Background:Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.Methods:Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.Results:Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10–0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13–0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.Conclusions:The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

Background: Mutant Niemann-Pick C1 (NPC1) is degraded by the proteasome. Results: NPC1 is one of the clients of HSP/CHIP (heat shock protein/carboxyl terminus of Hsp70-interacting protein) complexes and accepts ubiquitin at multiple lysine residues. Conclusion: HSPs are critical in the quality control of NPC1. Significance: Unraveling the mechanisms of NPC1 degradation is crucial for development of a chaperone therapy.

ARID1A may be a biomarker that is predictive of the outcome of FIGO stage I and II CCC.

The present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma.

Abstract.Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC 50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC 50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC 50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G 1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent. IntroductionClear cell carcinoma of the ovary (OCCC) is recognized in the World Health Organization classification of ovarian tumors as a distinct histological entity. Its clinical behavior is distinctly different from other epithelial ovarian cancers (1). OCCC accounts for 3.7-12.1% of epithelial ovarian cancers (2,3). We found that response rates for platinum-based chemotherapy were 11.1% for OCCC and 72.5% for serous adenocarcinoma (SAC), suggesting that OCCC resists conventional platinumbased chemotherapy (4). A novel therapeutic strategy is needed to improve the prognosis of patients with OCCC.PIK3CA is located at the 3q26.3 locus and encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K), p110α (5). In response to an extracellular signal, the activated p110α phosphorylates PIP2 to generate PIP3. The PIP3 recruits AKT to the plasma membrane, where it is phosphorylated and activated by phosphatidylinositol-dependent kinase 1 (PDK1) and PDK2. Activated AKT can directly activate the mammalian target of rapamycin (mTOR) by phosphorylation at Ser2448. mTOR ...