positive surgical margins. Compared to men with a normal DRE, the mean tumor volume was significantly higher in those with a suspicious DRE (3.3 cc vs. 1.7 cc, p=0.018).
Despite PSA levels <2.5 ng/ml at diagnosis, a considerable proportion of men had aggressive pathology features at RRP. DRE remains an important component of early PCa detection.
PMCID: PMC3155762  PMID: 19371879
Prostate Cancer; PSA; Prostate Cancer Screening
12.  Pathologic Outcomes Associated with the 17q Prostate Cancer Risk Variants 
The Journal of urology  2009;181(6):2502-2507.
Recent studies have identified 2 distinct genetic variants along chromosome 17 (allele T of SNP rs4430796 on 17q12 and allele G of SNP rs1859962 on 17q24) that have been linked to prostate cancer (CaP) risk. Less is known about tumor pathology features in carriers of these variants.
Materials and Methods
Genotypes for regions 17q12 and 17q24 were determined for 759 Caucasian men with CaP and compared to 790 healthy control volunteers using logistic regression. For CaP patients, Fisher’s Exact tests or Kruskal-Wallis tests, when appropriate, were used to assess the relationship(s) between clinical and pathologic characteristics with 17q carrier status.
The frequencies of the 17q12 and 17q24 genetic variants were significantly higher in CaP patients compared to controls (OR 1.32 and 1.15, respectively). Eighty-three percent and 77% of CaP patients, as well as 75% and 75% of controls were carriers of the 17q12 and 17q24 variants, respectively. Carriers of the 17q12 risk variants were significantly more likely to have high-grade disease using an additive best-fit genetic model. In addition, there were trends for adverse pathologic features associated with 17q12 independent of the best-fit genetic model.
Sequence variants along 17q12 and 17q24 are present in a significantly higher proportion of our CaP cases than among our controls. Adverse pathologic features, including higher Gleason grade and pathologic stage, were more frequent among 17q12 carriers. Since these alleles may act in conjunction with variants on other chromosomes to influence CaP risk, additional research is required to determine the cumulative associations of genetic risk variants with prognosis.
PMCID: PMC3140699  PMID: 19371897
chromosome 17; genetics; prostate cancer
13.  Can Prostate Specific Antigen Velocity Thresholds Decrease Insignificant Prostate Cancer Detection? 
The Journal of urology  2010;183(1):112-116.
A controversy of current PSA-based prostate cancer screening is the overdetection of potentially insignificant prostate cancer. Because PSA kinetics have previously been linked to prostate cancer-specific mortality, our objective was to determine whether PSA velocity (PSAV) was associated with clinically significant prostate cancer.
Materials and Methods
From 1992 to 2008, 1073 men underwent radical prostatectomy with data on PSA velocity and tumor volume. “Insignificant” cancer was defined by the Ohori criteria (organ-confined, tumor volume ≤0.5 cc, no primary or secondary Gleason pattern 4 or 5). We calculated the proportion of men with pathologically “insignificant” prostate cancer, stratified by PSAV.
A preoperative PSAV >0.4 ng/ml was significantly associated with high-grade disease (p=0.008), positive surgical margins (p=0.003), and seminal vesicle invasion (p=0.007) at radical prostatectomy. The median tumor volume was also significantly higher among men with a preoperative PSAV >0.4 ng/ml/year (3.1 vs. 2.4 cc, p=0.0001). Overall, 69 (6%) met the Ohori criteria for “insignificant” cancer. Patients with a preoperative PSAV >0.4 ng/ml/year were 50% less likely to have “insignificant” disease (10% vs. 5%, respectively, p=0.003).
A PSAV threshold of 0.4 ng/ml/year distinguished between men who did or did not meet published pathology criteria for potentially “insignificant” prostate cancer. These results suggest that PSAV may be a useful adjunct in prostate cancer screening to increase the specificity for identifying patients with clinically significant disease.
