Dissertation
Dissertation > Medicine, health > Oncology > Genitourinary tumors > Female genital tumors > Ovarian tumors

Research on BRCA1/2 Mutations and Its Clinical Importance in Ovarian Cancer Patients from Families at Risk of Hereditary Ovarian Cancer and Patients with Sporadic Ovarian Cancer

Author TaoTao
Tutor ShenZuo;YangJiaXin;CaoDongZuo
School Peking Union Medical College , China
Course Obstetrics and Gynaecology
Keywords Ovarian Cancer Breast Cancer BRCA1 gene BRCA2 gene Gene mutation Founder effect HPLC analysis DNA sequence determination Pedigree analysis
CLC R737.31
Type PhD thesis
Year 2010
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Background and Purpose: epithelial ovarian cancer (ovarian cancer) is the highest fatality rate of gynecological malignancies, family history is considered one of the most powerful tumor predictor of The study showed that about 5% to 10% of the patients with ovarian cancer is a genetic, wherein hereditary ovarian cancer patients, about 80 to 90% associated with susceptibility gene BRCA1 / 2 mutations. Currently, BRCA1 / 2 gene testing has become a high risk for ovarian cancer population screening method. About high-risk familial ovarian cancer patients and sporadic ovarian cancer patients in China, the peripheral blood of the BRCA1 / 2 gene mutation is not in-depth, ovarian cancer population BRCA1 / 2 gene mutation has not been good to clarify. Therefore, in order to further clarify the ovarian cancer population BRCA1 / 2 gene mutations in BRCA1 / 2 gene the sequence mutation detection and control analysis, the subject of high-risk patients with familial ovarian cancer and sporadic ovarian cancer patients in order to understand the two gene mutation status and differences in the two groups of patients with ovarian cancer; analysis associated with BRCA1 / 2 gene mutations in ovarian cancer patients with clinical features and pathological features of a different genetic background of patients with ovarian cancer clinical and biological characteristics and differences ; also female members of the four ovarian cancer in high-risk family mutation detection and pedigree analysis of peripheral blood BRCA1 / 2 gene sequences. Objects and methods: The study inclusion criteria: (1) high-risk familial ovarian cancer: ① family has at least two first-or second-degree relatives suffering from primary ovarian cancer or ovarian cancer and breast cancer; ② family at least one The members of the breast - ovarian double primary cancers, with or without other members of the immediate three generations of blood relatives suffering from ovarian cancer or breast cancer. (2) sporadic ovarian cancer: breast / ovarian cancer family history and breast cancer, personal history of ovarian cancer patients. Diagnosis of all ovarian cancer patients are the pathological diagnosis. Last selected high-risk patients with familial ovarian cancer 39 cases, 32 cases of patients with sporadic ovarian cancer. Research methods: (1) extracted from peripheral blood mononuclear cell DNA using denaturing high-performance liquid chromatography analysis (DHPLC) DNA sequencing, BRCA1 and BRCA2 gene exons and exon intron splice per patient District of mutation detection; (2) the age of onset of high-risk patients with familial ovarian cancer with sporadic ovarian cancer patients, the biological characteristics of the pathological type, tumor stage and grade, chemotherapy sensitivity, statistical analysis and comparison; (3) We collected four complete familial breast cancer - ovarian cancer pedigrees, pedigree qualified female members of DHPLC analysis of DNA sequencing, and the pedigree of the BRCA1 and BRCA2 gene mutations characteristics were analyzed. Results: A total of 39 cases of ovarian cancer patients from 35 independent high-risk family, and 32 cases of sporadic ovarian cancer patients included in this study. In 71 patients, a total of 20 patients carrying the BRCA1 or BRCA2 gene mutation was BRCA gene mutation rate was 28.2%, which BRCA1 mutations, 22.5% (16 cases) and BRCA 2 mutations in 5.6% (4 cases ), the rate of mutations in two genes, there is a significant difference (P = 0.004). In 39 cases of patients with high-risk familial ovarian cancer carry the BRCA1 or BRCA2 gene mutation was 41.0% (16 cases), and 32 patients with sporadic ovarian cancer patients, only 12.5% ??(4 cases) carry the BRCA1 or BRCA2 genes pathogenic mutations in the two groups, a significant difference (P = 0.008). 