Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures

Abstract

Background It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs. Methods We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF). Results We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p<0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I /II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype. Conclusions Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.

Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes

“…Gene expression analysis of fresh frozen ovarian cancers performed in the Australian Ovarian Cancer Study and The Cancer Genome Atlas (TCGA) has led to a molecular classification of four subtypes of high-grade serous (HGS) ovarian cancer: proliferative, mesenchymal, immunoreactive and differentiated 3,4 . In contrast to the original TCGA report, we recently demonstrated that these four subgroups have prognostic significance when well-annotated with complete clinical follow-up 5,6 . Furthermore, we demonstrated that these molecular subtypes could also be used to classify high grade, advanced stage endometrioid and clear cell ovarian cancers 6 .…”

“…In contrast to the original TCGA report, we recently demonstrated that these four subgroups have prognostic significance when well-annotated with complete clinical follow-up 5,6 . Furthermore, we demonstrated that these molecular subtypes could also be used to classify high grade, advanced stage endometrioid and clear cell ovarian cancers 6 . However, the clinical practice of stratifying ovarian cancer patients into different targeted treatment subgroups based on their molecular classification has not yet been adopted.…”

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer

“…The molecular landscape of each histotype of EOC is distinct (3, 4). However, all patients are treated similarly with standard of care debulking surgery and chemotherapy regimens, with dismal “cure” rates of 20% (1).…”

“…Each histotype is thought to arise from distinct precursor lesions of the female reproductive tract (2). Molecularly, the landscape of each individual EOC histotype is distinct at the gene expression and genomic DNA level, allowing novel means to classify tumors beyond traditional histology (3, 4). …”

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

“…The mainstay treatment for women with high-grade serous ovarian cancer (HGSOC) remains cisplatin, which was introduced in the late 1970s (8), and while survival rates have largely unchanged since then (9), emerging therapeutic strategies that include surgical improvements, use of anti-VEGF antibodies, and recent approvals for PARP inhibitors indicate that significant progress is being made (10)(11)(12). While profiling in HGSOC has led to important insights for the molecular classification of ovarian cancer subtypes, there persists a gap at the level of finding lesions that act as oncogenic drivers and are validated as clinically relevant targets in these patients (13)(14)(15). Synthetic lethality, commonly based on tumor suppressor loss, emerges as an alternative approach.…”