[Research subject]

Research on individualized treatment of ovarian cancer based on gene expression profiles

[Description]
Serous ovarian cancer is the most frequent tissue type of epithelial ovarian cancer. Its 5-year survival rate is around 40%, and new therapeutic strategies for improving prognosis have been awaited. In recent years, ovarian cancer, from a molecular biological standpoint, is considered to be a heterogeneous disease. This research focused on this molecular biological heterogeneity to establish a prognostic system for predicting advanced serous ovarian cancer based on gene expression profiles for improving prognosis by individualized treatment.
An elastic net analysis with 10-fold cross validation was performed using gene expression data from 260 patients with advanced serous ovarian cancer, and a prognostic index composed of 126 genes was developed. Based on the prognostic index, high and low risks were determined, and the predictive performance of these classifications was checked with validation data (816 patients). Furthermore, changes in the immune system, particularly antigen presentation pathways in cancer cells, were identified as being strongly inhibited in the high risk group.
Currently, we are performing research to clinically apply genetic testing in the high risk group, promote enhancement of the antitumor effect of host immune cells by the reactivation of antigen presentation pathways, and improve the prognosis of the high risk group.
(Yoshihara K & Tajima A, et al. Cancer Sci 2009; Yoshihara K, et al. PLoS ONE 2010; Yoshihara K, et al.: Clin Cancer Res, 18:1374-85, 2012.)

[Research subject]

Research on gene polymorphisms of detoxification enzymes for habitual abortion of unknown cause

[Description]
In recent years, the involvement of detoxification genetic factors has been suggested to be a cause of habitual abortion. Toxic substances contained in favorite foods are activated by CYP1A1 and detoxified by GSTs. Decreased activation of detoxification enzymes during pregnancy delays the elimination of toxic substances from the body, and abortion may occur. However, the cause has not been fully elucidated such that this research aimed to reveal this aspect. A questionnaire survey on favorite foods was carried out in 96 patients who had habitual abortions (at least 3 abortions early in pregnancy) (patient group). A gene polymorphism analysis was conducted using genomic DNA to determine the gene polymorphisms of each enzyme including CYP1A1, GST-π, GST-μ, and GST-θ by the PCR-RFLP method. A total of 96 women who had experienced childbirth at least twice and had no history of abortion were included in the control group. There were no significant differences in gene frequencies between the two groups for CYP1A1, GST-π, GST-μ, or GST-θ. Favorite foods and gene frequencies were compared between the two groups. The results showed GST-μ deletions in 41 of 67 patients (61%) in the patient group and 28 (41%) of 68 patients in the control group in relation to coffee drinking; the rate was significantly higher in the patient group (chi-square test). The above results suggested that coffee drinking might be associated with the onset of habitual abortion in women with deletion of GST-μ among the detoxification factors, and this could be used for lifestyle habit guidance for the prevention of habitual abortion.
(Nonaka T, Takakuwa K, et al.Journal of Obstetrics and Gynaecology Research, 37:1352-1358, 2011.)

[Description]
With the improvement of treatment drugs, HIV-infected patients can live for a long time and may wish to get married and have children. When 100 married couples consisting of HIV-positive men and HIV-negative women attempted to get pregnant by usual intercourse, 4.8 women/year were reported to be infected with HIV, and secondary infection of women by artificial insemination has also been reported. From this standpoint, it is important to establish safe assisted reproduction technologies without the risk of secondary infection for married couples consisting of HIV-positive men and HIV-negative women. In our department, we have been performing in vitro fertilization-embryo transfer using the modified swim-up technique and RT-nested PCR method as safer assisted reproduction technologies for married couples consisting of HIV-positive men and HIV-negative women since 2001. We have implemented this therapy in 58 such married couples so far. The women underwent 102 cycles of ovulation induction, and pregnancy was achieved following 29 fresh embryo transfer cycles (42.0%) and 8 frozen embryo transfer cycles (25.8%). A total of 28 married couples (48.3%), excluding women with abortions, who underwent this therapy, delivered children. In addition, no secondary infections were noted in any of the wives who underwent embryo transfers or their babies born after this procedure. Based on the above, this therapy has been determined to be effective and safe.
(Kato S, Takakuwa K, et al. AIDS, 20:967-73, 2006. Kashima K, Takakuwa K, et al. Japanese Journal of Infectious Disease. 62: 173-176, 2009.)