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Clinical Cancer Research Vol. 11, 8391-8397, December 1, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

The Use of Genetic Markers to Determine Risk for Prostate Cancer at Prostate Biopsy

Robert K. Nam1, William W. Zhang1, Michael A.S. Jewett3, John Trachtenberg3, Laurence H. Klotz1, Marjan Emami1, Linda Sugar2, Joan Sweet4, Ants Toi5 and Steven A. Narod6

Authors' Affiliations: 1 Division of Urology and 2 Department of Pathology, Sunnybrook and Women's College Health Sciences Centre; 3 Division of Urology and Departments of 4 Pathology and 5 Medical Imaging, University Health Network; and 6 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Robert K. Nam, 2075 Bayview Avenue, MG-406, Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-5075; Fax: 416-480-6121; E-mail: robert.nam{at}utoronto.ca.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: We examined a panel of 13 polymorphisms in 13 different genes to determine whether specific genotypes can help predict prostate cancer at the time of biopsy among men prescreened with prostate-specific antigen and digital rectal exam.

Experimental Design: We examined 2,088 consecutive men who were referred for prostate biopsy from 1997 to 2003. Thirteen genes were examined, including TNF308, GSTT1, KLK2, endostatin, MCRA, MCRV, tyrosinase, MSR1, CHK2, RNasel, HOGG1-326, HOGG1-11657, and HRAS1. Odds ratio for detection of prostate cancer were adjusted for age, race, prostate-specific antigen, digital rectal exam, family history of prostate cancer, and urinary symptoms.

Results: Of the 2,088 men, 996 (47.7%) had cancer detected. Four genes (TNF308, GSTT1, KLK2, and HOGG1-326) were significantly associated with prostate cancer. The adjusted odds ratios (OR) for prostate cancer for patients with the AA genotype of the TNF308 gene was 1.92 [95% confidence interval (95% CI), 1.0-1.5, P = 0.05], compared with those with the GG genotype, and for patients with the TT genotype of the KLK2 gene, the OR was 1.5 (95% confidence interval, 1.0-2.2, P = 0.04), compared with the CC genotype. The OR for patients with a homozygous deletion of the GSTT1 gene was 0.81 (95% CI, 0.6-1.0, P = 0.06) compared with those with the deletion, and the OR for patients with the GG genotype of the HOGG1-326 gene was 0.68 (95% CI, 0.5-1.0, P = 0.05) compared with the CC genotype. Patients who had all four alleles that were positively associated with prostate cancer had an OR of 9.33 (95% CI, 2.4-35.8, P = 0.0005) for prostate cancer compared with patients with alleles that were negatively associated with prostate cancer.

Conclusions: Of the 13 polymorphisms, two were found to be positively associated with prostate cancer (TNF308 and KLK2) and two were negatively associated with prostate cancer (GSTT1 and HOGG1-326). Future studies are required to confirm these results.

New biomarkers for prostate cancer detection are needed. Currently, the measurement of serologic levels of prostate-specific antigen (PSA) is used to screen for prostate cancer (1). Although many new serologic markers for prostate cancer have been evaluated as an adjunct test to PSA (2, 3), there are a limited number of studies examining genetic-based factors.

Many association and linkage studies have been conducted for prostate cancer but no single genetic mutation has been found to be strongly associated with the risk of prostate cancer. There have been numerous studies examining the association between specific polymorphisms of candidate genes and prostate cancer. However, these studies have mainly been case-control or nested-case control study designs (4–29).

Although a number of these polymorphisms have been positively associated with prostate cancer, no clinical test is in current use based on these results. The reasons are 2-fold; first, the odds ratios (OR) for having prostate cancer based on these polymorphisms are generally not very high (often <2). The second reason is a lack of replication of results. No study has examined these polymorphisms in a clinical setting with a large sample of patients.

Our goal is to determine whether one or more genetic polymorphisms can be used to predict prostate cancer risk (8, 22, 23). We previously reported a panel of 11 polymorphisms found by others to be associated with increased prostate cancer risk. We determined whether these factors could predict the presence of prostate cancer among 1,031 patients who were referred for a prostate biopsy (22). Polymorphisms in the KLK2 and GSTT1 genes were found to be associated with prostate cancer risk (OR, 2.1 and 0.6, respectively; refs. 22, 23).