PMCID: PMC3140466  PMID: 19913814
prostate cancer; insignificant; screening; PSA; PSA velocity
14.  Preoperative PSA Doubling Time is Not a Useful Predictor of Biochemical Progression Following Radical Prostatectomy 
The Journal of urology  2010;183(5):1816-1821.
Postoperative PSA doubling time (PSADT) may be used as a surrogate for prostate cancer (PCa)-specific mortality in patients with biochemical recurrence after radical prostatectomy. Less is known about the utility of preoperative PSA doubling time (PSADT) for the initial prediction of prostatectomy outcomes.
Materials and Methods
Preoperative PSADT was calculated in 1208 men from a large PCa screening study who were treated with radical prostatectomy. We then examined the relationship between PSADT with tumor features and biochemical progression-free survival (PFS).
Overall, PSADT was associated with non-organ-confined disease (OR 0.996, 95% CI 0.992–0.999, p=0.013), but not with biochemical progression (HR 1.000, 95% CI 0.998–1.001, p=0.66). Using previously published thresholds for PSADT of 18 months and 36 months, respectively, there was no significant relationship between PSADT with specific adverse pathology features or biochemical progression. Using the concordance index, PSADT did not enhance the prediction of biochemical progression beyond that achieved with a model with PSA, clinical stage and biopsy Gleason score.
In our series of men with newly diagnosed clinically localized PCa, shorter preoperative PSADT was associated with non-organ confined disease, but not with biochemical progression following radical prostatectomy. All PSA kinetics calculations may not be equivalent, and caution should be exercised in using PSADT in the pretreatment setting.
PMCID: PMC3132416  PMID: 20303104
prostate-specific antigen; PSA kinetics; doubling time; biochemical progression; radical prostatectomy
15.  Reducing blood loss in open radical retropubic prostatectomy with prophylactic periprostatic sutures 
BJU international  2009;105(12):1650-1653.
To determine whether the placement of small-calibre, rapidly absorbed prophylactic periprostatic sutures before the mobilization of the prostate could reduce blood loss during open retropubic radical prostatectomy (RRP).
In 2007, during open RRP, we began placing prophylactic haemostatic sutures of 4-0 and 3-0 plain catgut in the anterior portions of the distal neurovascular bundles (NVBs) and lateral to the proximal NVBs and prostate pedicles before initiating the nerve-sparing dissection and mobilizing the prostate gland. To evaluate whether this reduced intraoperative blood loss, we compared estimated blood loss (EBL), non-autologous transfusion rates, and postoperative haemoglobin (Hb) levels between 100 consecutive patients treated immediately before and 100 consecutive patients treated immediately after the adoption of the prophylactic periprostatic suture technique.
Before the use of prophylactic haemostatic sutures, the mean intraoperative blood loss was 1285 mL, and one patient (1%) received an intraoperative non-autologous transfusion. After the adoption of prophylactic sutures, the mean EBL was 700 mL (P < 0.001), and there were no transfusions. The mean Hb concentration the morning after RRP was 10.9 g/dL before and 11.8 g/dL after the initiation of prophylactic haemostatic sutures (P < 0.001).
Prophylactic periprostatic haemostatic sutures significantly reduce intraoperative blood loss during open RRP.
PMCID: PMC3072845  PMID: 19888968
blood loss; radical prostatectomy; prophylactic; sutures; haemostasis
16.  Is statin use associated with prostate cancer aggressiveness? 
BJU international  2009;105(9):1222-1225.
To further examine the association between statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) and pathological features in a large group of patients undergoing radical prostatectomy (RP), as epidemiological studies have suggested that statins, in addition to their beneficial cardiovascular effects, might reduce the risk of aggressive prostate cancer.
From 2003 to 2009, 1351 men with data on preoperative statin use had RP by one surgeon. The clinical and pathological tumour features were compared between 504 users of statins and 847 who were not users.
