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[Cancer Research 60, 1371-1375, March 1, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

BRCA1 and BRCA2 Have a Limited Role in Familial Prostate Cancer1

Colleen Schehl Sinclair, Rebecca Berry, Daniel Schaid, Stephen N. Thibodeau2 and Fergus J. Couch

Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidemiological studies have suggested that the breast cancer susceptibility genes, BRCA1 and BRCA2, may be involved in the development of prostate cancer. Several studies have screened prostate cancer populations for the presence of BRCA1 and BRCA2 mutations, with few mutations identified. In this study, 22 high-risk prostate cancer families (at least three cases of prostate cancer) were screened by conformation-sensitive gel electrophoresis (CSGE) for mutations in BRCA1 and BRCA2. To maximize the chance of finding mutations in these two genes, families were also selected for the presence of at least two cases of breast and/or ovarian cancer. We identified one previously reported BRCA2 missense mutation and two previously unreported BRCA2 intron polymorphisms. No BRCA1 or BRCA2 truncating mutations were detected. Thus, BRCA1 and BRCA2 appear to have a limited role in familial prostate cancer, and families with both prostate and breast cancer may result from mutations in other predisposition genes.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidemiological studies of prostate and breast cancer have suggested that a clustering of these cancers occurs in certain families (1, 2, 3, 4, 5) . In fact, one of the strongest risk factors for both prostate cancer and breast cancer is family history. Although the search for dominantly inherited prostate cancer susceptibility genes continues, some evidence suggests that the breast cancer susceptibility genes, BRCA1 (6) and BRCA2 (7 , 8) , may play a role in prostate cancer development. Mutations in these genes account for 20–50% of familial breast cancer and >80% of familial breast and ovarian cancer (9) . Both genes are also associated with elevated risks of prostate (10, 11, 12, 13) , pancreatic (11 , 13 , 14) , and hepatocellular (12) cancers.

In an early study of seven large Icelandic breast cancer families, two with linkage to BRCA1, prostate cancer was second to breast cancer in occurrence (15) . In the two BRCA1-linked families, 44% of the presumed paternal carriers of BRCA1 mutations had been diagnosed with prostate cancer. Additional evidence for the involvement of BRCA1 in prostate cancer was identified in a cooperative study of 33 BRCA1-linked families (16) . An estimated relative risk of prostate cancer of 3.33 was calculated for men carrying a BRCA1 mutation when compared with the general population. A relative risk of 2.89 was later identified by Easton et al. (17) for men carrying a mutant BRCA2 gene. Recently, a relative risk of prostate cancer of 7.33 was reported for men <65 years of age carrying a mutant BRCA2 gene (13) .

In light of the apparent elevated relative risk of prostate cancer associated with BRCA1, a number of prostate cancer populations have been screened for BRCA1 and BRCA2 mutations to assess the possible role of these genes in the development of prostate cancer. Forty-nine men <65 years of age from a population-based case-control study of prostate cancer were screened for germ-line BRCA1 mutations (18) . One protein truncating mutation, the Ashkenazi Jewish founder mutation 185delAG, and six rare sequence variants in coding and noncoding regions were identified from the population. Recently, Uchida et al. (19) studied 24 prostate cancer samples and found only 1 to contain a BRCA1 mutation. This particular sample came from a man whose sister died of ovarian cancer at age 57. In a separate study, Edwards et al. (20) screened for allelic loss of markers, both flanking and within the BRCA2 gene. Of the 73 sporadic and familial prostate cancer samples screened, 11 had loss of one marker and 6 had loss of more than one marker. The 17 samples with loss of a marker were associated with a poorer prognostic phenotype. There was, however, no statistically significant difference in the frequency of allelic loss between sporadic cases, 24% (10 of 41), and familial cases, 22% (7 of 32).

The BRCA1 185delAG mutation was first identified in Ashkenazi Jewish breast and ovarian cancer families and is estimated to be carried by 0.9% of the Ashkenazi population (21) . 185delAG and the BRCA2 6174delT mutation, which is found in 1% of the Ashkenazi population (22) , are considered founder mutations in this ethnic population. Lehrer et al. (23) screened 60 Ashkenazi Jewish men with prostate cancer for both the 185delAG and the 6174delT mutations to determine whether these mutations had a role in prostate cancer in this population. None of the men screened carried either of the mutations. Wilkens et al. (24) screened 47 individuals from 18 Ashkenazi Jewish families with three or more first-degree relatives with prostate cancer for the BRCA1 185delAG and 5382insC and BRCA2 6174delT mutations. Only one unaffected individual carried a mutation, 6174delT. In a more recent study, Nastiuk et al. (25) screened Ashkenazi Jewish prostate cancer patients, those diagnosed with the disease at a young age, for the 185delAG and 6174delT mutations. One of the 83 patients carried the 185delAG mutation. Similarly, 1 of the 82 patients carried the 6174delT mutation. Both Wilkens et al. (24) and Nastiuk et al. (25) suggest that mutations in BRCA1 and BRCA2 do not have a significant role in prostate cancer in the Ashkenazi Jewish population.

