Prevalence of Mutations in the BRCA1 Gene Among Chinese Patients With Breast Cancer

Inherited mutations in the tumor susceptibility genes BRCA1 and BRCA2 account for about 70%–90% of familial breast cancer in most Caucasian populations while BRCA1 mutations alone contribute to about half of the cases (1– 3). Epidemiologic data from Caucasians show that BRCA1 mutations occur in the general population at a frequency between 0.05% and 0.2%. BRCA1 mutations account for about 5% of all breast cancers and up to 12% of earlyonset breast cancers (3,4). The relative contribution of BRCA2 may be slightly lower (2,3). The BRCA1 tumor suppressor gene is composed of 22 coding and two noncoding exons (5,6). The BRCA1 protein may play a role in cell cycle regulation (7) and control of DNA repair (8,9). More than 300 heritable mutations in the BRCA1 gene have been found spread throughout the whole coding sequence (10). All known BRCA1 mutations are germline and more than 85% are nonsense or frameshift mutations leading to premature termination of protein translation (2). Ancient and founder BRCA1 mutations have been identified, such as 185delAG mutation in exon 2, which is found in almost 1% of the Ashkenazi Jewish population (11,12). Studies of the BRCA1 gene in Oriental populations are few. There is no information on the frequency of BRCA1 mutation in the Chinese population. However, a lower prevalence of BRCA1 mutations has been suggested in the Japanese population (13–15). Although the incidence of breast cancer among Chinese women is about half of that seen in Caucasians, the proportion of familial cases and incidence of early-onset cancer are similar (16,17). Here, we report our investigation of mutations in BRCA1 among unselected consecutive samples of archived tumor tissues to determine an unbiased estimation of the prevalence of BRCA1 mutations among Chinese patients with breast cancer. Frozen tumor tissues were obtained for BRCA1 mutation analysis from 130 female Chinese patients, who underwent mastectomy for carcinoma of breast at the Prince of Wales Hospital in Hong Kong during the period of 1992 through 1993. As informed consent was not available for these stored samples, mutation analysis was performed in an anonymous manner. The patient identifier codes of these specimens had been removed before mutation analysis was performed. This procedure conforms to the consensus statement on use of stored samples in genetic research (18). Estrogen receptor and progesterone receptor statuses were determined by immunohistochemistry employing commercially available antibodies (DAKO, Glostrup, Denmark). In addition, truncating and missense mutations identified from this series of 130 tissue samples were also screened for in another group of 56 patients with early-onset breast cancers who were diagnosed with cancer before 45 years of age. This prospective group of patients had consented to participate in an ongoing BRCA1/BRCA2 genetics study. The study protocol was approved by a local Institutional Research Ethics Committee. The entire BRCA1 coding region was covered by 35 amplicons amplified by polymerase chain reaction (PCR) from genomic DNA (19). Mutations were screened by single-strand conformational polymorphism (SSCP) analysis under three different electrophoresis conditions. PCR products showing mobility shift on SSCP were sequenced by cycle sequencing in both sense and antisense directions (Life Technologies, Inc., Gaithersburg, MD). The chisquared test was used to compare frequency of alleles. Fisher’s exact test was used to compare clinical parameters between patients with and without BRCA1 mutation. Exact 95% confidence intervals (CIs) of prevalence data were determined by StatXact software (CYTEL, Cambridge, MA). Three nonsense (589delCT, Q356X, and Q1458X) and one presumptive disease-related (P1150S) BRCA1 mutations were found in five of 130 patients, which represented a prevalence of 3.8% (95% confidence interval [CI] 4 1.3%– 8.8%). Three nonsense mutations were identified in four patients (Table 1). Mutation 589delCT was found in two patients aged 24 years and 34 years, respectively, with infiltrating ductal carcinoma (IDC). The other two mutations were novel. The Q1458X mutation was found in a 44-year-old patient having a medullary carcinoma. Q356X was found in an 80-year-old patient with IDC. A missense mutation P1150S was detected in a 31-year-old woman with IDC. Fifty of 130 patients had breast cancer before the age of 45 years, and the prevalence of BRCA1 mutation among this subgroup of early-onset patients was 8.0% (95% CI 4 2.2%–19.2%). Additional screening specifically for these four mutations among another group of 56 patients with early-onset breast cancer further identified one more patient who was a heterozygote for 589delCT. The hometowns of these three unrelated patients sharing 589delCT mutation were different cities within the Guangdong Province of Southern China, but, as far as we know, the patients were not related. Although P1150S was reported as a disease-associated mutation in the Breast Cancer Information Core, the original report that described P1150S in a Japanese patient with a positive family history (15) did not include details on familial segregation of this mutation. As restricted by the retrospective nature of our analysis, we could not further our investigation into the inheritance of P1150S in our patient. Therefore, this