Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate cancer and chromosome 8p21–23. In this study, we analysed eight microsatellite (MS) markers in that region in order to confirm previous results and narrow down the location of candidate prostate cancer genes.
292 cases and 278 controls were selected from the Netherlands Cohort Study (NLCS). The following MSs were used in the analyses: D8S136, D8S1734, D8S1742, D8S261, D8S262, D8S351, D8S511 and D8S520. Associations were evaluated using a χ2 test and logistic regression. We checked for any effects on the association by tumour stage.
Associations that were found confirmed previous research that pointed to the 8p21–23 region. Two MSs: D8S136 (odds ratio (OR), 0.69; P=4.00 × 10−28), and D8S520 (OR, 0.80; P=3.37 × 10−11), were consistently and strongly related with prostate cancer. Genotype analysis showed an additive effect for D8S136 (P-trend=6.22 × 10−03) and D8S520 (P-trend=2.62 × 10−22), suggesting an increased risk for people with a short number of repeats on both alleles at those markers.
This study provides strong evidence that the 8p21–23 region is likely to harbour prostate cancer genes.
Prostate cancer was the most frequent cancer amongst men in the United States in 2012 according to research by the Surveillance, Epidemiology and End Results (SEER) project. It was estimated that 241 740 incident cases occurred, accounting for 29% of all incident cancers in men (excluding non-melanoma skin cancer).1 In Europe, prostate cancer is also the most frequent cancer amongst men. Approximately 382 251 incident cases were estimated to have occurred in the year 2008, which accounts for 22.2% of all incident cancers in men (excluding non-melanoma skin cancer).2
To date, the only known risk factors for prostate cancer are advancing age, African ancestry and family history.3 A meta-analysis of 32 epidemiological studies in 2003 showed that the risk of prostate cancer for first-degree family members increases with increasing numbers of affected relatives from 2.57 (95% confidence interval, 2.32–2.84) for men who had one first-degree family member to 5.08 (95% confidence interval, 3.31–7.79) for men who had two or more affected family members.4
A possible reason for this aggregation is inheritance of genetic variants that increase prostate cancer susceptibility. A twin study confirmed that 42% of the risk for prostate cancer may be explained by heritable factors.5 Family linkage studies have been undertaken in order to identify prostate cancer susceptibility loci. These studies have reported several candidate genes, such as HPC1,6 RNASEL,7 and BRCA2.8 Evidence for linkage on chromosome 8 is provided by two separate studies,9, 10 which both present logarithm of odds scores of 1.8 and higher in the region 8p22–23. Prostate cancer susceptibility genes in pedigrees affected with hereditary prostate cancer have also provided evidence for prostate cancer linkage on 8p.11
In addition to this, somatic mutations have been found on chromosome 8, which seemed to cluster on the short arm of chromosome 8. In particular, a number of candidate prostate cancer susceptibility genes have been located in the region of 8p22–23. Replications of the results of the candidate gene studies have been done for some such as LZTS112 and MSR1.13
Owing to the inconclusiveness of the candidate gene approach, genome-wide association studies (GWAS) have been conducted in search of prostate cancer susceptibility loci. In recent years, 19 GWAS have been published in relation to prostate cancer.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 Most of these studies found significant associations with prostate cancer on chromosome 8.16, 17, 18, 23, 24 Two recent GWAS found an association in region 8p21.2.15, 32
Despite this significant amount of evidence for an association between chromosome 8 and prostate cancer, not many new prostate cancer genes have been presented. This may be not only due to the complexity of the disease or the heterogeneity of study populations, but possibly also to the type of genetic markers that were chosen. Although single-nucleotide polymorphism (SNP) GWAS can be precise if an association is found, locating a functional SNP of interest is difficult. A microsatellite (MS) approach may offer a powerful alternative. MSs have a higher information content than SNPs, as they cover a broader band than SNPs. While a SNP only has four possible states (A, T, C or G), MSs can have many different pattern variants (number of repeats), which are also called alleles. They also have a smaller interpopulation variability.33, 34
We have previously investigated founder mutations among the Dutch and found mutations that were specific for this population, including those predisposing for hereditary breast and ovarian cancer, and malignant melanoma. We also identified short chromosomal regions that have remained identical by descent, resulting in relatively limited genetic heterogeneity within this population,35 thus increasing the power in detecting the associations among the Dutch.
MSs can be used to indicate a region that is genetically highly variable and that could have a role in cancer genesis. In other cases, such as the androgen receptor, the MS length relates directly to the disease.36
Not only is it important to detect specific MSs that are associated with prostate cancer, it is also clinically relevant to differentiate between localised and advanced tumours. Another important reason to study MSs is because they could be used as a prognostic tool.37
The present study aims to validate previous research that chromosomal region 8p21–23 is associated with prostate cancer, using a MS approach to identify specific MSs located in the region 8p21–23 associated with prostate cancer in a Dutch population, and whether this association is different for localised versus advanced tumours.
