**6. Recurrent clear cell ovarian carcinoma**

Clear cell ovarian cancers (CCOC) are a subtype of EOC with very distinct biology to HGSOC. They exhibit a very poor prognosis and a low response to platinum-based chemotherapy. This subtype is molecularly heterogeneous for point mutations, gene copy number, and alterations in the *PI3K/AKT/mTOR* pathway. Thus, these could affect response to targeted therapy [28, 29]. Histologically, patients with CCOC must be correctly diagnosed because HGSOC with clear cell features can easily be misdiagnosed as CCOC [30]. This might also result in the decreased or failed response to treatment in such CCOC patients misdiagnosed with HGSOC.

A tumour profiling study to identify potential druggable targets in CCOC was carried out by employing protein expression by immunohistochemistry (IHC), next-generation sequencing (NGS) and gene amplification by fluorescent in situ hybridization (FISH). On the basis of IHC, this study revealed an 80.8% *RRM1* loss, 79.6% *ERCC1* loss, 56.4% *MGMT* loss, 50.8% *TS* loss and a 62.6% *TOP2A* overexpression [31]. The NGS identified 50.5%, 18.1%, and 12.4% mutations in *PIK3CA, TP53, and KRAS* respectively. Of which *TP53* mutations were observed on exons 4 to 8, while most *PIK3CA* mutations occurred on exons 9 and 20. For FISH analyses, *HER2* was amplified in 9.3% of pure and 3.8% of mixed CCOC samples, while *cMET*, was amplified in 3.2% of pure CCOC and none was amplified in mixed CCOC. Mutations in *ATM* and *APC* were also observed only in pure CCOC tumours [31].

Even though CCOCs are mostly chemoresistant, few patients do respond to platinum chemotherapy. Different mechanisms of CCOC chemoresistance have been reported including increased drug detoxification, increased DNA repair, decreased

*A Succinct Molecular Profile of High-Grade Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.107369*

drug detoxification, abnormal growth factor signalling and cell cycle control. Loss of ARID 1A expression and alterations in the *PI3K/AKT/mTOR* pathway may also contribute to the chemoresistance in CCOC [32–34]. The *PI3K/AKT/mTOR* is a key mediator of oncogenic signalling, which may be overactive due to *PTEN* loss. The *PI3K* pathway is a complex signalling network that coordinates signals from other membrane receptors such as *MET* [35].

It is important to note that the signalling pathway of the receptor tyrosine kinase *MET* and its ligand hepatocyte growth factor (HGF) is crucial for cell motility, growth and survival, and is functionally linked to the *VEGF* signalling pathway [31]. Therefore, research into the kinase inhibitor agents that target *MET*, *VEGF* receptor 2 and other tyrosine kinases are urgently needed.