We now report on a larger study of 2,088 patients and have reexamined these two polymorphisms, and have studied 11 additional polymorphisms in determining prostate cancer risk among patients requiring a prostate biopsy.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Study subjects. Patients were drawn from a consecutive sample of 2,250 eligible men who were referred to two Prostate Centers at the University of Toronto (University Health Network and Sunnybrook and Women's College Health Sciences Centre), between June 1998 and January 2003, because of either a PSA value of >4.0 ng/mL or because of an abnormal digital rectal exam (DRE). In Ontario, there are no formal criteria for PSA screening but the practice is widespread. No patient had a history of prostate cancer before prostate biopsy and no patients were included who were referred for tertiary management.

Of the 2,250 patients, 2,088 (93%) consented to participate in the study. Blood samples were collected before clinical prostate examination. A urological history, which included the American Urological Association Symptom Score describing the severity of lower urinary tract voiding symptoms, was obtained (30). The results of DRE were recorded. Systematic ultrasound-guided needle biopsies obtaining 6 to 13 samples (median = 8) were done by using an 18-gauge spring-loaded biopsy device. The primary end point was the histologic presence of adenocarcinoma of the prostate in the biopsy specimen. Grade was evaluated by the Gleason scoring system (31). All research was conducted with informed consent and with the approval of the hospital research ethics board.

Genetic analysis. DNA samples from each patient were extracted from peripheral blood leukocytes using standard protocols. Thirteen polymorphisms were examined, including the TNF, GSTT1, KLK2, endostatin, MC1R-160, MC1R-92, tyrosinase, MSR1, CHK2, RNasel, HOGG1-326, HOGG1-11657, and HRAS genes (21–29, 32, 33), with each method and primers detailed in Table 1. To ensure for quality control of the restriction digests, we randomly duplicated 25% of samples for comparison for each polymorphism. All gel readers were blinded to the primary end point and covariates.


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  		Table 1. Summary of polymorphisms of the 13 candidate genes including method of DNA analysis and upstream/downstream primers used

 
Serologic analysis. Both free and total PSA levels were measured using commercially available kits done on the Immulite chemiluminescense immunoassay system (Diagnostic Products Corporation, San Diego, CA) according to the recommendations of the manufacturer.

Data analysis. Cases were defined as patients with adenocarcinoma of the prostate at biopsy. Controls were those with no evidence of cancer at biopsy. We compared the frequencies of the candidate polymorphic variants between prostate cancer cases and controls. The association between the polymorphisms and prostate cancer were examined using univariate and multivariate logistic regression modeling, controlling for age, serum PSA level, DRE, family history of prostate cancer, ethnic background, and the presence of lower urinary tract voiding symptoms.

The TNF, endostatin, MC1R-160, MC1R-92, tyrosinase, MSR1, RNasel, HOGG1-326, and HOGG1-11657 genes were categorized according to zero, one, or two variant alleles: (a) TNF, GG/GA/AA (21); (b) KLK2, CC/CT/TT (23); (c) endostatin, DD/DN/NN (24); (d) MC1R-160, AA/AT/TT (25); (e) MC1R-92, VV/VM/MM (26); (f) tyrosinase, CC/CA/AA (26); (g) MSR1, NN/NM/MM (32); (h) RNasel, GG/GA/AA (33); (i) HOGG1-326, CC/CG/GG (28); and (j) HOGG1-11657, AA/AG/GG (28). The GSTT1 gene was dichotomized into either homozygous deletions (zero) or at least one nondeleted allele (one), according to Rebbeck et al. (20), who showed a positive association between the nondeleted genotype of the GSTT1 gene and prostate cancer risk. The CHK2 gene was examined for the 1100delC mutation and was dichotomized into present or absent (27). HRAS was categorized into the presence of zero, one, or two common alleles (29).

Total serum PSA level was categorized into four groups: (a) ≤4.0 ng/mL; (b) 4.1-10.0; (c) 10.1-20.0 ng/mL; and (d) >20.0 ng/mL. DRE was dichotomized into normal or abnormal. Lower urinary tract symptoms were dichotomized as present or absent. Ethnicity was categorized into four groups: (a) Caucasian; (b) Black; (c) Asian; and (d) other. Family history of prostate cancer was defined as having at least one or more relatives with a history of prostate cancer.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The mean age at biopsy of the 2,088 men was 65.0 years (range, 39.9-93.8 years). The mean PSA level was 11.0 ng/mL (range, 0.1-498.8 ng/mL), whereas 52.3% had a normal DRE. The majority of the patients were White (1724, 82.6%); however, 212 (10.2%) and 99 (4.7%) were Black and Asian, respectively. Fourteen percent of patients had at least one relative with prostate cancer. More than half of the patients (56.8%) reported no obstructive voiding symptoms (i.e., they were asymptomatic).

