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Summary Background The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. Methods This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. Findings Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1–58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0–19·8) in the surgery group and 11·9 months (10·0–13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45–0·74; p Interpretation Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. Funding Zhongshan Development Program. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Chemotherapy resistance remains a blockade for successful treatment and longer overall survival of patients with epithelial ovarian cancer (EOC). CTNNBIP1 is an inhibitor of β-catenin that is a chemotherapeutic target for EOC treatment. In the present study, we investigated associations between single nucleotide polymorphisms (SNPs) of CTNNBIP1 and platinum treatment response of Han Chinese EOC patients and subsequently performed functional prediction and validation of the resultant SNPs. We found that CTNNBIP1 rs935072 AT/TT variant genotypes were associated with platinum treatment response in the multivariate logistic regression analysis of EOC patients. Specifically, the CTNNBIP1 rs935072 AT/TT genotypes were associated with a decreased risk of developing chemoresistance ([adjusted odds ratio (OR)] = 0.89, 95% confidence interval (CI) = 0.82-0.97 and P=0.010), compared with the AA genotype. Further experiments showed that the underlying mechanism for the CTNNBIP1 rs935072 A>T change in chemotherapy treatment response resulted from a lower binding affinity of miR-27a-3p, thereby leading to up-regulation of the CTNNBIP1 expression. We further found that overexpression of CTNNBIP1 sensitized ovarian cancer cells to platinum treatment. Thus, the present study provides evidence that functional variants of CTNNBIP1 may regulate the expression of CTNNBIP1, a possible mechanism affecting platinum treatment response of EOC patients.

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76–6.25 and P = 2.01E–04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19–2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Developing effective analytical method for sulfadimethoxine (SDM) detection is highly desirable and vitally crucial for protecting environment safety and human health. Herein, a highly selective and sensitive photoelectrochemical (PEC) aptasensor for accurate detection of SDM was proposed, which employed zinc phthalocyanine/graphitic carbon nitride (ZnPc/CN) nanocomposite as photosensitive material. The ZnPc/CN nanocomposite was constructed by modification of CN nanosheet with visible/near-infrared light responsive photosensitizer ZnPc. The introduction of ZnPc into CN exhibited amplified PEC response, which was 5.7 and 18.3 times than pure ZnPc and CN, attributed to the enhanced light harvesting ability and improved photoelectric conversion efficiency of such nanocomposite. By using ZnPc/CN and sulfadimethoxine (SDM) aptamer as PEC response material and specific probe, a PEC aptasensor was established for SDM detection. The aptamer was connected to the surface of chitosan/ZnPc/CN/ITO through the formation of phosphoramidate bonds between the amino group of the chitosan and phosphate group of the aptamer at 5′ end. The fabricated aptasensor displayed good detection linearity of 0.1 ~ 300 nM and low detection limit of 0.03 nM (S/N = 3) under optimized conditions, and the potential applicability of the PEC aptasensor was confirmed by detecting SDM in milk powder samples.

Background Two randomized phase III trials (EORTC55971 and CHORUS) showed similar progression-free and overall survival in primary or interval debulking surgery in ovarian cancer, however both studies had limitations with lower rate of complete resection and lack of surgical qualifications for participating centers. There is no consensus on whether neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) could be a preferred approach in the management of advanced epithelial ovarian cancer (EOC) in the clinical practice. Methods The Asian SUNNY study is an open-label, multicenter, randomized controlled, phase III trial to compare the effect of primary debulking surgery (PDS) to NACT-IDS in stages IIIC and IV EOC, fallopian tube cancer (FTC) or primary peritoneal carcinoma (PPC). The hypothesis is that PDS enhances the survivorship when compared with NACT-IDS in advanced ovarian cancer. The primary objective is to clarify the role of PDS and NACT-IDS in the treatment of advanced ovarian cancer. Surgical quality assures include at least 50% of no gross residual (NGR) in PDS group in all centers and participating centers should be national cancer centers or designed ovarian cancer section or those with the experience participating surgical trials of ovarian cancer. Any participating center should be monitored evaluating the proportions of NGR by a training set. The aim of the surgery in both arms is maximal cytoreduction. Tumor burden of the disease is evaluated by diagnostic laparoscopy or positron emission tomography/computed tomography scan. Patients assigned to PDS group will undergo upfront maximal cytoreductive surgery within 3 weeks after biopsy, followed by 6 cycles of standard adjuvant chemotherapy. Patients assigned to NACT group will undergo 3 cycles of NACT-IDS, and subsequently 3 cycles of adjuvant chemotherapy. The maximal time interval between IDS and the initiation of adjuvant chemotherapy is 8 weeks. Major inclusion criteria are pathologic confirmed stage IIIC and IV EOC, FTC or PPC; ECOG performance status of 0 to 2; ASA score of 1 to 2. Major exclusion criteria are non-epithelial tumors as well as borderline tumors; low-grade carcinoma; mucinous ovarian cancer. The sample size is 456 subjects. Primary endpoint is overall survival. Trial Registration ClinicalTrials.gov Identifier: NCT02859038

