Germline Mutational Landscape and Novel Targetable RAD51D Variant in Chinese Patients With Ovarian Cancer.

PURPOSE: Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant. METHODS: Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays. RESULTS: Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin. CONCLUSION: Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.

PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/ß-catenin signalling pathway.

Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/ß-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/ß-catenin pathway by stabilising FOXQ1 expression.

KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.

One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately promote cancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance; and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.

Predicting Lymph Node Metastasis From Primary Cervical Squamous Cell Carcinoma Based on Deep Learning in Histopathologic Images.

We developed a deep learning framework to accurately predict the lymph node status of patients with cervical cancer based on hematoxylin and eosin-stained pathological sections of the primary tumor. In total, 1524 hematoxylin and eosin-stained whole slide images (WSIs) of primary cervical tumors from 564 patients were used in this retrospective, proof-of-concept study. Primary tumor sections (1161 WSIs) were obtained from 405 patients who underwent radical cervical cancer surgery at the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014; 165 and 240 patients were negative and positive for lymph node metastasis, respectively (including 166 with positive pelvic lymph nodes alone and 74 with positive pelvic and para-aortic lymph nodes). We constructed and trained a multi-instance deep convolutional neural network based on a multiscale attention mechanism, in which an internal independent test set (100 patients, 228 WSIs) from the FUSCC cohort and an external independent test set (159 patients, 363 WSIs) from the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program database were used to evaluate the predictive performance of the network. In predicting the occurrence of lymph node metastasis, our network achieved areas under the receiver operating characteristic curve of 0.87 in the cross-validation set, 0.84 in the internal independent test set of the FUSCC cohort, and 0.75 in the external test set of the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program. For patients with positive pelvic lymph node metastases, we retrained the network to predict whether they also had para-aortic lymph node metastases. Our network achieved areas under the receiver operating characteristic curve of 0.91 in the cross-validation set and 0.88 in the test set of the FUSCC cohort. Deep learning analysis based on pathological images of primary foci is very likely to provide new ideas for preoperatively assessing cervical cancer lymph node status; its true value must be validated with cervical biopsy specimens and large multicenter datasets.

Risk-reducing salpingo-oophorectomy among Chinese women at increased risk of breast and ovarian cancer.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of breast and ovarian cancer. We launched a prospective study of women receiving RRSO, including those with mutations in genes beyond BRCA1/2. PATIENTS AND METHODS: 80 women were enrolled for RRSO with sectioning and extensively examining the fimbriae (SEE-FIM) protocol between October 2016 and June 2022. The majority of participants had inherited susceptibility gene mutations or a family history suggesting ovarian cancer risk, while patients with isolated metastatic high-grade serous cancer of unknown origin were also included. RESULTS: Overall, two patients had isolated metastatic high-grade serous cancer with unknown origin, and four patients had family histories but refused to take genetic tests. The rest 74 patients harbored deleterious susceptible gene, including 43 (58.1%) with BRCA1 mutation, and 26 (35.1%) with BRCA2 mutation, respectively. Other mutated genes included ATM (1), BRIP1(1), PALB2(1), MLH1(1) and TP53 (1) in each patient. Among the 74 mutation carriers, three (4.1%) cancers were recognized, one (1.4%) was found to have serous tubal intraepithelial carcinoma (STIC), and five patients (6.8%) was diagnosed with serous tubal intraepithelial lesions (STILs). P53 signature was recognized in 24 patients (32.4%). For other genes, MLH1 mutation carrier had endometrial atypical hyperplasia and p53 signature in fallopian tubes. The germline TP53 mutation carrier had STIC in the surgical specimens. Evidence for precursor escape was also recognized in our cohort. CONCLUSION: Our study demonstrated clinic-pathological findings of patients at increased risk of breast and ovarian cancer, and expand the clinical application of SEE-FIM protocol.

Diffusion-weighted magnetic resonance imaging for the pre-operative evaluation of epithelial ovarian cancer patients.

