Increased incidence of brain metastases in BRCA1-related ovarian cancers.

AIM: Brain metastasis from ovarian cancer is a very rare phenomenon. BRCA1-related ovarian cancers show specific pathobiological profiles, advanced stage, and sensitivity to chemotherapeutic agents. However, no clear relationship to any known metastatic behavior has yet been found, so we examined the BRCA1 mutation and expression profiles in ovarian cancer cases with brain metastases. MATERIAL AND METHODS: We examined our clinical records of 340 ovarian cancer cases from 1983 to 2007 to ascertain cases with brain metastases. In the molecular genetic analyses, we performed loss of heterozygosity (LOH), direct sequence and immunohistochemical staining analysis of BRCA1. RESULTS: We ascertained seven cases with brain metastases in 340 ovarian cancer cases (7/340=2.1%). Among the seven cases, three cases had ovarian and/or breast cancer patients in third-degree relatives. We detected four LOH-positive cases and a germline mutation of BRCA1 in two of the four cases. Furthermore, the remaining two cases showed absent staining of the BRCA1 protein. Therefore, four of seven cases with brain metastases were considered BRCA1-related ovarian cancers (4/7=57.1%). All four of the cases were serous adenocarcinoma. CONCLUSION: Our results suggest that the loss of BRCA1 function may be involved in the phenomenon of brain metastasis from ovarian cancer. Further molecular biologic analyses will be required for a better understanding of this rare phenomenon.

Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis.

To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18,716 genes. By non-negative matrix factorization analysis using 178 genes, which were extracted as stage-specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression-free survival (log rank test, P = 0.03). Of the 178 stage-specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression-free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression-free survival was validated by real-time RT-PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E-cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial-mesenchymal transition-related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer.

The prevalence of hereditary breast/ovarian cancer risk in patients with a history of breast or ovarian cancer in Japanese subjects.

AIM: Women at high risk for hereditary breast/ovarian cancer require specific management strategies for cancer prevention and early detection. The authors sought to determine the prevalence of family histories suggestive of a hereditary breast/ovarian cancer syndrome in patients with a personal history of breast or ovarian cancer in Japanese women. METHODS: Family history (first- and second-degree relatives) data were collected by a self-administered questionnaire for women with a history of breast or ovarian cancer in six major cancer treating hospitals in Niigata prefecture, Japan. RESULTS: Data were obtained from 1463 women: 626 women with a history of breast cancer, 289 women with a history of ovarian cancer and 548 women without a history of any cancer as controls. Women with a family history of breast and/or ovarian cancer had OR of breast cancer of 2.3 (95% confidential interval [CI] 1.5-3.7) and ovarian cancer of 2.2 (95% CI 1.3-3.8). The risk was higher when the proband was younger or when two or more relatives were affected. Among women with a history of breast or ovarian cancer, 7.5% met the criteria for a 10% risk of a BRCA1 or BRCA2 mutation according to the Myriad model. CONCLUSION: Obtaining a detailed breast and ovarian cancer family history and the application of the Myriad model is useful for identifying women at an elevated genetic risk of breast and ovarian cancer. The estimation for the prevalence of hereditary breast/ovarian cancer syndrome has significant implications for a patient's management, as well as for the capacity for risk assessment and testing.