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Clinical Cancer Research 13, 839, February 1, 2007. doi: 10.1158/1078-0432.CCR-06-2164
© 2007 American Association for Cancer Research
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Human Cancer Biology

Germline Mutations in the BRCA2 Gene and Susceptibility to Hereditary Prostate Cancer

Ilir Agalliu1, Erika M. Kwon3, Daniel Zadory3, Laura McIntosh1, Joseph Thompson3, Janet L. Stanford1,2 and Elaine A. Ostrander3

Authors' Affiliations: 1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; 2 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington; and 3 Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland

Requests for reprints: Elaine A. Ostrander, Cancer Genetics Branch, National Human Genome Research Institute, 50 South Drive, MSC 8000, Room 5351, Building 50, Bethesda, MD 20892. Phone: 301-594-5284; Fax: 301-594-0023; E-mail: eostrand{at}mail.nih.gov.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Several epidemiologic studies have reported that carriers of germline mutations in the BRCA2 gene have an increased risk of prostate cancer, with the highest risk observed in men diagnosed at earlier ages. However, studies of the contribution of BRCA2 mutations to the etiology of hereditary prostate cancer (HPC) have been inconsistent.

Experimental Design: To further address this issue, 266 subjects from 194 HPC families participating in the Seattle-based Prostate Cancer Genetic Research Study were screened for BRCA2 mutations by sequencing the coding regions, intron-exon boundaries, and suspected regulatory elements of this gene. Of selected HPC families, 32 had multiple breast or ovarian cancer cases, 16 were Jewish, 8 had a pancreatic cancer case, and 138 had at least one affected man diagnosed with prostate cancer at an early age (<60 years).

Results: No disease-associated protein truncating BRCA2 mutations were found in 266 subjects from HPC families. There were 61 DNA sequence variants, of which 31 (50.8%) changed the predicted amino acids. No associations were found between these missense changes and family characteristics. Among affected men with prostate cancer, there were no statistically significant differences between the genotype frequencies of DNA variants with a minor allele frequency of 1% or higher and between the strata defined by median age at diagnosis or by clinical features.

Conclusion: No evidence was found in this study for an association between BRCA2 mutations and susceptibility to HPC in men selected from high-risk families.

An estimated 10% of all prostate cancers cluster in families and is presumed to be hereditary (1). Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, and attempts to identify genes that confer a high risk for prostate cancer, such as the BRCA1 and BRCA2 genes for breast and ovarian cancer, have been challenging (2–4). The BRCA2 gene has been the focus of investigations of prostate cancer etiology for several reasons. First, studies of cancer clusters in families, identified as those with three or more affected individuals, have reported the co-occurrence of breast, ovarian, and prostate cancers (5–10), which may reflect a shared susceptibility. Moreover, families with carriers of BRCA2 mutations, in addition to having a higher risk of breast and ovarian cancers, also have an increased relative risk of prostate cancer (5- to 8-fold elevations) among men with protein truncating BRCA2 mutations (11–17). These studies suggest that the risk is higher in men diagnosed with prostate cancer at earlier ages (<60 years), and that mutations in the BRCA2 gene may be important in prostate cancer susceptibility. However, few studies have assessed the contribution of such mutations in HPC families, and results have been inconsistent across studies (18–20). The goal of the current study was to further examine the role of BRCA2 mutations in a large collection of well-characterized HPC families.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Study population. Subjects (n = 266) included in this study were selected from 194 HPC families participating in the Seattle-based Prostate Cancer Genetic Research Study and are a subset of 254 HPC families described previously for a genome-wide scan analysis (21). In these 194 HPC families, the average number of sampled affected men (i.e., men with prostate cancer who also provided a blood sample) per family was 3.4 (range, 2-11), and 145 (75%) families had three or more sampled affected men per family. The median age at prostate cancer diagnosis was 63.4 years.

The selection of study subjects for this analysis was based on several criteria with the goal to enrich the sample set with subjects who theoretically may have a higher probability of harboring germline BRCA2 mutations. Families that met the criteria for BRCA2 screening had one of the following characteristics: families with multiple breast cancer cases (breast cancer cases are genetically related to prostate cancer cases) or an ovarian cancer case in a first-degree relative to a prostate cancer case (n = 32), families with Jewish ancestry (n = 16), or families with a pancreatic cancer case (n = 8). In the remaining 138 HPC families, men with younger ages at diagnosis (<60 years) were oversampled with the goal to select two affected men per family. Of these 138 HPC families, 34 had at least two sampled affected men diagnosed with prostate cancer at ages <60 years, and 104 had one sampled affected man diagnosed at ages <60 years and another randomly selected affected man diagnosed at ages <75 years. The median age at prostate cancer diagnosis for the sampled affected men selected from these 138 HPC families was 57 years. When considering the above criteria, there was some overlap between families. Three families with multiple breast or ovarian cancer cases were also Jewish or reported a pancreatic cancer case, and one Jewish family had a family member with pancreatic cancer. In addition to affected men with prostate cancer, women with breast or ovarian cancer or subjects with pancreatic cancer were selected for BRCA2 screening if DNA was available (n = 13). The study was approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center and the National Human Genome Research Institute, and written informed consent was obtained from study participants.

