Etiology and Pathogenesis of Epithelial Ovarian Cancer

Ovarian cancer is complex disease composed of different histological grades and types. However, the underlying molecular mechanisms involved in the development of different phenotypes remain largely unknown. Epidemiological studies identified multiple exogenous and endogenous risk factors for ovarian cancer development. Among them, an inflammatory stromal microenvironment seems to play a critical role in the initiation of the disease. The interaction between such a microenvironment, genetic polymorphisms, and different epithelial components such as endosalpingiosis, endometriosis, and ovarian inclusion cyst in the ovarian cortex may induce different genetic changes identified in the epithelial component of different histological types of ovarian tumors. Genetic studies on different histological grades and types provide insight into the pathogenetic pathways for the development of different disease phenotypes. However, the link between all these genetic changes and the etiological factors remains to be established

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

Funder: National Health and Medical Research Council; doi: http://dx.doi.org/10.13039/501100000925Abstract: Background: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. Methods: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. Results: These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. Conclusions: These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC

The Molecular Origin and Taxonomy of Mucinous Ovarian Carcinoma

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases

INC280, an orally available small molecule inhibitor of c-Met, reduces migration and adhesion in ovarian cancer cell models

Overall 5-year survival rates for ovarian cancer have remained stable at only 40% for more than two decades. Furthermore, women diagnosed at late stage, who make up a majority of ovarian cancer patients, carry 5-year survival rates of just 27%. These figures indicate a dire need for new therapeutic treatments to help improve survival rates in ovarian cancer. Recent advances in molecular and histological characterization of ovarian cancer have greatly improved our understanding of the disease and have allowed the identification of potential new targets. Although no targeted therapies are currently approved for treatment of ovarian cancer, a pathway of interest is the HGF/c-Met axis. Activation of the HGF/c-Met axis has been demonstrated in certain ovarian tumors, and has been found to be associated with decreased overall survival, suggesting its potential as a therapeutic target. The objective of this study was to determine the efficacy of a novel, highly potent, orally-bioavailable c-Met inhibitor, INC280, in blocking cell behaviors important in ovarian cancer metastasis. Using in vitro and ex vivo models, we demonstrate that INC280 inhibits HGF-induced c-Met phosphorylation for at least 48 hours, and reduces downstream signaling via ERK and Akt. Both chemotactic and random migration are decreased by INC280 treatment, to levels seen in non-stimulated cells. In addition, HGF-induced adhesion to peritoneal tissue is also significantly decreased by INC280 treatment. Overall, these data indicate that INC280 inhibits many cell behaviors that promote ovarian cancer metastasis, and merits further investigation as a therapeutic candidate in the treatment of patients with ovarian cancer

Open Access

ZNF300P1 Encodes a lincRNA that regulates cell polarity and is epigenetically silenced in type II epithelial ovarian cance