Materials and methods
Incident prostate cancer cases and controls were identified in the population of the Netherlands Cohort Study (NLCS); further details can be found elsewhere.38, 39 In brief, the NLCS includes 58 279 men aged 55–69 years at baseline in 1986. This paper reports from the data set after 8.3 years of median follow-up. A case–control nested in a cohort design was used. Cases were defined as men with histologically confirmed prostate cancer and they were identified using computerised record linkage with all nine cancer registries in the Netherlands. Prostate cancer stage, being localised (T0–2, M0) or advanced (T3–4, M0 and T0–4, M1), was reported by the cancer registries and coded according to the UICC TNM.40 Controls were selected from a random subcohort sample of 2411 men and followed up for information on vital status biennially. Case and control selection is depicted graphically in the flow diagram, Figure 1.
The NLCS cohort was linked to the Dutch pathology database (PALGA), through which paraffin blocks of tumour and normal tissue samples of prostate cancer cases were collected. For the PCRs and genotyping, only the normal tissue samples were used. After exclusion of prevalent cases and those with insufficient non-tumorous tissue, 300 cases out of 1405 were available for analysis. No difference in age (P=0.13) or family history (P=0.61) was found between the cases (N=300) and the patients that were excluded (N=1105). We obtained buccal swab samples from 300 controls from the NLCS subcohort.
PCRs were set up using a HYDRA workstation (Matrix Technologies, Hudson, NH, USA) and run on MJR Thermocyclers (MJ Research, Waltham, MA, USA), amplifying the following MSs: D8S136 (71–80 bp, 8p21.3), D8S1734 (98–120 bp, 8p21), D8S1742 (130–150 bp, 8p23), D8S261 (128–144 bp, 8p22–p21.3), D8S262 (110 bp, 8p23.2), D8S351 (109–127 bp, 8p22–23), D8S511 (238 bp, 8p22) and D8S520 (179–199 bp, 8p23.1); all MSs can be found in Figure 2.
The PCR products of cases and subcohort controls were sized on the Applied Biosystems 3730 Sequencer (Applied Biosystems, Foster City, CA, USA) in comparison with CEPH1347-02 reference specimen. Genotyping was performed using Genemapper software version 4.0 (Applied Biosystems). To ensure reliability of the results, duplicate samples and/or known genotyped samples were included in the analysis as quality controls.
The frequency distributions of important variables and potential risk factors for prostate cancer were examined for discrepancies between cases and controls. These risk factors included age at recruitment and first-degree family history for prostate cancer. Linkage disequilibrium between markers was tested by χ2 tests for all MSs.
We have carried out analyses interpreting MS alleles as both binary and continuous factors. In binary analyses, the risk of prostate cancer was assessed for those having short versus long alleles, using the most common estimated size of PCR product amongst the controls as a breakpoint.36, 39 In continuous analyses, the risk increase of prostate cancer was expressed for each base-pair increase in size of the PCR product. All analyses included odds ratio (OR) calculations by means of age-adjusted logistic regression using robust s.e. (all analyses have also been carried out using non-robust s.e., which gave the same results, only more extreme P-values; thus, the more conservative approach has been published here) and for each chromosome separately, in order to account for systematic bias. We applied a Bonferroni correction to take into account multiple testing of the eight genetic markers. Consequently, P-values <1.25 × 10−3 were considered statistically significant.
As chromosome-specific analyses are independent due to Mendelian randomisation, any consistency in results across chromosomes was interpreted as an internal validation. Subsequent analyses were only performed for validated markers. These include analyses for both chromosomes combined and separately for localised and advanced prostate cancer. We also tested for age interaction. In a last step, the validated markers were recategorised in binary genotypes (long/long, long/short and short/short). In this analysis, the long/long was considered to be the reference group. All statistical analyses were performed using Stata 12 for Mac (StataCorp 2011, College Station, TX, USA).
A false-positive report probability for the statistically significant results was estimated using the methods described by Wacholder et al.41 The prior probability used in this analysis is a subjective measure and can vary between investigators, depending on the importance that is assigned to different pieces of evidence. We have ranged the prior probability between 10 and 0.1%.
After excluding all subjects with missing data for age or MS, 292 cases and 285 controls were eligible for analysis. No major difference was detected in family history for prostate cancer between cases and controls, although the cases (63.1 years) were on average older than the controls (60.0 years), as can be seen in Table 1. No linkage disequilibrium between the markers was found (data not shown).