Of the 2,088 men, 996 (47.7%) men were found to have adenocarcinoma of the prostate at biopsy (cases) and 1,092 (52.3%) men had no evidence of invasive cancer (controls). The mean age of the cases (66.2 years) was higher than that of the controls (63.8 years, P = 0.0001). Cases were more likely to have had an abnormal DRE, and on average, had a higher PSA level than controls (Table 2). Asians had a lower rate of prostate cancer than Whites or Blacks and patients with voiding symptoms were less likely to have prostate cancer (Table 2).


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  		Table 2. Frequency distribution of established risk factors for prostate cancer among cases and controls

 
Of the 13 polymorphisms, four (TNF, GSTT1, KLK2, and HOGG1-326) were associated with prostate cancer at the level of P = 0.05 but none were found to be significant at the P = 0.01 level (Table 3). The distributions of the genotypes of the other nine polymorphisms were similar between cases and controls.


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  		Table 3. Frequency distribution of the 13 polymorphic genotypes among cases and controls

 
Of the four genes that were associated with prostate cancer, there were significant differences in the distribution of the genotypes by ethnic backgrounds (Table 4). The rare genotypes were less common among Asians except for the HOGG1-326 polymorphism. The distributions of the genotypes of the other nine polymorphisms were also different between ethnic groups but there were no significant associations found with prostate cancer. When we restricted the study to White subjects, the TNF and KLK2 polymorphisms were significantly positively associated with prostate cancer. However, for the GSTT1 and HOGG1-326, there were no significant differences among Whites. Both polymorphisms were negatively associated with prostate cancer among Asians.


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  		Table 4. Frequency distribution of genotypes by ethnic background of four positive genes

 
After adjusting for the established factors associated with prostate cancer in a multivariate model, including age, ethnicity, family history of prostate cancer, DRE, and PSA, the four polymorphisms were still significantly associated with prostate cancer (Table 5). The ORs for prostate cancer for patients with the rare genotype compared with patients with the common genotype ranged from 0.7 to 1.9 (Table 5).


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  		Table 5. Adjusted ORs for four positive candidate genes according to their variant alleles

 
To determine whether these polymorphisms could predict prostate cancer in a clinical setting, we examined all possible combinations of the genotypes for the four positive polymorphisms and calculated the probability for having prostate cancer based on these combinations (Table 6). We defined high-risk alleles as those of the four genes to be associated with increased probability for prostate cancer, and low-risk alleles as those of the four genes to be associated with a decreased probability for prostate cancer. For patients who carried all four high-risk alleles, 64.0% had prostate cancer (n = 25). For patients with all four low-risk alleles for prostate cancer, 16.0% had prostate cancer (n = 25). The crude OR for having prostate cancer was 9.33 [95% confidence interval (95% CI), 2.4-35.8, P = 0.0005] for patients with the high-risk alleles compared with patients with the low-risk alleles (Table 6). When restricted to White subjects, for patients with all four high-risk alleles, 66.7% had prostate cancer (n = 13); for patients with all low-risk alleles, 30.8% (n = 15) had prostate cancer (crude OR, 4.50; 95% CI, 1.0-22.1, P = 0.05).


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  		Table 6. Probabilities for cancer based on combinations of four positive genes by each allelic combination

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We studied associations between polymorphisms of 13 candidate prostate cancer genes and the probability for prostate cancer among a group of men prescreened with PSA and DRE. Among these, four genetic polymorphisms (TNF, GSST1, KLK2, and HOGG1-326) were associated with prostate cancer at biopsy. The variant alleles for the TNF and KLK2 genes were positively associated with prostate cancer (adjusted ORs of 1.9 and 1.5, respectively), whereas the variant alleles for the GSST1 and HOGG1-326 genes were negatively associated with prostate cancer (adjusted ORs 0.8 and 0.7, respectively). In this patient population, combinations of these four variant alleles significantly changed the predictive value for having prostate cancer at biopsy. However, these findings will need validation in future studies before they can be introduced into clinical practice. Further identification of new polymorphisms will be needed to increase the number of patients with variant alleles and where the predictive value can exceed that of current markers, such as PSA.