20 carry BRCA gene mutations are divided into four kinds of mutation type, 75% (15 cases) of the pathogenic gene mutations frameshift mutation, which bases lost 12 cases and insertion of three cases; gene mutations were nonsense mutation in two cases, mutations in introns 2 cases and a missense mutation in one cases. The pathogenic mutation point 20 cases of BRCA mutations located in 16 different loci, 50% (8/16) for the first time found that is not recorded in the database of the Breast Cancer Information Center (BIC), five kinds in the BRCA1, 3 species in the BRCA2. BRCA1 5589del8 repeated in this study appeared in three independent high-risk patients with familial ovarian cancer, and had previously been reported in the Chinese population, considering a possible mutation hotspot of the Chinese population, with part of the Founder effect. Pathogenic mutations in the BRCA gene BRCA1 outside exon 11 of the most common, non-pathogenic gene mutation hot spot areas also focus on the outside of the BRCA1 and BRCA2 gene exon 11, the future should exon 11 hot zone as the BRCA gene. The study of high-risk familial ovarian cancer patients with sporadic ovarian cancer patients carry and do not carry the BRCA gene mutations in patients with age of onset statistics, found no significant difference. Pathological differentiation in terms of ovarian cancer, poorly differentiated accounted for 65.6% (19/32) of sporadic ovarian cancer patients; patients with ovarian cancer in high-risk family accounted for 76.9% (32/39); carry pathogenic mutations of the BRCA genes 20 patients, poorly differentiated, 85% (17/20), but not carry the BRCA gene mutation, only 66.7% (34/51), the differences between the groups were statistically significant (P lt; 0.05). High-risk familial ovarian cancer patients with preoperative serum CA125 levels significantly higher than the sporadic ovarian the cancer (3018.8U/MLvs 1120.4U/ML), a statistically significant difference; However, two sets of blood after chemotherapy CA125 decline satisfaction rate and resistance no statistically significant difference between the drug rate. The overall recurrence time of patients with high-risk familial ovarian cancer than patients with sporadic ovarian cancer later, overall survival; carry the BRCA gene pathogenic mutation than patients not carrying patients, the overall recurrence time later. In this study, 10 cases of breast - double primary ovarian cancer patients, tumors were the first breast cancer, and ovarian cancer incidence interval an average of 13.1 years, the average age of onset of breast cancer is only 44.4 years. A family history of breast / ovarian cancer patients, the tumors were obvious descendants onset earlier trend;-risk family, the family, the more the number of incidence of malignant tumors carry a mutation probability may be greater, and gastrointestinal tumors poly hair are more common. Pedigree analysis, 42 women from four independent ovarian cancer in high-risk family members, 11 members of the two family carry the BRCA gene mutation was mutation carrier rate is 26.2 percent, are located in the BRCA1 gene. Some variations of unknown significance in the distribution of these pedigrees certain rules: (1) carry a higher rate of unknown significance of variation points are located in the BRCA1 gene, polymorphic loci are located in the BRCA2 gene, BRCA1 gene in plays a more important role in the pathogenesis of ovarian cancer at high risk. (2) BRCA1 P1099Q, V1181I and IVS13 117C> higher frequency of variant A and other sites, respectively, 28.6%, 7.1% and 4.8%, which, BRCA1 P1099Q the most widely distributed, found a family of one, two, four three family members, it may be for the Chinese population frequency of mutation. (3) BRCA gene mutations and variations performance for the family specificity and familial poly hair phenomenon in the BRCA1 P1099Q, Ⅳ S13 117C> A and BRCA2 N854K other variations were not reported in the BIC database, it is worth further study. (4) The age of onset of ovarian cancer in high-risk families is smaller, late surgical stage, a higher proportion of poorly differentiated serous adenocarcinoma, but sensitive to chemotherapy, the recurrence interval is longer. Conclusion: This subject is the largest number of cases for the comparative study of mainland China in patients with high-risk familial ovarian cancer and sporadic ovarian cancer patients with BRCA1 / 2 mutations of the gene sequence. Study: (1) discovery of a new pathogenic BRCA gene mutation monk unknown variable sites, which BRCA1 5589del8 repeated, and may have some ancestor effect; (2) high-risk familial ovarian cancer patients with BRCA1 / 2 conducive ovarian cancer gene mutation rate was significantly higher than patients with sporadic ovarian cancer, and its incidence descendants of early onset BRCA1 / 2 mutation testing for breast cancer - a family history of ovarian cancer, the crowd is very necessary, / prediction of breast cancer and early intervention; (3) The BRCA1 gene in hereditary ovarian cancer / breast cancer incidence, may play a more important role; (4) high-risk patients with familial ovarian cancer and carry the BRCA1 / 2 gene mutations, although the higher the degree of malignancy of the tumor, but chemotherapy is more sensitive, the prognosis seems good, still need a randomized controlled study to give the bulk of cases confirmed; (5) different genetic background of the patients, the genetic basis of tumor incidence might different; frequent mutation of the BRCA gene of unknown significance point is likely to be a unique variation of the Chinese population, it is worth further study, to clarify its clinical significance.

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