Table 2 shows ORs of prostate cancer by increase in size of PCR product for each MS markers presented for each chromosome separately. Interestingly, D8S136 and D8S520 had statistically significant results on both alleles. D8S511 seemed interesting as well, as it had the most extreme OR of 0.33 and a very low P-value of 3.02 × 10−11, although this result was lacking in the other allele. D8S136 had the lowest P-value for both alleles 1.97 × 10−14 and 6.61 × 10−20. Based on these analyses, only D8S136 and D8S520 were selected for further exploration.
In addition, as a sensitivity analysis, each MSs was incorporated as a dichotomised variable (long/short) as well. These analyses produced similar results, which can be found in Appendix 1.
Both markers remained significant when the analyses were repeated for both chromosomes combined (Table 3). We could not find evidence for an age interaction. Stratification by advanced versus localised prostate cancer did not produce substantially different results for D8S136 or D8S520 (Table 4).
Table 5 shows the result of the genotypic analysis for D8S136 and D8S520. Here, both D8S136 and D8S520 showed a higher OR when more than one allele was shortened. When the genotype long/long was compared with short/short, D8S136 had an OR of 17.58 and a P-value of 2.00 × 10−29 and D8S520 reports an OR of 8.79 and a P-value of 1.76 × 10−23. The effect seems to be additive for both D8S136 (P-trend=6.22 × 10−3) and D8S520 (P-trend=2.62 × 10−22).
The findings of the combined analysis for D8S520 and D8S136, presented in Table 3, remained statistically noteworthy after the false-positive report probability test, with a 8.0% probability of being false positive and a prior probability of 1%. The false-positive report probability test did not alter the noteworthiness of the result for D8S136, even with the most stringent false-positive report probability priors.
A great deal of research has been devoted to chromosome 8, particularly to its short arm, as genetic variations on this region have frequently been associated with prostate cancer. These variations usually entail a deletion. Furthermore, multiple genetic linkage studies, candidate gene association studies and GWAS have provided evidence that several prostate cancer susceptibility genes are located on chromosome 8p21–23, in addition to a number of loss of heterozygosity studies.42, 43, 44, 45 In this paper, we have analysed the association between MSs in this region and prostate cancer in a relatively homogeneous population. The positive associations of markers D8S136 and D8S520 contribute to the evidence of possible prostate cancer genes on 8p21–23.
We believe that it is likely that the observed associations for D8S136 and D8S520 are true positives (not being explained by type 1 errors) because of their high level of statistical significance, the consistent findings among both independent chromosomes and their biological plausibility, with several prostate cancer genes being located in close proximity (Figure 2). Moreover, the false report probability did not alter the noteworthiness of our results.
All significant findings are located on a small chromosomal region between 8p21.3 and 8p23.1, indicating that this region may harbour functional genetic variants. As illustrated in Figure 2, multiple putative tumour suppressor genes are indeed located in this region. Prostate cancer susceptibility gene, PG1, is a tumour suppressor gene that was associated with prostate cancer but has not been replicated by any other study.9 Lipoprotein lipase (LPL) has been associated with prostate cancer since 1994, most recently in a small study in 2009.46 Since a study in 200347 first associated macrophage scavenger receptor 1 (MSR1) with prostate cancer, there have been numerous studies into the role of this gene, yet conclusive evidence is still lacking. It is found that a deletion of leucine zipper putative tumour suppressor 1 (LZTS1/FEZ1) is associated with prostate cancer12 as well as several other cancers, such as lung48 and ovarian cancer.49 And finally, microtubule-associated tumour suppressor 1 (MTUS1/MTSG1) has recently been associated with prostate cancer.50
The results published in this paper confirm nearly a decade of previous research where researchers point to chromosome 8. Although this specific region has not received as much attention, there has been one study that pointed to the exact location in which we found our most consistent significant results, that is, 8p21.3–8p23.1, and thereby supports the importance of combining different types of research approaches.51 We describe novel findings by reporting statistically significant ORs on two different MSs.
To summarise, we were able to support the evidence that 8p21–23 is a likely region for harbouring prostate cancer genes. This will in turn provide future candidate gene research with a more specific region, and thus, a higher probability of finding prostate cancer susceptibility genes.
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This study was established with financial support from the Dutch Cancer Society and the US Department of Defense.
The authors declare no conflict of interest.
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Zeegers, M., Nekeman, D., Khan, H. et al. Prostate cancer susceptibility genes on 8p21–23 in a Dutch population. Prostate Cancer Prostatic Dis 16, 248–253 (2013). https://doi.org/10.1038/pcan.2013.9
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