Statin users were significantly older and had a higher mean body mass index than non-users. The preoperative serum prostate-specific antigen levels, tumour volume and percentage of cancer in the RP specimen were significantly lower in patients taking statins. Overall, statin users had a proportionately lower rate of adverse tumour pathology features, including a significantly lower risk of positive (cancerous) surgical margins.
Our results suggest that the use of statins might be associated with more favourable pathological features at RP. The long-term disease-specific outcomes and the underlying link between statins and prostate cancer require further investigation.
PMCID: PMC3081618  PMID: 19888973
statins; prostate cancer; prostatectomy; pathology; aggressive
17.  Treatment Outcomes of Radical Prostatectomy in Potential Candidates for Three Published Active Surveillance Protocols 
Urology  2009;75(2):414-418.
Active surveillance (AS) protocols are designed to spare patients with ‘low risk’ prostate cancer (PCa) the potential morbidity of treatment. Our objective was to examine the treatment outcomes of men who would have been eligible for AS but rather underwent immediate radical prostatectomy (RRP).
From a prospective RRP database, we evaluated the tumor features and treatment outcomes for men who would have met one of three published AS criteria: (1) clinically localized disease, Gleason ≤ 7, and no significant comorbidities (Patel et al.) (2) T1b-T2b N0M0 disease, Gleason ≤ 7, and PSA ≤ 15 ng/ml (Choo et al.), or (3) T1c PCa (Mohler et al.).
3959, 3536, and 2330 RRP patients, respectively, would have met these AS criteria. At surgery, 3–4% had a Gleason score of 8–10, 16–19% had positive surgical margins, 15–18% had extracapsular tumor extension, 3–5% had seminal vesicle invasion, and 0.4–1% had lymph node metastasis. The 5–year progression-free survival rate ranged from 84–89%. Metastasis occurred in 0.1–1.2%, and 0.1– 0.9% died from PCa. On multivariate analysis, Gleason score > 6 was the strongest predictor of biochemical progression.
A substantial proportion of men who might have been considered potential AS candidates had aggressive tumor features at RRP and/or progression. Biopsy Gleason score > 6 was the strongest predictor of adverse outcomes, highlighting the importance of limiting active surveillance to patients with Gleason ≤ 6. Overall, the accurate identification of patients with truly indolent PCa at the time of diagnosis remains challenging.
PMCID: PMC3072831  PMID: 19963249
active surveillance; prostate cancer; prostatectomy; candidate; outcomes
18.  A genome-wide linkage study of GAW15 gene expression data 
BMC Proceedings  2007;1(Suppl 1):S87.
Recently, gene expression levels have been shown to demonstrate familial aggregation, suggesting a direct role of heritable DNA variation. We studied the gene expression levels in lymphoblastoid cells of the Centre d'Etude du Polymorphisme Humain Utah families made available to Genetic Analysis Workshop 15 (GAW15), using genome-wide linkage analyses.
Heritability was estimated for the expression levels of each individual phenotype. Genome wide linkage analysis was then performed using the 2819 SNPs for the expression levels of all the genes.
Heritability exceeded 0.21 for 50% of the expressed phenotypes. Genome-wide linkage analysis demonstrated that 19 of them reached significance after correcting for multiple comparisons, only 4 of which were reported previously. We did not identify any hot spots of transcriptional regulation when assuming LOD score > 5.3 for significant linkage evidence.
Our analysis suggests that inconsistent results in comparison to the previous report may be due to the different approaches, phenotype transformation, and different pedigree data used in the analyses.
PMCID: PMC2367464  PMID: 18466590
19.  A genome-wide linkage and association study using COGA data 
BMC Genetics  2005;6(Suppl 1):S128.
Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses.
Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs.
Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism.
Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.
PMCID: PMC1866809  PMID: 16451586
20.  Identifying genetic variation affecting a complex trait in simulated data: a comparison of meta-analysis with pooled data analysis 
BMC Genetics  2005;6(Suppl 1):S97.
We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.
PMCID: PMC1866682  PMID: 16451713

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