BRCA2 gene sequencing. Genomic DNA was extracted as described previously (21, 22). All coding and noncoding regions of the BRCA2 gene were screened for mutations using 47 primer pairs described previously (23). Exons 5 and 6 were amplified in a single fragment, and longer exons were amplified as subfragments. There were five fragments for exon 10 (10A-10E), 16 fragments for exon 11 (11A-11P), and two fragments for each of the following exons: 14 (14A and 14B), 18 (18A and 18B), and 27 (27A and 27B). PCR reactions were done in a 10 µL volume containing 5 ng of genomic DNA, 1 mmol/L deoxynucleotide triphosphates, 1.5 or 2.5 mmol/L MgCl2, 1 µmol/L of both the forward and reverse primers, and 0.25 unit Amplitaq DNA polymerase (Applied Biosystems, Foster City CA).

PCR products were treated using the ExoSAP-IT method (U.S. Biochemical Corp., Cleveland, OH). DNA-sequencing reactions were carried out using BigDye Terminator v3.1 Cycle Sequencing kits (Applied Biosystems) and sequence data were obtained on both forward and reverse PCR primers using the ABI 3730xl Genetic Analyzer (Applied Biosystems). Contigs were assembled using PhredPhrap/Consed (24). Variants were detected using Polyphred (25) and MutationSurveyor4 by three independent researchers. All variants were unanimously confirmed.

Statistical analyses. {chi}2 tests were used to evaluate whether the distribution of genotype frequencies for single nucleotide polymorphisms (SNP) in the BRCA2 gene were different among four groups of families [i.e., those with multiple breast or ovarian cancers, Jewish heritage, pancreatic cancer, or HPC families with at least one affected man diagnosed at an early age (<60 years)]. We also examined genotype frequencies for SNPs with a minor allele frequency of ≥1% among affected men with prostate cancer, stratified by age at diagnosis (the median age at prostate cancer diagnosis of genotyped affected men was used as the cutoff point), or by clinical features of prostate cancer using {chi}2 tests. To group prostate cancers into categories of aggressive versus less aggressive clinical features, we used the definition of aggressive disease described previously (22), which included regional or distant stage disease, or a Gleason score of 7 to 10, or a diagnostic serum prostate-specific antigen >20 ng/mL, or death from metastatic prostate cancer at ages <65 years. Subjects with missing data due to failed sequencing of the BRCA2 gene were excluded from the respective analysis. SAS version 9.1 (SAS Institute, Cary, NC) was used for statistical analyses.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Most of the 266 individuals screened for BRCA2 mutations in this study were men with prostate cancer (n = 253). The median age at diagnosis of prostate cancer was 58 years, and 47% of the cases were categorized as having aggressive prostate cancer. Descriptive characteristics of study subjects are provided in Table 1 . HPC families were assigned to one of the four categories: those with multiple breast cancers or ovarian cancer in first-degree relatives to a prostate cancer case (n = 32), families with Jewish heritage (n = 16), families with a pancreatic cancer case (n = 8), and other HPC families (n = 138) that included at least one case diagnosed with prostate cancer at ages <60 years. As expected, the median age at diagnosis among affected men in the last group of HPC families was younger (57 years) compared with the other three groups of families. The distribution of aggressive clinical features of prostate cancer was not different across families, except the Jewish prostate cancer cases were more likely to have less aggressive clinical features.


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  		Table 1. Characteristics of 266 subjects from 194 HPC families selected for BRCA2 screening

 
No disease-associated protein truncating mutations in the BRCA2 gene were found in any of the 266 subjects tested from these 194 HPC families. There were 61 DNA sequence variants detected: one SNP was in the 5' untranslated region of exon 2; 8 (13.2%) SNPs were intronic; 31 (50.8%) SNPs resulted in amino acid changes; and 21 (34.4%) synonymous SNPs were in the coding regions of the BRCA2 gene. Eleven SNPs were unique to this study population and were not previously reported in the Breast Cancer Information Core database.5 Of the 61 SNPs found in this study, 13 (21%) had a minor allele frequency of ≥1%; and of these, five resulted in an amino acid change. The frequency distribution of SNPs with a minor allele frequency of ≥1% was not different according to family characteristics (data not shown). Table 2 summarizes the frequency distribution of SNPs with a minor allele frequency of ≥1% among affected men, by median age at prostate cancer diagnosis and by clinical features. As shown, the distribution of these SNPs did not differ by age at diagnosis or by more aggressive features of prostate cancer.


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  		Table 2. Distribution of SNPs with a minor allele frequency of ≥1% among 253 affected men, by age at diagnosis and disease aggressiveness

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, 266 subjects from 194 HPC families were screened for germline mutations in the BRCA2 gene by sequencing the coding regions, intron-exon boundaries, and suspected regulatory elements of this gene, with the goal of estimating the frequency and contribution of BRCA2 mutations and variants to HPC susceptibility. HPC families were selected to maximize the possibility of finding BRCA2 disease-associated mutations and included families with multiple breast cancers or ovarian cancer, with a pancreatic cancer case, with Jewish heritage, or HPC families with men diagnosed at earlier ages (<60 years). However, no disease-associated BRCA2 mutations were found.

