Japanese Journal of Clinical Oncology 30:343-348 (2000)
© 2000 Foundation for Promotion of Cancer Research
BRCA1 Mutations in Taiwanese with Epithelial Ovarian Carcinoma and Sporadic Primary Serous Peritoneal Carcinoma
1Department of Obstetrics and Gynecology, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei and 2Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan,+
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Germline BRCA1 mutations of sporadic ovarian cancers are presumed to be rare events, except among specific populations. To date, the status of germline BRCA1 mutations in Taiwanese with primary epithelial ovarian carcinoma (PEOC) is still unknown. In this study, we tried to answer part of this question.
Methods: Sixty-four patients documented with PEOC, four patients with family history of breast and/or ovary cancer syndrome and five patients with sporadic primary serous peritoneal carcinoma (PSPC) were enrolled in this retrospective study from January 1994 through June 1999. At the same time, 50 normal healthy Taiwanese without family history were enrolled in this study. Germline DNA from these patients was screened for mutations in the BRCA1 gene using polymerase chain reaction-based single-stranded conformation polymorphism analysis (PCR-SSCP). Shifting DNA bands were sequenced.
Results: One of the 64 patients with PEOC (1.6%) exhibited germline BRCA1 heterozygous mutation which was exon11 single-base substitution at nucleotide1047 (CAG to TAG). One of the five patients with PSPC (20%) exhibited an exon11 single-base substitution at nucleotide 914 (TCT to TCC) with resultant silent mutation. One of the normal healthy Taiwanese (2%) was found to have an exon 2 single-base substitution at nucleotide 152 (A
C) which was also a silent mutation. No mutations of BRCA1 were detected in four patients with a family history of breast and/or ovarian cancer.
Conclusions: Based on this study, it was very difficult to obtain precise data to prove the value of applying genetic testing of BRCA1 mutations in Taiwanese patients with sporadic epithelial ovarian cancers or sporadic PSPC and even with a family history of breast and/or ovarian cancer because of its rare event and because of the too small number of cases available in this study.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The BRCA1 gene, located on chromosome 17q12–21, comprises 5592 nt with 22 coding exons and is predicted to encode a protein of 1863 amino acids with little homology to other known proteins (1). In Western countries, germline mutations in the BRCA1 gene are estimated to account for
50% of early-onset familial breast cancers in females and most of the early onset breast and ovarian cancers (2,3). Germline mutations in the BRCA1 gene predispose not only to breast cancer with a penetrance of 85% by 70 years of age but also ovarian cancer with a penetrance of 40% by 70 years of age (4,5). So far, over 130 distinct germline mutations have been identified among pedigrees of hereditary breast and ovarian cancer syndromes (6,7). In Taiwan, germline mutations of BRCA1 have not been reported before, partly owing to insufficient interest and partly because more common diseases such as hepatic cell cancer, cervical cancer, lung cancer and nasopharyngeal cancer have public preference. However, the notoriously poor prognosis in women with ovarian carcinoma (cumulative 5-year disease-free survival of 31.6% in surgical–pathological stage IIIC patients) made us pay more attention to this disease (8). An understanding of ovarian cancers and primary serous peritoneal carcinoma in patients at the molecular level is required to control these types of cancers. The present study was initiated to clarify the possible involvement of BRCA1 gene mutations in Taiwanese patients with primary epithelial ovarian cancers (PEOC) and primary serous peritoneal carcinoma (PSPC). DNA from 64 Taiwanese ovarian cancer patients without family history of breast cancer or ovarian cancer, from four ovarian cancer patients with at least one first-degree relative or two second-degree relatives having breast and/or ovarian cancers and five patients with primary serous peritoneal carcinoma were analyzed for mutations at exons 2, 11 and 20 of BRCA1 gene using polymerase chain reaction-based single-stranded conformation polymorphism analysis (PCR-SSCP).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Human Tissue Samples
All 68 ovarian cancer specimens and five primary serous peritoneal carcinomas were surgically resected and histologically diagnosed at the Department of Obstetrics and Gynecology and the Department of Pathology, Veterans General Hospital, Taipei from January 1994 through June 1999. The patients with tumors included 13 with mucinous carcinomas (one with family history), nine with clear cell carcinomas, 15 with endometrioid carcinomas (one with family history), 31 with serous carcinomas (two with family history) and five with primary serous peritoneal carcinomas (PSPC). Patients with family history of breast and/or ovarian carcinoma were defined when their families with at least one or more first-degree relatives with ovarian cancer and/or breast cancer or two or more second-degree relatives having breast and/or ovarian cancers. Among them, patient A had two first-degree relatives with PEOC; patient B had one first-degree relative with PEOC and one first-degree relative with breast cancer; patient C had one first-degree relative with breast cancer and two second-degree relatives with ovarian cancers; and patient D had two first-degree relatives with breast cancers. Patients with PSPC (9) who met the criteria of the Gynecologic Oncology Group (10) entered this study. The criteria included the following: (A) both ovaries must be either physiologically normal in size or enlarged by a benign process; (B) involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary; (C) microscopically, the ovarian component must be one of the following: (a) non-existent, (b) confined to ovarian surface epithelium with no evidence of cortical invasion, (c) involving ovarian surface epithelium and underlying cortical stroma but with any given tumor size less than 5 x 5 mm, (d) tumor less than 5 x 5 mm within ovarian substance associated with or without surface disease; (D) the histological and cytological characteristics of the tumor must be predominantly of the serous type, which is similar to or identical with ovarian serous papillary adenocarcinoma, any grade. Patients with borderline ovarian cancer malignancies were excluded. Corresponding constitutional DNAs were obtained from the peripheral blood leukocytes. Five ovarian cancer patients with onset ages of less than 40 years were included. The mean age of the patients analyzed was 55.1 years.
