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Clear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late-stage CCOC is not responsive to gold-standard chemotherapy and results in suboptimal outcomes for patients. In-depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.

Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.

Endometrioid ovarian cancer (ENOC) and clear cell ovarian cancer (CCOC) share a common precursor lesion, endometriosis (ectopic growth of uterine lining), hence the designation endometriosis-associated ovarian cancer (EAOC). Women with endometriosis have up to three-fold increased risk of developing ENOC and CCOC. Efforts have been made to look for biomarkers that can help identifying women at risk of developing cancer; however, there are currently no biomarkers that stratify risk of cancer development. We performed whole-genome sequencing (WGS) on 29 ENOC and 35 CCOC cases and observed a frequent transduction event originating from an active LINE-1 (L1) retrotransposable element in the TTC28 gene. Such event occurred in 34% (10/29) of ENOC, and 31% (11/35) of CCOC cases. L1 retrotransposons are repetitive, mobile genetic elements capable of taking downstream DNA fragments and inserting them into random genomic locations via a process called 3’ transduction. Approximately 70-100 different potentially active L1s are epigenetically silenced in normal tissues, but tend to be reactivated in cancers. We subsequently used PCR to validate these TTC28-L1 transductions, and compared their presence to single nucleotide variations (SNVs) and frameshift mutations in formalin-fixed, paraffin-embedded (FFPE) tumor tissues from different tumor sites for 4 ENOC and 3 CCOC cases. We found that these transduction events along with classical driver mutations were almost ubiquitous across the tumor sites, suggesting these L1 events likely occurred early in the malignant transformation of EAOCs. We developed a low-input, probe-based capture assay to test the presence of TTC28-L1 transductions as an alternative method to performing WGS. Oligonucleotide probes tiling 1 kb downstream of active L1s are used to capture DNA fragments containing the transduced DNA, and the fragments are sequenced on the MiSeq next-generation sequencing platform. Analyses are performed using the Geneious software and the published bioinformatics tool Socrates, specific for detecting DNA fragments with split reads (fragments with ends aligning to different parts of the genome). We successfully validated the assay on 9 cases with WGS data: 7 EAOC cases with TTC28-L1 transductions and 2 EAOC cases without TTC28-L1 transductions. DNA extracted from frozen tumor and buffy coat (normal control) were used for each case, and FFPE tissues were used for selected cases. All reads containing the transduction events aligned to genomic coordinates corresponding to the WGS data. While L1-mediated DNA transductions are often passenger events during tumorigenesis, our data suggest that they likely occur early in ovarian cancer tumorigenesis. Our data show that this probe-based capture assay provides an alternative method to WGS, and may be useful in detecting active 3’ transductions in novel cases to track the development of ovarian tumors. Citation Format: Zhouchunyang Xia, Dawn Cochrane, Michael Anglesio, Winnie Yang, Miguel Alcaide, Tayyebeh Nazeran, Janine Senz, Amy Lum, Ali Bashashati, Yikan Wang, Ryan Morin, Sohrab Shah, David Huntsman. Capturing L1 retrotransposon-mediated DNA transductions in endometriosis associated ovarian cancers as a way to track tumor development. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B22.

Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation-induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression-free (p = 0.0232), disease-specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease-specific [hazard ratio (HR): 2.55 (95% CI 1.21-5.37); p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00-3.77); p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia-related proteins carbonic anhydrase-IX and HIF-1α. The functional link between hypoxia and autophagy was demonstrated using clear cell and high-grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high-grade serous lines. Together, our findings indicate that hypoxia-induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes.