| Background and Objectives: Germline mutations in BRCA1 (MIM#113705) and BRCA2 (MIM#600185) genes result in a significantly increased risk of breast and ovarian cancer. Genetic cancer risk assessment has been practiced in developed countries for many years, and genetic testing for inherited breast cancer susceptibility has become a standard of care option for appropriately selected patients in those countries. In China mainland, however, little has been recognized in this field. The purpose of this study was to determine the prevalence of BRCA1 and BRCA2 mutations more comprehensively among clinic-based Chinese high-risk breast cancer families, and to help the establishment of the genetic cancer risk assessment system and genetic testing strategy in China mainland. Subjects and Methods: The inclusion criteria were: (1) at least one first or second degree relatives with breast cancer and/or ovarian cancer, regardless of age, or (2) breast cancer diagnosed below 35 years of age. Two hundred and eighty-eight such high-risk breast cancer patients from four breast disease clinical centers in China were enrolled. Two hundred and forty-seven of them have been detected for both BRCA1 and BRCA2 mutations by using PCR-DHPLC-DNA sequencing analysis. The other 41 patients were only analyzed BRCA1 mutation by PCR-SSCP-DNA sequencing analysis. For those families with affected first-degree relatives but no BRCA1/2 mutation detected, MLPA detection of BRCA1 and BRCA2 genes was offered. A total of 426 sporadic breast cancer controls and 564 normal controls were detected specifically for the recurrent mutations observed in this study. Allelotype analysis was done at five short tandem repeat markers (D17S855, D17S1322, D17S1323, D17S1326, and D17S1327) in or adjacent to BRCA1 on the recurrent mutation carriers. Results: A total of 19 disease-associated mutations were detected in 23 independent families in this series, 13 mutations in BRCA1 and 6 in BRCA2. Most of the mutations are novel. For those analyzed both genes, in the 148 early-onset breast cancer patients (≤35 of age), a total of 13 cases (8. 8%) were found to carry BRCA1/2 mutations, 8 (5. 4%) in BRCA1 and 5 (3. 4%) in BRCA2; in the 119 patients with affected relatives, 14 (11.8%) were found to carry BRCA1/2 mutations, 11 (9.2%) in BRCA1 and 3 (2.5%) in BRCA2; in the 21 patients with both early-onset breast cancer and affected relatives, 7 (33. 3%) BRCA mutations were identified, 5 (23. 8%) in BRCA1 and 2 (9.5%) in BRCA2. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1 mutation is about 16.7%, as compared with the 37.5% of cases with stomach cancer family history (P=. 051). Two recurrent mutations in BRCA1 gene, 1100delAT and 5589del8, were identified in three families, respectively. The recurrent mutations account for 26.1% (6/23) mutations in our series. One 1100delAT mutation (0.18%) was found in a 37-year-old healthy woman and two 5589del8 mutations (0. 47%) were found in two sporadic breast cancer cases. Similar allelotypes were detected in most STR status for those harboring the same mutations. No large genomic rearrangement was identified in either BRCA1 gene. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P<.05).Conclusions: We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patients in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of founder effect for the two recurrent BRCA1 1100delAT and 5589del8 mutations in Chinese. A detection of these two recurrent mutations before the assay of the whole genes could be a cost-effective approach to screening of Chinese populations. Large genomic rearrangement might be rare in Chinese population and might not be recommended in the genetic analysis.
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