Numerous studies have examined the association between specific polymorphisms of candidate genes and prostate cancer. These studies have mainly been case-control or nested-case control study designs with some studies using control groups where the absence of cancer was not definitively established (4–29). The primary advantage from our cross-sectional study is that the cases and controls originated from the same population of men (those with an abnormal PSA or DRE). All control patients had one or biopsies to establish the absence of cancer from the same group as the cases. Thus, our results could have clear clinical applications by these markers because they can be applied to men referred for consideration of a prostate biopsy because of an elevated PSA or DRE.

We chose 13 polymorphisms from genes that have been linked to increased prostate cancer risk in the past. In previous studies, we showed that the GSTT1 and KLK2 polymorphisms were associated with prostate cancer (22, 23) and we wished to study these genes in a larger group. We chose the MSR1, RNasel, and CHEK2 polymorphisms as they have been found from linkage studies (27, 32, 33). The TNF (21), MCR (25), HOGG (28), endostatin (24), and tyrosinase (26) polymorphisms were found from large associations studies that found strong relationships with prostate cancer.

The highly polymorphic HRAS1 minisatellite locus just downstream from the proto-oncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles. Krontiris et al. (34) found previous associations of the rare mutant alleles with many forms of cancer, including a possible association with prostate cancer. This polymorphism also has shown strong associations with other androgen-dependent malignancies (29).

None of the three genes found to be associated with familial prostate cancer risk through linkage studies, including RNasel (33), MSR1 (32), and CHEK2 (27), were found to predict prostate cancer at biopsy. Even among men with a positive family history of prostate cancer status, there were no significant differences observed in the frequency of genotypes between cases and controls (data not shown). Further sequencing of these loci may identify other relevant polymorphisms.

The four genes found to be associated with prostate cancer have been implicated to play important roles in carcinogenesis. The role of the glutathione transferase enzymes has been well established in regulating oxidative stress and cancer development (18). The HOGG1 DNA repair enzyme is important in regulating oxidative damage to DNA (28). Further, the role of tumor necrosis factor and the kallikrein family may each have independent roles in paracrine mechanisms for promoting carcinogenesis within the prostate epithelium (21, 23).

A limitation of our study is the potential misclassification of our controls. Patients with no evidence of cancer at biopsy have a 15% to 30% chance of having cancer detected at repeat prostate biopsy (35–41). However, several other established risk factors, including age, ethnicity, family history of prostate cancer, DRE, and PSA, were found to be strongly predictive of prostate cancer in this patient population. The effect of misclassifying controls would bias our results toward a null finding.

For a large number of the polymorphisms, there were significant differences in the allelic frequencies between ethnicities. However, when we adjusted for ethnicity within the multivariate model, the ORs for prostate cancer did not significantly change for the four positive polymorphisms.

Our objective was to determine whether these genetic factors would be an important adjunct to demographic and serologic factors to enhance the ability to detect prostate cancer in a clinical setting for any patients. It is important to note that these results apply only to men faced with an abnormal PSA or DRE, rather than the general population, with the eventual goal to provide adjunctive tests based on selected polymorphisms to increase the positive predictive value for prostate cancer. Among the combination of the four polymorphisms found to be associated with prostate cancer, we found that patients who had the variant alleles with increased risk (TNF and KLK2) and who lacked the variant alleles with decreased risk (GSTT1 and HOGG1) had a 9-fold increase in risk compared with patients who did not have any of the variant alleles. However, the number of patients who had this combination was small and adjustment by ethnicity could not be done. Nevertheless, when restricted to White subjects, the combination of the four high-risk alleles was still predictive of prostate cancer (OR, 4.5; P = 0.05). Indeed, examining various combinations of the genotypes may provide a useful platform to determine which patients require further biopsy or who do not need biopsy. Further study will be required to confirm these results in a separate patient population. This approach can be applied to other polymorphisms linked to prostate cancer.

In summary, from this article and from our previous study (22), we found 4 of 22 polymorphisms studied to date to be associated with prostate cancer at the time of prostate biopsy. Future larger studies will be required to evaluate these and other polymorphic variants implicated to be associated with prostate cancer.


   Footnotes
 
Grant support: National Cancer Institute of Canada grants 010284 and 015164, and Canadian Urological Association Young Investigators Award (R.K. Nam).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 8/05; revised 8/ 4/05; accepted 9/21/05.


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