Acquired platinum resistance impedes successful treatment of epithelial ovarian cancer (EOC), and this resistance may be associated with inherited DNA damage–repair response. In the present study, we performed a two-phase analysis to assess associations between 8191 single-nucleotide polymorphisms within 127 genes of nucleotide excision repair pathway from a genome-wide association study dataset and platinum treatment response in 803 Han Chinese EOC patients. As a result, we identified that platinum-based chemotherapeutic response was associated with two potentially functional variants MNAT1 rs2284704 T>C [TC + CC versus TT, adjusted odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.83–0.95 and P = 0.0005] and HUS1B rs61748571 A>G (AG + GG versus AA, OR = 1.10, 95% CI = 1.03–1.18 and P = 0.005). Compared with the prediction model for clinical factors only, models incorporating HUS1B rs61748571 [area under the curve (AUC) 0.652 versus 0.672, P = 0.026] and the number of unfavorable genotypes (AUC 0.652 versus 0.668, P = 0.040) demonstrated a significant increase in the AUC. Further expression quantitative trait loci analysis suggested that MNAT1 rs2284704 T>C significantly influenced mRNA expression levels of MNAT1 (P = 0.003). These results indicated that MNAT1 rs2284704 T>C and HUS1B rs61748571 A>G may serve as potential biomarkers for predicting platinum treatment response of Chinese EOC patients, once validated by further functional studies.

Background In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. Methods SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. Trial registration ClinicalTrials.gov Identifier: NCT03983226.

To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r 2 = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.

The TP53 gene product is an important regulator of cell growth and a tumor suppressor. The association between TP53 Arg72Pro polymorphism and ovarian cancer risk has been widely investigated, but the results are contradictory. We therefore searched the PubMed, EMBASE and Chinese Biomedical databases for studies on the relation between TP53 Arg72Pro polymorphism and ovarian cancer risk. Our final meta-analysis included 24 published studies with 3271 cases and 6842 controls. Pooled results indicated that there was no significant association between TP53 Arg72Pro polymorphism and ovarian cancer risk [Pro/Pro vs. Arg/Arg: odds ratio (OR) =1.04, 95% confidence interval (CI) = 0.81-1.34; Arg/Pro vs. Arg/Arg: OR = 1.14, 95% CI = 0.96-1.36; recessive: OR = 1.05, 95% CI = 0.90-1.22; dominant: OR = 1.12, 95% CI = 0.94-1.33; and Pro vs. Arg: OR = 1.06, 95% CI=0.93-1.20]. Likewise, stratified analyses failed to reveal a genetic association. Despite some limitations, the present meta-analysis provides statistical evidence indicating a lack of association between TP53 Arg72Pro polymorphism and ovarian cancer risk.

Tingyan Shi,1,2 Rong Jiang,1 Pan Wang,1 Yuan Xu,2 Sheng Yin,1 Xi Cheng,3 Rongyu Zang1,3 1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, 2Cancer Institute, 3Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Background: Exonuclease 1 (EXO1), one of DNA mismatch repair pathway genes, functions in maintaining genomic stability and affects tumor progression. We hypothesized that genetic variations in EXO1 may predict clinical outcomes in epithelial ovarian cancer (EOC). Methods: In this cohort study with 1,030 consecutive EOC patients, we genotyped four potentially functional polymorphisms in EXO1 by the Taqman assay and evaluated their associations with patients’ survival. Results: Using multivariate Cox proportional hazards regression models, we found that rs851797AG/GG genotypes were significantly associated with recurrence and cancer death (HR =1.30 and 1.38, 95% CI =1.11–1.52 and 1.02–1.88, respectively). Kaplan–Meier survival estimates showed that patients who carried rs851797AG/GG genotypes had poorer progression-free survival and poorer overall survival, compared with rs851797AA genotype carriers (log-rank test, P=0.002 and 0.025, respectively). Moreover, patients with older age at menophania, advanced stage tumor, or being received incomplete cytoreduction were more likely to be recurrent and dead. Conclusion: EXO1 rs851797 polymorphism can predict the clinical outcomes in EOC patients. In addition, age at menophania, FIGO stage, and complete cytoreduction might be independently prognostic factors of ovarian cancer. Large studies with functional experiments are warranted to validate these findings. Keywords: EXO1, ovarian cancer, polymorphism, prognosis