OBJECTIVE: To investigate the value diffusion-weighted magnetic resonance imaging (DWI/MR) in the selection of ovarian cancer patients suitable for primary debulking surgery. METHODS: Patients with suspected ovarian cancer who underwent pre-operative DWI/MR were enrolled between April 2020 and March 2022. All participants received preoperative clinic-radiological assessment according to the Suidan criteria for R0 resection with a predictive score. Data for patients with primary debulking surgery were prospectively recorded. The diagnostic value was calculated with ROC curves, and the cut-off value for the predictive score was also explored. RESULTS: 80 patients with primary debulking surgery were included in the final analysis. The majority (97.5%) of patients were at advanced stage (III-IV), and 90.0% of patients had high-grade serous ovarian histology. 46 (57.5%) patients had no residual disease (R0), and 27 (33.8%) patients had optimal debulking surgery with zzmacroscopic disease less than or equal to 1 cm (R1). Patients with BRCA1 mutation had lower R0 resection rate, higher R1 resection rate compared with wild-type patients (42.9% vs 63.0%, 50.0% vs 29.6%, respectively). The median (range) predictive score was 4 (0-13), and the AUC for R0 resection was 0.742 (0.632-0.853). The R0 rates for patients with predictive score 0-2, 3-5, and ≥ 6 were 77.8%, 62.5% and 23.8%, respectively. CONCLUSION: DWI/MR was a sufficient technique for pre-operative evaluation of ovarian cancer. Patients with predictive score 0-5 were suitable for primary debulking surgery at our institution.

Developing a nomogram for preoperative prediction of cervical cancer lymph node metastasis by multiplex immunofluorescence.

BACKGROUND: Most traditional procedures can destroy tissue natural structure, and the information on spatial distribution and temporal distribution of immune milieu in situ would be lost. We aimed to explore the potential mechanism of pelvic lymph node (pLN) metastasis of cervical cancer (CC) by multiplex immunofluorescence (mIF) and construct a nomogram for preoperative prediction of pLN metastasis in patients with CC. METHODS: Patients (180 IB1-IIA2 CC patients of 2009 FIGO (International Federation of Gynecology and Obstetrics)) were divided into two groups based on pLN status. Tissue microarray (TMA) was prepared and tumor-infiltrating immune markers were assessed by mIF. Multivariable logistic regression analysis and nomogram were used to develop the predicting model. RESULTS: Multivariable logistic regression analysis constructs a predictive model and the area under the curve (AUC) can reach 0.843. By internal validation with the remaining 40% of cases, a new ROC curve has emerged and the AUC reached 0.888. CONCLUSIONS: This study presents an immune nomogram, which can be conveniently used to facilitate the preoperative individualized prediction of LN metastasis in patients with CC.

Homologous recombination deficiency status predicts response to platinum-based chemotherapy in Chinese patients with high-grade serous ovarian carcinoma.

BACKGROUND: Homologous Recombination Deficiency (HRD) is a predictive biomarker for ovarian cancer treated with PARP inhibitors or for breast cancer treated with first-line platinum-based chemotherapy. However, limited research is documented on platinum-based treatment prediction with HRD as a biomarker in ovarian cancer patients, especially in the Chinese population. METHODS: We investigated the association between HRD status and the response of platinum-based chemotherapy in 240 Chinese HGSOC patients. RESULTS: The Pt-sensitive patients showed higher HRD scores than Pt-resistant ones, but this was not significant(median: 42.6 vs. 31.6, p = 0.086). (Pt)-sensitive rate was higher in HRD + BRCAm tumors and in HRD + BRCAwt tumors (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) compared with 74% in the HRD-BRCAwt tumors. We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations or non-BRCA HRR pathway gene mutations (BRCA: 93.6% vs 75.4%, p < 0.001; non-BRCA HRR: 88.6% vs 75.4%, p = 0.062). Patients with HRD status positive had significantly improved PFS compared with those with HRD status negative (median PFS: 30.5 months vs. 16.8 months, Log-rank p = 0.001). Even for BRCAwt patients, positive HRD was also associated with better PFS than the HRD-negative group (median: 27.5 months vs 16.8 months, Log-rank p = 0.010). Further, we found patients with pathogenic mutations located in the DNA-binding domain (DBD) of BRCA1 had improved FPS, compared to those with mutations in other domains. (p = 0.03). CONCLUSIONS: The HRD status can be identified as an independent significance in Chinese HGSOC patients treated with first-line platinum-based chemotherapy.

Head-to-head comparison of [18F]-FDG and [68 Ga]-DOTA-FAPI-04 PET/CT for radiological evaluation of platinum-sensitive recurrent ovarian cancer.

