卵巣癌の分子生物学的特性を利用した新規治療法の開発(学術奨励賞受賞講演,第63回日本産科婦人科学会・学術講演会)

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On the basis of digital karyotyping, we have identified a new, discrete amplified region at ch19p13.2 in a high-grade ovarian serous carcinoma. To further characterize this region, we determined the frequency and biological significance of ch19p13.2 amplification by analyzing 341 highgrade serous carcinomas from The Cancer Genome Atlas (TCGA) and found an increased DNA copy number at this locus in 18% of cases. We correlated the DNA and RNA copy number by analyzing the TCGA data set for all amplified genes and detected seven genes within ch19p13.2 that were significantly correlated (R≥0.54) and were, in fact, listed as the top 100 potential 'driver' genes at a genome-wide scale. Interestingly, one of the seven genes, NACC1, encoding NAC1 was previously reported to be involved in the development of tumor recurrence in ovarian serous carcinoma and to have a causal role in the development of paclitaxel resistance. On the basis of fluorescence in situ hybridization, we found that 35 (20%) of 175 high-grade serous carcinomas had an increased DNA copy number at the NACC1 locus, and those amplified cases were associated with early disease recurrence within 6 months (P=0.013). Overexpression of NAC1 correlated with shorter relapse-free survival in patients with advanced stage (stage III/IV) ovarian carcinoma treated with platinum and taxane chemotherapy. Furthermore, overexpression of NAC1 in primary tumors predicted recurrence within 6 months after primary cytoreductive surgery followed by standard platinum and taxane chemotherapy. Both coimmunoprecipitation and double immunofluorescence staining demonstrate that NAC1 molecules homooligomerize through the BTB/POZ domain. Induced expression of the NAC1 mutant containing only the BTB/POZ domain disrupts NAC1 bodies, prevents tumor formation, and promotes tumor cell apoptosis in established tumors in a mouse xenograft model. Overexpression of full-length NAC1 enhanced tumorigenicity of ovarian surface epithelial cells and NIH3T3 cells in athymic nu/nu mice. In summary, NAC1 is a tumor recurrence-associated gene with oncogenic potential, and the interaction between BTB/POZ domains of NAC1 proteins is critical to form the discrete NAC1 nuclear bodies and essential for tumor cell proliferation and survival. Therefore, NAC1-targeted therapy may benefit ovarian cancer patients with NAC1 expression.
2011-12-01

卵巣癌の分子生物学的特性を利用した新規治療法の開発(学術奨励賞受賞講演,第63回日本産科婦人科学会・学術講演会)

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