Two other studies of BRCA2 and HPC have reported similar findings to ours (18, 19). In a small study of 18 Ashkenazi Jewish families, each having at least three first-degree relatives affected with prostate cancer, Wilkens et al. (18) reported no BRCA2 mutations among affected men; however, one unaffected man, aged 44 years, was positive for the 6174delT Ashkenazi Jewish founder mutation. In addition, Sinclair et al. (19), in an analysis of 43 individuals from 22 HPC families with at least three affected men, also selected for at least two cases of breast and/or ovarian cancers in the families, found no BRCA2 protein-truncating mutations. Only one study by Gayther et al. (20), in an analysis of 38 affected individuals from HPC families with two to five affected men per family, reported a prevalence of 5.3% for BRCA2 protein truncation mutations. In this study, the two men with BRCA2 mutations were diagnosed with prostate cancer at ages ≤56 years, and both had a brother with prostate cancer.

Other epidemiologic studies based on selection of breast and/or ovarian cancers in the families have reported that male members carrying BRCA2 mutations have an increased relative risk (RR) of prostate cancer (11–17). In the Breast Cancer Linkage Consortium (11) cohort of 173 breast and/or ovarian cancer families, there was a RR of 4.7 [95% confidence interval (95% CI), 3.5-6.2] for prostate cancer among BRCA2 mutation carriers. In that study, the RR was higher in men diagnosed at ages <65 years (RR, 7.3; 95% CI, 4.7-11.5). A Finnish study of 107 breast or ovarian cancer families (14) reported a 5-fold increase in the RR of prostate cancer among BRCA2 mutation carriers (RR, 4.9; 95% CI, 1.8-11.0). Similar findings were reported by Tulinius et al. (13) in an analysis of 995 breast cancer pedigrees from Iceland. In that study, first-degree male relatives of breast cancer cases carrying BRCA2 mutations had a RR of 4.8 (95% CI, 3.3-6.3) for prostate cancer (13).

Finally, Edwards et al. (26) evaluated the contribution of BRCA2 mutations to early-onset sporadic prostate cancer among a case series of 263 men in the United Kingdom diagnosed at ages ≤55 years, who were not selected on the basis of either breast or prostate cancer family history. They reported a prevalence of BRCA2 protein truncation mutations of 2.3% (95% CI, 0.8-5.0%) and an estimated RR of 23.0 (95% CI, 9.0-57.0). Interestingly, prostate cancer cases (n = 6) carrying BRCA2 mutations had an average age at diagnosis of 49.3 years, and most had no family history of prostate cancer (five of six) or breast cancer (four of six).

Although several DNA sequence variants were observed in this study, the majority of missense changes were rare and only five had a minor allele frequency of ≥1% in our subjects. Among affected men with prostate cancer, we observed no statistically significant differences in the frequency distributions of these SNPs by median age at diagnosis or by clinical features. The clinical significance of SNPs resulting in amino acid changes remains uncertain in hereditary prostate cancer. However, we only genotyped affected men with prostate cancer and a small number of individuals with the other cancer sites. Therefore, we do not have genotyping data from unaffected men of similar age to affected men within these families to evaluate the potential association of BRCA2 missense changes with risk of HPC.

Although the majority of BRCA2 missense changes observed in this study had been reported previously (27–29), little is known about the functional activity of these SNPs and their role in prostate cancer. Some investigators have used structural assays to predict the effect of missense changes on the RAD51 binding site in the BRCA2 gene (28, 29). RAD51 is an essential protein for error-free double-strand DNA break repair (DSB repair) that interacts directly with BRCA2 (30–32). This interaction occurs in the eight repeats of the ~40 amino acids, known as BRC motifs in exon 11 (33–37). Because the region of BRC motifs is well-conserved evolutionary (36), this supports the hypothesis that this region plays an important role in protein function. In our study, there were 10 missense changes in the BRC motifs region. Six of these variants, however, were observed only once among 266 subjects resulting in a minor allele frequency of 0.4%. The remaining four SNPs occurred at frequencies of 6.4% (N991D), 1.5% (D1420Y), 0.8% (D1902N), and 5.6% (T1915M), respectively. There were no significant differences in the genotype frequencies of these SNPs by age at diagnosis of prostate cancer or by aggressive features; hence, their role in HPC susceptibility remains unknown.

In conclusion, the results of this study suggest that mutations in the BRCA2 gene do not play a major role in explaining HPC susceptibility among men from high-risk families.


   Acknowledgments
 
We thank the family members of the Prostate Cancer Genetic Research Study for their ongoing participation in this research.


   Footnotes
 
Grant support: National Cancer Institute grant R01-CA80122, Prostate Cancer Foundation, Fred Hutchinson Cancer Research Center, and Intramural Program of the National Human Genome Research Institute.

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.

4 http://www.softgenetics.com/mutationSurveyor.html Back

5 http://research.nhgri.nih.gov/projects/bic/ Back

Received 8/30/06; revised 10/24/06; accepted 11/14/06.


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