Abstract
Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.
Highlights
Ovarian clear cell carcinomas (OCCCs) represent a distinct histological and clinical subset accounting for 5–10% of epithelial ovarian cancers (EOCs), but among Asian women, the rate is at least 15%
In a previous study of Lynch syndrome-associated ovarian cancer, we reported a distinct gene expression pattern of OCCC compared to other subtypes using unsupervised hierarchical clustering
We applied a variance filter to select the 2,500 genes with the highest variance across tumors. This was done to select as many targets as possible throughout the signaling network hierarchy, as proposed by Komurov and Ram [47]. This significance analysis of microarrays (SAM) analysis identified 504 significant genes (FDR < 10%), and the subsequent pathway enrichment analysis revealed genes belonging to both the NCAM signaling and TFAP2A transcription pathways, as well as pathways involved in MAPK signaling
Summary
Ovarian clear cell carcinomas (OCCCs) represent a distinct histological and clinical subset accounting for 5–10% of epithelial ovarian cancers (EOCs), but among Asian women, the rate is at least 15%. Of the four major histopathological subtypes [serous, endometrioid (EM), mucinous (MUC), and clear cell ovarian cancers], OCCCs stand out as a group with distinct clinical characteristics [5]. They are considered type 1 tumors, arising gradually through progression from benign precursors associated with endometriosis, and eventually developing into invasive carcinomas [6, 7]. The inferior prognosis may be related to a high prevalence of primary chemotherapy resistance, primarily to platinum-based drugs This may be due to both a low proliferation rate (a prototypic type 1 tumor feature) and intrinsic resistance mechanisms such as expression of apoptosis regulators, e.g., p53 and p21, this is not entirely clear [(11), reviewed in Ref. This may be due to both a low proliferation rate (a prototypic type 1 tumor feature) and intrinsic resistance mechanisms such as expression of apoptosis regulators, e.g., p53 and p21, this is not entirely clear [(11), reviewed in Ref. [12]]
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