PURPOSE: Precise radiological evaluation is pivotal for the management of platinum-sensitive recurrent ovarian cancer. We aimed to compare the value of [68 Ga]-FAPI and [18F]-FDG PET/CT for the detection of relapsed lesions. METHODS: Twenty-nine suspected platinum-sensitive recurrent ovarian cancers were enrolled from January 2022 to July 2022. [18F]-FDG and [68 Ga]-FAPI PET/CT were obtained within 1 week for radiological evaluation. Treatment strategies, visual scores, and Eisenkop scores were recorded. A paired T test was used to compare differences between two scans. Sensitivity, specificity, PPV, NPV, and accuracy were also evaluated. RESULTS: Up to 22 (75.86%) patients displayed inconsistency between two scans. Among them, 4 patients with negative [18F]-FDG imaging had measurable lesions in [68 Ga]-FAPI scans. The treatment strategies were changed in 5 patients (17.24%) due to discrepancies. Finally, 15 (35.7%) patients underwent surgeries, and 14 patients achieved complete resection, except for 1 patient who had milliarc residual disease. TBR, but not SUVmax, of [68 Ga]-FAPI was significantly higher than that of [18F]-FDG in recurrent lesions. Compared with [18F]-FDG, [68 Ga]-FAPI PET presented higher sensitivity and accuracy for lesion detection (96.30% vs. 49.07% and 97.40% vs. 63.87%, respectively). Additionally, [68 Ga]-FAPI PET showed a much higher visual score than [18F]-FDG PET (41 vs. 4), especially for peritoneal metastasis (35 vs. 1). [68 Ga]-FAPI PET also presented a larger tumor burden than [18F]-FDG according to the Eisenkop score (27 vs. 16, p = 0.025). CONCLUSIONS: [68 Ga]-FAPI was superior to [18F]-FDG PET/CT for the detection of recurrent lesions, which is pivotal for the individualized management of platinum-sensitive recurrent ovarian cancer.

SPOP promotes cervical cancer progression by inducing the movement of PD-1 away from PD-L1 in spatial localization.

BACKGROUND: Metastasis is a major obstacle in the treatment of cervical cancer (CC), and SPOP-mediated regulatory effects are involved in metastasis. However, the mechanisms have not been fully elucidated. METHODS: Proteomic sequencing and SPOP immunohistochemistry (IHC) were performed for the pelvic lymph node (pLN)-positive and non-pLN groups of CC patients. The corresponding patients were stratified by SPOP expression level for overall survival (OS) and relapse-free survival (RFS) analysis. In vitro and in vivo tests were conducted to verify the causal relationship between SPOP expression and CC metastasis. Multiplex immunofluorescence (m-IF) and the HALO system were used to analyse the mechanism, which was further verified by in vitro experiments. RESULTS: SPOP is upregulated in CC with pLN metastasis and negatively associated with patient outcome. In vitro and in vivo, SPOP promotes CC proliferation and metastasis. According to m-IF and HALO analysis, SPOP may promote CC metastasis by promoting the separation of PD-1 from PD-L1. Finally, it was further verified that SPOP can achieve immune tolerance by promoting the movement of PD-1 away from PD-L1 in spatial location and function. CONCLUSION: This study shows that SPOP can inhibit the immune microenvironment by promoting the movement of PD-1 away from PD-L1, thereby promoting pLN metastasis of CC and resulting in worse OS and RFS.

Treatment for clear cell carcinoma of the abdominal wall at a tertiary cancer center.

Clear cell carcinoma (CCC) of the abdominal wall is a rare and agressive disease. We aim to elucidate the clinical and prognostic characteristics of this disease. Medical records of ten patients diagnosed with CCC of the abdominal wall at Fudan University Shanghai Cancer Center were reviewed. We illustrate the clinical characteristics, treatment modality, and development of local recurrence or distant metastasis, as well as the survival outcome. The median (range) age of patients was 47 (39-61) years old. All patients had a history of cesarean section and abdominal wall endometriosis. All patients had primary surgery before referred to our center. Seven patients had only tumor resection, while two patients had lymph node metastasis at primary diagnosis. Four patients underwent supplementary surgery, and all postoperative pathology were negative. Genetic analyses had also been performed. The median (range) follow-up time was 20 (12-59) months. Local recurrence and lymph node metastasis were the most common recurrence types. The median (95% confidence interval) PFS was 11 (8.08-13.92) months. In summary, primary surgery should consider wide tumor resection and lymph node dissection. Adjuvant chemotherapy and radiotherapy should be recommended for potential benefits. More cases are still needed to elucidate the clinical management of this disease.

Progressive resistance exercise training to prevent lower-limb lymphedema after cervical cancer surgery: A feasibility study.

Objective: Radical hysterectomy with pelvic lymphadenectomy is the standard surgical treatment for early stage cervical cancer. One of the most common complications after this surgery is lower extremity lymphedema (LLL). Program of progressive resistance exercise training (PRET) is a possible way to prevent LLL for cervical cancer patients postoperatively. Before we start a randomized controlled trial to evaluate the preventive effect of PRET, we conducted this pilot study to assess the feasibility of PRET after cervical cancer surgery. Methods: The primary purpose of the pilot study was the feasibility of PRET, as well as the satisfaction and adherence to the PRET assessed by a questionnaire. We conducted a single-arm prospective study involving cervical cancer patients who underwent radical hysterectomy with pelvic lymphadenectomy. Participants exercised twice a day for 24 weeks (two weeks of supervised in hospital and then 22 weeks of home-based training) after surgical treatment. All patients were followed up for 12 months. Information that included the limb volume, BMI, perceived difficulty level and adherence rate was collected. Results: From February to April 2019, a total of 24 patients participated in the study. None of them dropped out. The adherence rate was more than 75% in majority of the patients, the perceived difficulty level of the PRET was high (for the first phase, the fourth phase and the fifth phase, more than half of the participants felt the intensity of the exercise appropriate), and no serious adverse events in the study were observed. Conclusions: Exercise training was safe and feasible. The preliminary results offered us the possibility to further test the preventive effect of PRET in a full-scale randomized controlled trial.

Extraperitoneal laparoscopy for para-aortic lymphadenectomy in endometrial carcinoma staging: an approach with higher efficiency.

BACKGROUND: Removing more inframesenteric nodes is not only significantly increases the likelihood of finding metastasis for endometrial cancer, but also can add survival advantage. As most patients diagnosed with endometrial cancer are overweight or obesity, a high efficiency approach is important. Aim of this study was to compare the surgical outcomes of extraperitoneal laparoscopic, transperitoneal laparoscopic, and laparotomic para-aortic lymphadenectomy in endometrial carcinoma staging. METHODS: We retrospectively reviewed data of all patients diagnosed with primary endometrial carcinoma who were treated at the Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center from 1 January 2017 to 31 December 2019. The numbers of para-aortic lymph nodes, surgical time, complications, blood loss and hospital stay were compared. The patients' medical records and pathological reports were carefully reviewed. Statistical significance was defined as p < 0.05. RESULTS: We retrospectively compared patients who underwent extraperitoneal laparoscopy (Group E, n = 20), transperitoneal laparoscopy (group T, n = 21), and laparotomy (group L, n = 135). The median number of para-aortic lymph nodes was significantly higher in group E than in groups T and L (9.5, 5, and 6, respectively; p = 0.004 and 0.0004, respectively). All patients in group E underwent successfully dissection to the renal vessel level. The median operation time was significantly shorter in group L than in groups T and E (94, 174, and 233 min, respectively; p < 0.0001). The median estimated blood loss volume was higher in group L than in groups T and E (200, 100, and 142.5 ml, respectively; all comparisons p < 0.001), and the length of hospital stay was significantly longer in group L than in Groups T and E (6, 5, and 6 days, respectively; all comparisons p < 0.001). CONCLUSION: The extraperitoneal laparoscopic approach for staging endometrial carcinoma harvested higher numbers of para-aortic lymph nodes which could be considered for endometrial carcinoma staging, especially for para-aortic lymph node harvest.

Diagnostic accuracy of 18F-FDG PET/CT scan for peritoneal metastases in advanced ovarian cancer.

BACKGROUND: To assess the diagnostic accuracy of 18F-FDG PET/CT to determine the Eisenkop score and peritoneal cancer index (PCI) in correlation with surgical findings. METHODS: Forty-three patients underwent preoperative 18F-FDG PET/CT scan, followed by primary cytoreductive surgery for advanced ovarian cancer between September 2015 and February 2018. Clinical data were prospectively collected, including intraoperative assessment (with Eisenkop and PCI scores) and surgical results. The sensitivity, specificity, and accuracy were calculated at each anatomical site. The Eisenkop score, PCI score, and tumor volume of PET/CT scans were compared with surgical findings. RESULTS: A total of 32 (74.4%) patients were diagnosed with stage III, and 11 (25.6%) patients were stage IV. Among these individuals, 19 (44.2%) patients had no residual disease after primary surgery. The median [range] Eisenkop score on PET/CT scans and surgical findings were 5 [1-13] and 6 [2-13], respectively. PET/CT scans correctly predicted the Eisenkop score with high sensitivity (84.2%), specificity (87.0%), and accuracy (85.1%). The diagnostic accuracy of PET/CT scans for PCI scores was lower (78.5%), with 72.7% sensitivity and 84.9% specificity. Preoperative PET/CT scans might underestimate tumor volume compared with surgical findings. CONCLUSIONS: 18F-FDG PET/CT scans accurately predicted peritoneal metastases in advanced ovarian cancer before surgery using Eisenkop score.

HNRNPH1-stabilized LINC00662 promotes ovarian cancer progression by activating the GRP78/p38 pathway.

Numerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.