Fifty normal healthy Taiwanese also entered this study for the purpose of examining the frequency of these mutations among normal healthy Taiwanese. Written informed consent was obtained from all patients enrolled in the study, including 50 healthy Taiwanese.
PCR Analysis
DNA was available for analysis by extraction from buffy coat specimens, using phenol and chloroform. The oligonucleotide primers used in amplifying the PCR in the four individual regions of BRCA1 from genomic DNA were based on those described by Gayther et al. because they found that using their strategy could analyze one quarter of the coding sequence and detect 50% of all BRCA1 mutations so far reported in breast/ovarian cancer families (1). Those included the following: exon 2, forward 5'-gaagttgtcattttataaaccttt-3' and reverse 5'-tgtcttttcttccctagtatgt-3' exon11A, forward 5'-cttgtgaattttctgagacgg-3' and reverse 5'-gcctcatgaggatcactgg-3'; exon11B, forward 5'-aggggccaagaaattagagtc-3' and reverse 5'-aagtttgaatccatgctttgctct-3'; exon 20, forward 5'-atatgacgtgtctgctccas-3' and reverse 5'-tgcaaaggggagtggaatac-3'. The PCR mixture consisted of Taq DNA polymerase, 200 µM dNTP, 1.5 mM MgCl2, reaction buffer and genomic DNA. PCR was carried out in a Perkin-Elmer 9600 Cycler for 30 cycles under the following conditions: 1 min at 94°C, 50 s at 55°C and 1 min at 72°C. The quality of PCR products was determined using agarose gel electrophoresis.
SSCP Analysis
Single-stranded conformation polymorphism analysis was performed using four primer sets flanking exons 2, 11 and 20 of the BRCA1 gene. Following amplification, PCR products of 11A and 11B were cut to 200–300 base pairs using restriction enzyme BglII and PstI, respectively. Then, 5 µl of PCR products (exons 2, 11A, 11B and 20) were mixed with loading dye comprising 95% formamide, 20 mM EDTA, 0.05% bromphenol blue and 0.02% xylene cyanole FF. Samples were denatured for 10 min at boiling water temperature and immediately placed on ice and 5 µl were loaded on to a 12.5% polyacrylamide gel (Pharmacia, Piscataway, NJ) run at 20 mA for 2.5 h at 5°C. The gel was detected using silver staining.