Several studies have also examined the role of the BRCA2 Icelandic founder mutation, 999del5, in prostate cancer. This mutation has an estimated frequency of 0.4% in the general Icelandic population (26) . Johannesdottir et al. (26) screened 65 Icelandic men diagnosed with prostate cancer <65 years of age and 499 controls. Only 2 of the 65 (2.7%) prostate cancer patients and 2 of the 499 (0.4%) controls carried the 999del5 mutation. The differences between the prostate cancer patients and the population controls were statistically insignificant. In contrast, a study by Thorlacius et al. (27) found that prostate cancer was the second most prevalent cancer in male first-degree relatives of 999del5 mutation carriers affected with breast cancer. Relative risk of prostate cancer in first-degree relatives was estimated at 3.46. Sigurdsson et al. (28) analyzed men affected with prostate cancer from 16 BRCA2 999del5 families and a random group of men diagnosed with prostate cancer over a 1-year period. Relative risk of prostate cancer was calculated to be 4.6 in first-degree relatives and 2.5 in second-degree relatives. The study also noted that 8 of 12 familial prostate cancer cases and 2 of 65 random prostate cancer cases carried the 999del5 founder mutation, and each of the 10 carriers developed advanced prostate cancer and died. The authors proposed that the 999del5 mutation may be useful as a prostate cancer marker for poor prognosis in the Icelandic population.

Although these studies have found some evidence of BRCA1 and BRCA2 involvement in prostate cancer etiology, a clear understanding of the importance of these genes in familial prostate cancer remains to be elucidated. To assess the involvement of BRCA1 and BRCA2 mutations in familial prostate cancer, we selected families with at least two cases of breast and/or ovarian cancer from a large collection of high-risk prostate cancer families. We selected these families to maximize the odds of detecting mutations in BRCA1 and BRCA2. Mutation screening was performed on the prostate cancer proband and an additional family member affected with breast or prostate cancer from each of the 22 selected families.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Family Ascertainment
All men who received a radical prostatectomy for clinically localized prostate cancer, in the Department of Urology, or who received radiation therapy, in the Division of Radiation Oncology at the Mayo Clinic (Rochester, MN), were sent a family cancer history survey. From a total of 12,675 surveys sent on two separate occasions, 196 high-risk families were identified. More detailed family histories were obtained over the telephone and three-to-four generation pedigrees were constructed. From this group, blood samples from a total of 163 families with a minimum of 3 men affected with prostate cancer were collected. The average age of diagnosis was 66.7 years (range, 47–82 years). The average number of affected men per pedigree was 4.2 (range, 3–11).

A total of 21 families with at least two cases of breast and/or ovarian cancer in each pedigree were identified (Table 1)Citation . One additional family with a single case of breast cancer was also included in the analysis. This subset was selected for BRCA1 and BRCA2 mutation screening of two individuals/pedigree. All 22 probands plus an additional affected (either prostate or breast cancer) relative from 21 of the pedigrees were screened.


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  		Table 1 Demographic data on prostate cancer families screened for BRCA1 and BRCA2 mutations

 
The research protocol and informed consent forms were approved by the Institutional Review Board at the Mayo Clinic. DNA was isolated from peripheral blood lymphocytes using standard methods. All men who contributed a blood specimen and who had prostate cancer had their cancers verified by review of medical records.

CSGE3
Mutations in BRCA1 and BRCA2 have been found throughout the entire coding regions of the genes. To screen the entire coding region of each gene, we used intron-based primers for PCR amplification of the 22 and 26 coding exons of BRCA1 and BRCA2, respectively. To ensure complete screening of larger exons, BRCA1 exon 11 and BRCA2 exons 10, 11, and 27 were divided into multiple overlapping fragments, resulting in a total of 31 BRCA1 primer sets and 42 BRCA2 primer sets.

