Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.

Exploring the Potential of Natural Killer Cell-Based Immunotherapy in Targeting High-Grade Serous Ovarian Carcinomas.

High-grade serous ovarian cancers (HGSOCs) likely consist of poorly differentiated stem-like cells (PDSLCs) and differentiated tumor cells. Conventional therapeutics are incapable of completely eradicating PDSLCs, contributing to disease progression and tumor relapse. Primary NK cells are known to effectively lyse PDSLCs, but they exhibit low or minimal cytotoxic potential against well-differentiated tumors. We have introduced and discussed the characteristics of super-charged NK (sNK) cells in this review. sNK cells, in comparison to primary NK cells, exhibit a significantly higher capability for the direct killing of both PDSLCs and well-differentiated tumors. In addition, sNK cells secrete significantly higher levels of cytokines, especially those known to induce the differentiation of tumors. In addition, we propose that a combination of sNK and chemotherapy could be one of the most effective strategies to eliminate the heterogeneous population of ovarian tumors; sNK cells can lyse both PDSLCs and well-differentiated tumors, induce the differentiation of PDSLCs, and could be used in combination with chemotherapy to target both well-differentiated and NK-induced differentiated tumors.

Analysis of Omics Data Reveals Nucleotide Excision Repair-Related Genes Signature in Highly-Grade Serous Ovarian Cancer to Predict Prognosis.

Most of the high-grade serous ovarian cancers (HGSOC) are accompanied by P53 mutations, which are related to the nucleotide excision repair (NER) pathway. This study aims to construct a risk signature based on NER-related genes that could effectively predict the prognosis for advanced patients with HGSOC. In our study, we found that two clusters of HGSOC with significantly different overall survival (OS) were identified by consensus clustering and principal component analysis (PCA). Then, a 7-gene risk signature (DDB2, POLR2D, CCNH, XPC, ERCC2, ERCC4, and RPA2) for OS prediction was developed subsequently based on TCGA cohort, and the risk score-based signature was identified as an independent prognostic indicator for HGSOC. According to the risk score, HGSOC patients were divided into high-risk group and low-risk group, in which the distinct OS and the predictive power were also successfully verified in the GEO validation sets. Then we constructed a nomogram, including the risk signature and clinical-related risk factors (age and treatment response) that predicted an individual's risk of OS, which can be validated by assessing calibration curves. Furthermore, GSEA showed that the genes in the high-risk group were significantly enriched in cancer-related pathways, such as "MAPK signaling pathway", "mTOR signaling pathway", "VEGF signaling pathway" and so on. In conclusion, our study has developed a robust NER-related genes-based molecular signature for prognosis prediction, and the nomogram could be used as a convenient tool for OS evaluation and guidance of therapeutic strategies in advanced patients with HGSOC.

Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling.

Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.

CD105 Is Expressed in Ovarian Cancer Precursor Lesions and Is Required for Metastasis to the Ovary.

: Most high-grade serous ovarian cancers (HGSCs) initiate from the fallopian tube epithelium and then metastasize to the ovary and throughout the abdomen. Genomic analyses suggest that most HGSCs seed the ovary prior to abdominal dissemination. Similarly, animal models support a critical role for the ovary in driving abdominal dissemination. Thus, HGSC cell recruitment to the ovary appears to be a critical component of HGSC cell metastasis. We sought to identify factors driving HGSC recruitment to the ovary. We identified CD105 (endoglin, or ENG, a TGF- receptor family member) as a mediator of HGSC cell ovarian recruitment. We found that CD105 was expressed on both serous tubal intraepithelial carcinoma (STIC) cells (STICs-HGSC precursors in the fallopian tube epithelium) and HGSC cells. Using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), we showed that high CD105 expression by HGSC cells correlated with a metastatic signature. Furthermore, intravenous injection of CD105(+) HGSC tumor cells, but not CD105(-), resulted in ovarian-specific metastasis and abdominal dissemination of disease. CD105 knockdown or blockade with a clinically relevant CD105-neutralizing mAb (TRC105), inhibited HGSC metastasis, reduced ascites, and impeded growth of abdominal tumor nodules, thereby improving overall survival in animal models of ovarian cancer. CD105 knockdown was associated with a reduction in TGF-signaling. Together, our data support CD105 as a critical mediator of ovarian cancer spread to the ovary and implicate it as a potential therapeutic target.