DNA Sequence
DNA fragments showing mobility shifts using SSCP analysis were eluted from the acrylamide gel as described by Suzuki et al. (11) and were amplified by 30 cycles of PCR using the same primers under the same conditions as described in the previous section. Fluorescent sequencing was performed using a semiautomatic sequencing system (Model 373A, Applied Biosystems). The dideoxy chain-termination method was performed using a Prism Sequenase Terminator Single-Stranded Sequencing Kit (Applied Biosystems).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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There were no mutations detectable in the four ovarian cancer patients with family histories of breast and/or ovarian cancer. One of the 64 patients with PEOC (1.6%) and one of the five patients with PSPC (20%) exhibited the germline BRCA1 mutation using PCR-SSCP (Fig. 1). The former patient (I) with mucinous ovarian carcinoma, pathological staging IV was found to have an exon 11 single-base substitution at nucleotide 1047 (CAG to TAG) which resulted in a premature termination (glutamine to stop codon). This patient underwent a sub-optimal debulking surgery and followed by eight courses of postoperative adjuvant chemotherapy including cyclophosphamide 500 mg/m2, adriamycin 50 mg/m2 and cisplatin 50 mg/m2, but died of disease 11 months later after initial surgery. The latter patient (II) with PSPC was found to have an exon 11 single-base substitution at nucleotide 914 (TCT to TCC) but this substitution was a silent mutation (serine to serine). This change with resultant meaning is not clear because we failed to detect this substitution in the 50 controlled Taiwanese. By contrast, in 50 normal healthy Taiwanese based on analyzing PCR-SSCP (Fig. 2), we found one patient showing an exon 2 single-base substitution at nucleotide 152 (A
C); however, it also presented a silent mutation because the amino acid was still a valine. This patient underwent optimal debulking surgery and eight-cycle multi-agent chemotherapy with 500 mg/m2 cyclophosphamide, 50 mg/m2 adriamycin and 50 mg/m2 cisplatin intravenously every 3 weeks. She had a recurrent tumor which was detected by whole-body positron emission tomography (9) and was successfully treated by a second operation and further six-cycle chemotherapy with 50 mg/m2 cisplatin and 225 mg/m2 taxol. At present, the patient is alive without evidence of recurrent disease after 14 months. Both patients denied having any other first-, second- or third-degree relatives having suffered from breast and/or ovarian cancer after considering the precise family history; however, patient I had one elder brother who had died from stomach cancer 3 years earlier when he was 65 years old.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The results demonstrated that ovarian cancers can occur in Taiwanese women with germline mutations of the BRCA1 gene. Ford et al. even estimated that the frequency of germline BRCA1 mutations in patients with sporadic ovarian cancers was 2.8% (12). A study in the UK suggested that germline mutations in BRCA1 in patients with sporadic ovarian cancer were uncommon (only 3–5% of cases had mutations) (13). Matsushima et al. found that the frequency of germline BRCA1 mutations in an unselected group of 76 Japanese women with ovarian cancer was 5.3% (14). Lu et al. demonstrated that 25% of Jewish women with PEOC had germline BRCA1 mutations (15). In fact, in the Jewish population, the rate of founder mutations in unselected patients with PEOC was
20–30% (16–18). Patients with PEOC and/or breast cancer might seem interested in the results of studying germline BRCA1 mutations; however, studying different populations shows that the data vary between them (12–20). Tonin et al. suggested that the identification of founder BRCA1 and BRCA2 mutations in patients with ovarian cancer unselected through family history could facilitate carrier detection when the expected yield of a comprehensive screening may be low (21). Collins suggested that the benefits of presymptomatic testing to determine susceptibility to common cancers such as breast, ovarian, colon and prostate cancers were potentially substantial and concluded that the identification of BRCA1 and other cancer-susceptibility genes could permit the development of new and more effective therapies (22,23). Almost paradoxically, the BRCA1 gene did not seem to be involved in sporadic ovarian cancers, which constitute the vast majority of ovarian malignancies (24), just like in our study that showed a rare event of germline BRCA1 mutations in an unselected group of 68 Taiwanese patients with PEOC. Germline BRCA1 mutations in patients with PSPC may be an interesting subject although only a few workers have tried to study these patients because PSPC is an extremely rare disease (25). Recent reports have concluded that the study of BRCA1 mutations would benefit molecular pathogenic research on PSPC (26,27) and that PSPC should be considered a malignancy expressed in the familial breast ovarian cancer syndrome (28). Bandera et al. reported three out of 17 PSPC with germline mutations of the BRCA1 (26). Two cases showed 185 delAG germline mutations of the BRCA1, which is one of the three mutational hotspots in the Ashkenazi Jewish population, and the patients have a strong family history or a history of multiple breast/ovarian cancer. The third patient had a missense mutation in exon 11 of the BRCA1 gene and did not show a familial background. Pathogenicity of the third case is not clear and it is strongly suggested that two cases showing 185 delAG are Ashkenazi descendents. The frequency of the heterozygous carrier in the Ashkenazi tribe is exceedingly high and more than 90% of the germline mutations are accumulated in the three mutational hotspots, due to the founder’s effect. In addition, the frequency of 185 delAG in Ashkenazi Jewish patients with ovarian cancer is as high as 25% (15). We found one germline BRCA1 silent mutation based on five patients with PSPC. However, this mutation was not detected in the analysis of normal healthy controls. This might indicate that the frequency of this DNA variant is very low and does not mean the pathogenicity of this mutation in PSPC.