Effect of the Number of Removed Lymph Nodes on Survival in Patients with FIGO Stage IB-IIA Cervical Squamous Cell Carcinoma following Open Radical Hysterectomy with Pelvic Lymphadenectomy: A Retrospective Cohort Study.

OBJECTIVE: To determine whether the number of removed lymph nodes (RLN) is associated with survival in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIA cervical squamous cell carcinoma (CSCC). METHODS: We reviewed the medical records of FIGO stage IB-IIA CSCC patients who underwent standardized radical hysterectomy with pelvic lymphadenectomy (RHPL) in our center between 2006 and 2014. The X-tile software was performed to calculate the optimal grouping of cutoff points for RLN. The impact of RLN on progression-free survival (PFS) and overall survival (OS) was analyzed using Cox regression analysis. RESULTS: Among 3,127 patients, the mean number of RLN was 22, and positive lymph node (LN) was found in 668 (21.4%) patients. X-tile plots identified "21" and "16" as the optimal cutoff value of RLN to divide the patients into two groups in terms of PFS and OS separately. In all patients, the number of RLN was not associated with PFS (P=0.182) or OS (P=0.193). Moreover, in both LN positive and negative patients, the number of RLN was not associated with either PFS (P=0.212 and P=0.540, respectively) or OS (P=0.173 and P=0.497, respectively). Cox regression analysis showed that the number of RLN was not an independent prognostic factor for PFS or OS. CONCLUSION: If standardized RHPL was performed, the number of RLN was not an independent prognostic factor for survival of patients with FIGO stage IB-IIA CSCC.

Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients.

BACKGROUND: The purpose of our study was to identify germline and somatic homologous recombination repair (HRR) pathway gene mutations and their clinical-prognostic impact in Chinese high-grade serous ovarian cancer (HGSC) patients. METHODS: We applied next-generation sequencing (NGS) in consecutive patients who underwent primary surgery for HGSC in November and December 2015 at our institution. Paired peripheral blood (or para-carcinoma tissue) samples and tumor samples from 42 Chinese women were tested to identify both germline and somatic deleterious mutations through all exons in BRCA1/2 and 22 other core HRR genes. Clinic-pathological data were collected until February, 2020. Associations between HRR gene mutations and clinical characters and outcomes were also evaluated. RESULTS: Deleterious germline HRR mutations were identified in 16.7% (7/42) of the HGSC patients. One patient had both germline BRCA2 and ATM mutations. Six patients had only somatic mutations, increasing the HRR mutation rate to 31.0% (13/42). Neither germline nor somatic HRR gene mutations were related with residual disease (P=0.233) nor platinum sensitivity (P=0.851). In the univariate and multivariate analyses, germline HRR gene mutation status was not associated with progression-free survival (PFS) or overall survival (OS). In addition, no prognostic differences between somatic HRR mutated patients and wild-type patients were found. CONCLUSIONS: Our results suggest that the HRR gene defect was not associated with improved survival in our Chinese HGSC patient cohort.

Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia.

BACKGROUND: Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC. METHODS: Bioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment. RESULTS: EOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO. CONCLUSIONS: The above results suggest that NPTX2 may play a novel role in ovarian cancer's malignant phenotype and act as a promising treatment target for EOC molecular therapy.

The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B.

An increasing number of studies have clarified the functional roles of RNA-binding proteins (RBPs) in driving post-transcriptional mechanisms of cancer progression. In this study, we integrated data from the RBP database and Gene Expression Omnibus (GEO) data with RNA sequencing (RNA-seq) data from 10 ovarian cancer tissues and 8 normal ovarian tissues and identified an RBP, CUGBP- and ETR-3-like family 2 (CELF2). We found that CELF2 expression was downregulated in ovarian cancer and positively correlated with the overall survival (OS) and progression-free survival (PFS) of patients with ovarian cancer. Altered CELF2 expression led to changes in the proliferation, migration, and invasion of ovarian cancer cells in vitro and in vivo. CELF2 expression increased the stability of its target, FAM198B, by binding to AU/U-rich elements (AREs) in the 3' untranslated region (3' UTR). FAM198B knockdown restored the CELF2-mediated suppression of proliferation and migration. We also found that CELF2/FAM198B may repress ovarian cancer progression by inhibiting the mitogen-activated protein kinase/extracellular-regulated protein kinase (MAPK/ERK) signaling pathway. Finally, a curcumin-induced increase in CELF2 expression resulted in increased ovarian cancer cell sensitivity to cisplatin. Our study elucidated a novel mechanism by which the CELF2/FAM198B axis regulates proliferation and metastasis in ovarian cancer, providing novel, potential therapeutic targets for ovarian cancer.