PCR was performed using standard conditions containing 25 ng of genomic DNA, 1x buffer (Promega), 1.5 mM MgCl2 (Promega), 0.2 mM deoxynucleotide triphosphates, 0.5µM each primer, and 1 unit of Taq DNA polymerase (Promega). Amplification conditions were as follows: denaturing at 93°C for 3 min, 35 cycles of denaturing at 93°C for 30 s, annealing for 30 s, and extension at 72°C for 1 min, followed by a final extension at 72°C for 5 min. For heteroduplex formation, the products were then denatured at 98°C for 5 min and allowed to reanneal at 68°C for 30 min. A 10-µl volume of the PCR product was combined with 2 µl of nondenaturing loading dye, and the entire 12-µl sample was loaded onto a CSGE gel. Gels were prepared with 10% polyacrylamide [99:1 acrylamide:1,4-bis(acroyl)piperazine (Fluka)], 10% ethylene glycol, 15% formamide, 0.5x TTE buffer (44.4 mM Tris, 14.25 mM taurine, and 0.1 mM EDTA, pH 9.0). Gels were run at 400V overnight in 0.5x TTE buffer, stained with ethidium bromide (0.5 mg/µl), and photographed with UV illumination.

Variant Sequencing
PCR products displaying variant gel migration patterns were purified as follows. One µl exonuclease I (Amersham Pharmacia Biotech) was added to 5 µl of PCR product and incubated at 37°C for 15 min and 80°C for 15 min. The incubation was then repeated after the addition of 1 µl of shrimp alkaline phosphatase (SAP) (Amersham Pharmacia Biotech). Upon completion of the incubation cycles, 4 µl of distilled H2O and 3.2 pM of the appropriate primer were added. The sample was then sequenced by the Molecular Core Facility at Mayo on an ABI 377 sequencer and analyzed for sequence alterations.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We screened 43 genomic DNA samples, 2 from each of 21 prostate cancer families and a single sample from 1 additional family (family 18) for mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. Twenty-one families had at least two individuals in the pedigree that were affected with breast and/or ovarian cancer, whereas the remaining family (family 16) had only one individual affected with breast cancer. Six of the pairs consisted of the prostate proband and a family member affected with breast cancer. Fifteen of the pairs consisted of the proband and another family member affected with prostate cancer. Only the proband was screened for the one remaining family.

We identified one previously reported missense mutation in BRCA2, C1206A, which results in the substitution of an arginine for a serine at codon 326. This BRCA2 missense mutation has been identified previously on three occasions as reported on the BIC website.4However, it is not known if the mutation is disease associated. To address this uncertainty, DNA samples from five additional members of this family were examined (Fig. 1)Citation for segregation of the mutation with cancer. The additional five members consisted of the proband’s brother, two nieces, and two nephews. The brother and one nephew were both diagnosed with prostate cancer at age 72 and 63, respectively, and one niece was diagnosed with skin cancer at age 54. We identified the missense mutation in the proband’s brother only. Unfortunately, we were unable to obtain DNA from the proband’s father or remaining sibling, both of whom had been diagnosed with prostate cancer. The availability of these samples would have facilitated a more complete analysis of segregation of the mutation with cancer in this family.



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  		Fig. 1. Partial pedigree of family 8 with BRCA2 C1206A missense mutation screening results. Samples II-2, II-3, and II-4 show variant CSGE results, whereas samples III-1, III-2, III-3, and III-4 are normal. Ages at diagnosis are given below the symbols.

 
We also detected 20 previously reported intron and exon polymorphisms in BRCA1 and BRCA2 and two previously unreported BRCA2 intron polymorphisms (Table 2)Citation . Allele frequencies were calculated by using the two alleles contributed by each proband (total, 44). The frequencies of all alleles are shown in Table 2Citation . Three reported polymorphisms in BRCA1, A1186G, IVS16–68AtoC, and IVS16–92AtoG, were found in the family member other than the proband. The remaining polymorphisms and missense mutation were found in all of the probands. Most of the polymorphism allele frequencies were in agreement with or were lower than the frequencies listed on the BIC website.


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  		Table 2 BRCA1 and BRCA2 sequence alterations identified in prostate cancer families

 
The BRCA2 polymorphism IVS16–14TtoC had an allele frequency of 41% in our study population. Surprisingly, this polymorphism is not reported on the BIC website. The unique BRCA2 polymorphism, IVS-49TtoG, has an allele frequency of 18% in our study population. This base change in the intron, however, does not appear to affect splicing and is likely to be a rare benign variant in intron 7. Several BRCA1 and BRCA2 polymorphisms that were identified in only one allele in the entire population have been reported on the BIC website at a higher frequency. BRCA1 A1186G (Gln356Arg) has reported allele frequency of 6% (29) , whereas this polymorphism accounted for 2% of the alleles in this study. BRCA2 A1093C (Asn289His) has a reported allele frequency of 7% (30) , whereas we identified this polymorphism in 2% of the alleles in this study population. BRCA2 A1342C (His372Asn) has reported allele frequencies of 30% (31) but again accounted for only 2% of the alleles in this population.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have screened 22 prostate cancer families, 21 that were selected for the presence of at least two cases of breast and/or ovarian cancer and one family with one case of breast cancer, for mutations in the BRCA1 and BRCA2 genes. None of the 43 samples screened contained a protein truncating mutation in either BRCA1 or BRCA2. We identified the BRCA2 C1206A missense mutation in three members of one prostate cancer family. The family has six members affected with prostate cancer, two affected with breast cancer, and four additional members affected with other forms of cancer. The three individuals that carry the C1206A missense mutation are siblings, a sister affected with breast cancer and two brothers affected with prostate cancer. One of these individuals was the proband for the family. The remaining four samples that were negative for the mutation were children of another brother who also had prostate cancer. It is possible that the nephew affected with prostate cancer but who is negative for the C1206A mutation is a sporadic case of prostate cancer within this pedigree. If samples had been available from the proband’s father and remaining sibling, both of whom had been diagnosed with prostate cancer, a more complete analysis of the segregation of this mutation with the cancer in this family would have been possible.