Our approach to DNA testing did not require initial direct sequencing for screening, although direct sequencing is believed to be the most sensitive and specific BRCA1 mutation testing method available. However, because sequencing is labor intensive, it is the most expensive mutation detecting technique (28). Therefore, we selected a gel shift assay with SSCP for screening and direct sequencing for confirmation. Although this method can reduce the number of samples that must be sequenced, the sensitivity of this assay is variable based on the number of primers used. In our study, the four sets of primers were the most economical which could be used to detect about 50% of all BRCA1 mutations (1,29,30). Based on this assumption, we estimated that the probability rate of germline BRCA1 mutations in Taiwanese women with sporadic PEOC was 3.2%. Other assays included multiplex heteroduplex analysis (1), allele specific oligonucleotide hybridization and protein truncation assay (31,32). New technologies are being developed, one of which includes the use of computer-based analysis for full automation of completed gene sequence analysis (33). These techniques should significantly improve the efficiency of mutation detection, decrease the cost of clinical testing and permit population-based studies of mutation prevalence and disease penetrability
In this study, one patient showed a heterozygous germline change in a single substitution at nucleotide 1047. We also checked the somatic changes but failed to demonstrate any new mutations in the other allele. Although loss of heterozygosity of this patient could not be confirmed, partly owing to the up to 50% false-negative rate, we did not know whether this mutation was indeed related to the tumor that originated in this particular patient. Somatic mutations in BRCA1 have been seen in only 3% (5/191) of patients with sporadic ovarian cancers, so it seems unlikely that mutations or deletions of the BRCA1 gene play a major role in the development of sporadic ovarian cancers (34). Furthermore, based on some reports from population-based data, no clear differences exist in clinical characteristics between the BRCA-positive and the BRCA-negative groups (33). In addition, Pharoah et al. found that no differences existed in histopathological type, grade or stage according to germline BRCA1 mutation status (35). Finally, currently there are inadequate data to support the use of BRCA1 and BRCA2 status to counsel individuals regarding their prognosis or to select treatment (36). Clearly, a definitive comparison of prognosis between sporadic and BRCA-associated cancers will have to await large, population-based analyses (37).
Some clinical characteristics of hereditary patients with ovarian cancer may differ from those of the sporadic nature (33). In fact, it is well known that patients with inherited ovarian cancer have distinctive clinical features: age of onset is considerably younger than in sporadic cases, the prevalence of bilateral ovarian cancer is higher and the presence of associated tumors in affected individuals is noted in some families (28). BRCA1-associated tumors include breast, colon and prostate cancer (38).
Although the function of the BRCA1 gene is not clear, it has been considered as a tumor suppressor gene. There is at least some evidence that supports this hypothesis. Elevated p53 expression seems to be common in cancers in patients who are BRCA1 mutation carriers (39). The same study also demonstrated that BRCA1 cancer phenotype has an exceptionally high proliferation rate (38). Zhang et al. demonstrated that BRCA1 increased p53-dependent transcription from the p21WAF1/CIP1 and bax promoters and concluded that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors (40). BRCA1 regulated the behavior of c0Myc and provided a molecular explanation for some of its effects such as tumor suppressor of the BRCA1 gene products (41).
Despite our apparent knowledge, we still cannot explain why individuals with the same germline BRCA1 mutation do not develop breast or ovarian cancer in a well-predicted pattern (42). The penetrance of BRCA1 for hereditary ovarian cancer is only 70%, while the penetrance for hereditary breast cancer approaches 90% (42). Such information is necessary if we are to provide accurate genetic counseling. Because ethnicity is critical in assessing the data of genetic analysis, unfortunately, based on this study, it was very difficult to obtain precise data to prove the value of applying genetic testing of BRCA1 mutations in Taiwanese patients with sporadic epithelial ovarian cancers or sporadic PSPC and even with a family history of breast and/or ovarian cancer, because of its rare event and too small number of cases available in this study. More research is required to clarify these aspects.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This study was supported in part by grants (88VGH-99 and 89VGH-225) from the Taipei Veterans General Hospital, Taiwan and in part by a grant (NSC-89-2314-B-075-047) from the National Science Council, Taiwan. This work forms part of a doctoral thesis by Peng-Hui Wang.
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FOOTNOTES |
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+ For reprints and all correspondence: Chiou-Chung Yuan, Department of Obstetrics and Gynecology, Veterans General Hospital Taipei, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail: ccyuan@vghtpe.gov.twAbbreviations: PCR-SSCP, polymerase chain reaction-based single-stranded conformation polymorphism analysis; PEOC, primary epithelial ovarian carcinoma; PSPC, primary serous peritoneal carcinoma
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received February 14, 2000; accepted June 16, 2000.
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