Study On BRCA1/BRCA2Germline Mutation In Chinese Women With High-risk Breast Cancer

Background and objectiveBreast cancer has become one of the most common malignancies among Chinese women. It is a serous threat to Chinese women’s health and life. Early detection, early diagnosis and early treatment are the most important means to reduce cancer mortality. Breast cancer has a strong genetic background. Detection of susceptibility gene mutations is an important mean to screening population with high-risk breast cancer. Germline mutations in BRCA1and BRCA2result in a significantly increased risk of breast cancer and ovarian cancer. The two genes are associated with the majority of hereditary breast cancer. In developed countries, women with high-risk of breast cancer can receive commercial mutation screening of the two genes. These countries have professional genetic services programs providing genetic counseling and genetic testing regarding risk of developing breast cancer. The research on hereditary breast cancer in the Chinese population started more lately, especially starting from the21st century some relevant studies have been reported in the Mailand China. However, most of these studies were from single research centers with a small number of cases, representing many shortcomings. These resulted in a small spectrum of BRCA1/BRCA2mutations in Chinese population. It does not match the fact that China has the1/5of the world’s population. The purpose of this study was to summary the spectrums of BRCA1/BRCA2mutaions in Chinese population with high-risk breast cancer, to analyze clinicopathological characteristics of BRCA-related breast cancer, and to help the establishment of the genetic cancer risk assessment system and genetic testing strategy for Chinse population wordwide.Subjects and MethodsThere were two parts in our study. Part one:we screened the complete coding regeions and exon-intron boundaries of BRCA1in62familial breast cancer patients from Zhejiang (eastern China) by polymerase chain reaction (PCR)-sequencing assay. And Immunohistochemistry analyses were performed on tumor samples to detect the expression of estrogen receptor, prosgesterone receptor, P53and human epidermal growth factor receptor-2. The inclusion criteria were:(1) at least one first or second degree relatives with breast cancer and/or ovarian cancer, regardless of age. Written consent was obtained from all participated patients. Genomic DNA samples were extracted from peripheral blood of the breast cancer probands. Part two:we searched all of the BRCA1and BRCA2germline mutations in Chinese population with high-risk breast cancer in databases, such as PubMed, Breast Cancer Information Core, VIP, wanfangdata, and so on. All of the mutations such as point mutations and large genomic rearrangments were enrolled. The characteristics of the mutations in Chinese population were analyzed.ResultsPart One:(1) In our study of62Chinese women with familial breast cancer, a total of7familial breast cancer patients with BRCA1germline point mutations were identified. The frequency of BRCA1mutaion was11.3%(7/62) in our study. Two novel mutations (3414delC and5208C> T) were found. Two recurrent mutations5273G>A and5589del8occurred twice in exons19and24, respectively. Moreover,3273C>T and4184del4were first reported in Chinese population.(2) BRCA1mutation tumors tended to be early onset, negative for ER, PR and HER-2, and exhibited high histological grade compared with tumors without BRCA1mutations.Part Two:(1) A total of21legislative literatures were enrolled. Among these literatures,16literatures were associated with BRCA1point mutation.11literatures were associated with BRCA1point mutation, and5literatures were associated with BRCA/BRCA2large genomic rearrangement.(2) Three assayes were performed in screening point mutation, such as PCR-single strand conformation polymorphism (SSCP)-sequencing assay, PCR-denaturing high performance liquid chromatography (DHPLC)-sequencing assay, and PCR-sequencing assay.In early studies, the PCR-SSCP-sequencing assay was the most commonly employed. The recent studies used the PCR-sequencing assay frequently for its high sensitivity.(3) A total of103BRCA1point mutations in Chinese women with high-risk breast cancer. The frequency of BRCA1point mutation in familial breast cancer patients and early breast cancer patients were5.0%(52/1045) and3.7%(20/546), respectively.(4) A total of91BRCA2point mutations in Chinese women with high-risk breast cancer. The frequency of BRCA2point mutation in familial breast cancer patients and early breast cancer patients were6.7%(51/757) and3.2%(10/313), respectively.(5) Mutations within exton11of the BRCA1and BRCA2genes were the most common and accounted for56.3%(58/103) and53.8%(49/91) of the total mutations, respectively.(6) The frame-shift mutation is the most common one, accounting for63.1% (65/103) and74.7%(68/91) of total mutations in BRCAl and BRCA2, respectively.(7) Some recurrent mutations were reported in Chinese women with high-risk breast cancer. The most common recurrent mutations in Chinese women were5589de18in BRCA1and3109C>T in BRCA2, respectively.5589de18accounted for10.7%(11/103) in the total of BRCA1point mutations, and3109C>T accounted for4.4%(4/91) in the total of BRCA2point mutations.(8) Of the total point mutations in BRCA1and BRCA2,56.3%and47.9%can not be found in the Breast Cancer Information Core database, respectively.(9)5literatures which associated with BRCAl and BRCA2large genomic rearrangementes were found in Chinese women with high-risk breast cancer. The multiplex ligation dependent probe amplification (MLPA) assay was the only method employed to screening large genomic rearrangement in the5literatures.(10) A total of7BRCAl or BRCA2large genomic rearrangements were found in Chinese women with high risk breast cancer. These accounted for3.5%(7/201) of the total BRCA1/BRCA2mutations. Among the7large genomic rearrangements,5were in BRCA1and2were in BRCA2, respectively.ConclusionsAccording to our research, it suggested that:(1) Although the frequency of BRCA1/BRCA2mutations in Chinese women with high-risk breast cancer was lower than that in other ethnicities, especially in the Caucasian women, the BRCA1and BRCA2genetic analysis could be done for high-risk breast cancer patients in Chinses population.(2) According to the characteristics of BRCA1/BRCA2mutations in the Chinese population, screening might detect the existence of recurrent mutations. Subsequent mutation-negative cases could be detected in exon11. If all above results are negative, testing can be done for other exons. This process can improve the detection efficiency and reduce the overall testing cost. (3) The spectrum of BRCA1/BRCA2mutations in Chinses women with high-risk breast cancer might be different with that in other ethnicities, for the nearly50%of the mutations were not reported in BIC database.(4) The BRCA1/BRCA2large genomic rearrangements exist in Chinese women with high-risk breast cancer, and they should be involved in genetic analysis.(5) The clinicopathological characteristics of BRCA1-related breast cancer in Chinese women were similar to that in Caucasian population. It might be usefull for establishment of the genetic prediction model.It may be usefull for the establishment of the genetic cancer risk assessment system and genetic testing strategy for Chinese and even Asian population.