The missense mutation, C1206A, results in the substitution of a charged arginine residue for a polar serine residue at codon 326. The introduction of a charged arginine residue may alter the protein conformation and as a result affect the function. Nucleotide 1206 is located in BRCA2 exon 10 at the site reported to be required for interaction with the transcriptional coactivator protein, P/CAF (33) . The C1206A missense mutation is located 36 nucleotides into the 163 nucleotides essential for P/CAF interaction. It is possible that the introduction of a positively charged amino acid through the substitution of arginine for serine may disrupt P/CAF binding to BRCA2. Loss of P/CAF binding may inhibit histone acetylation and chromatin remodeling and lead to disruption of BRCA2-dependent transcription and/or DNA repair.

We were unable to perform Southern blot analysis of each sample to check for BRCA1 gene rearrangements that cannot be detected by PCR screening methods because of a lack of sufficient DNA. Because genomic rearrangements may account for up to 15% of all BRCA1 mutations (34) , it is possible that we may have missed one or more mutations. We did identify an interesting CT repeat region in BRCA2 intron 7 when we screened exon 7 for mutations. Previously reported intron-based primers for the exon 7 region are located upstream of the CT repeats. Our reverse primer for exon 7 is located downstream of the repeats. Although any sequence alterations in this repeat region are unlikely to affect the actual coding sequence or splicing, it is interesting to note that every one of the 43 samples we screened had one of three sequence variants in this region.

Three of the families (nos. 2, 3, and 14) studied had one individual with male breast cancer in addition to two, six, and two female relatives affected with breast and/or ovarian cancer, respectively (Table 1)Citation . Mutations in BRCA2 have been associated with 14% of male breast cancer cases with a family history (31) and 4% of male breast cancer cases unselected for family history (30) . Recent studies in Sweden and Hungary reported BRCA2 mutations in 21% (35) and 33% (36) of male breast cancer patients without a family history of breast cancer. None of the three families with cases of male breast cancer in our population carried BRCA2 sequence variants that might be disease associated; therefore, it is unlikely that BRCA2 plays any role in the etiology of the male breast cancers in this population.

It is possible that the breast cancer in these prostate cancer families may be sporadic cases. No evidence has been found to date to show that BRCA1 or BRCA2 have a significant role in sporadic forms of female breast cancer. Therefore, if the breast cancers are sporadic, selection of families with cases of breast and/or ovarian cancer along with prostate cancer would not be expected to enrich for carriers of BRCA1 and BRCA2 mutations. From the data presented here, it would appear that BRCA1 and BRCA2 have little or no role in hereditary prostate cancer. However, it remains possible that other tumor suppressor genes account for the cancers in these families. Sixteen of the 22 families have other cancers in addition to breast, ovarian, and prostate. Although there is no obvious pattern to the cancer occurrences, it is premature to dismiss these as unrelated in breast and prostate cancer families. The search is ongoing for prostate and breast cancer predisposition genes. Once identified, it will quickly be determined whether these genes cause both prostate and breast cancer in families.


   ACKNOWLEDGMENTS
 
We thank Tammy Greenwood for assistance with BRCA1 and BRCA2 mutation screening.


   FOOTNOTES
 
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.

1 This study was supported in part by a grant from the Breast Cancer Research Foundation and Grant CA72818. Back

2 To whom requests for reprints should be addressed, at the Mayo Clinic and Foundation, Hilton Building 970, Rochester, MN 55905. Phone: (507) 284-4696; Fax: (507) 284-0043; E-mail: Stephen.Thibodeau{at}mayo.edu Back

3 The abbreviations used are: CSGE, conformation-sensitive gel electrophoresis; BIC, Breast Cancer Information Core. Back

4 Internet address: http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic.

Received 8/24/99. Accepted 1/ 5/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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