// Haixia Zhou 1, * , Ting-Yan Shi 2, * , Wenwen Zhang 3, * , Qiwen Li 3 , Jinhong Zhu 4 , Jing He 1, 5 and Jichen Ruan 1 1 Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China 2 Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai 200032, China 3 State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China 4 Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China 5 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China * These authors have contributed equally to this work Correspondence to: Jichen Ruan, email: ruanjichen@163.com Jing He, email: hejing198374@gmail.com Keywords: DNA repair, XPG, polymorphism, cancer susceptibility, meta-analysis Received: May 12, 2017 Accepted: June 12, 2017 Published: July 18, 2017 ABSTRACT The Xeroderma pigmentosum group G ( XPG ) gene promotes recognition and excision of damaged DNA during the DNA repair process. We conducted a comprehensive search of the MEDLINE, EMBASE, and Chinese Biomedical databases for publications evaluating the association XPG gene rs751402 C>T polymorphism and overall cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were adopted to assess the strength of the association. A total of 22 publications encompassing 10538 cases and 10511 control subjects were included in the final meta-analysis. We found the polymorphism to be associated with increased cancer risk (TT vs. CC: OR = 1.18, 95% CI = 1.01–1.38, P = 0.040; CT vs. CC: OR = 1.12, 95% CI = 1.01–1.24, P = 0.040; and CT/TT vs. CC: OR = 1.12, 95% CI = 1.002–1.26, P = 0.045). Stratification by cancer type indicated that this polymorphism may increase the risk of gastric cancer and hepatocellular carcinoma, which was further confirmed by a false-positive report probability analysis. Genotype-based mRNA expression provides further evidence that this polymorphism is associated with altered XPG mRNA expression. This meta-analysis suggests XPG gene rs751402 C>T polymorphism correlates with overall cancer risk, especially for gastric cancer and hepatocellular carcinoma.

// Yuqin Zhang 1, * , Tingyan Shi 1, * , Sheng Yin 1 , Sining Ma 1 , Di Shi 1 , Jun Guan 2, 3 , Libing Xiang 4 , Yang Liu 4 , Yulan Ren 4 , Deyan Tan 5 and Rongyu Zang 1 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Gynecology, Tumor Bank Ovarian Cancer, European Competence Center for Ovarian Cancer, Campus Virchow Clinic, Charite Medical University of Berlin, Berlin, Germany 3 Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, United Kingdom 4 Department of Gynecologic Oncology, Fudan University Cancer Center, Shanghai, China 5 Department of Anatomy, Shanghai Medical College, Fudan University, Shanghai, China * These authors contributed equally to the work Correspondence to: Rongyu Zang, email: ryzang@yahoo.com Keywords: paravesico-vaginal space, nerve-sparing radical hysterectomy, deep uterine vein, terminal ureter, cervical cancer Received: April 11, 2017 Accepted: June 16, 2017 Published: July 05, 2017 ABSTRACT Bladder dysfunction remains a major postoperative challenge for early stage cervical cancer patients. The present prospective phase 2 trial in patients with stage IB1 and IIA1 cervical cancer follows up on our previous, unpublished work describing a new surgical landmark, the paravesico-vaginal space. We describe a novel nerve-sparing radical hysterectomy (NSRH) approach to treat early stage cervical cancer without compromising local control rate or survival. Between September 2015 and August 2016, 49 patients were enrolled to receive NSRH. The bladder catheter was routinely removed on postoperative day 4. The primary endpoints were rate of postvoid residual urine volume (PVR) ≤ 50 ml and proportion of patients with successful catheter removal (ClinicalTrials.gov Identifier: NCT02562729). Anatomically, from ventral to dorsal, the terminal ureter, deep uterine vein, and cardinal ligament were the three markers of the paravesico-vaginal space. The median operative time was 100 min, and the median blood loss was 200 ml. Thirty-four patients (69.4%) had successful catheter removal on postoperative day 4, and 17 patients (34.7%) had a PVR ≤ 50 ml. Our results suggest that by accessing the paravesico-vaginal space landmark, the bladder branch of the inferior hypogastric plexus can be completely preserved, contributing to greater NSRH efficiency without compromising outcomes for patients with early stage cervical cancer.

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.

SummaryThe inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ∼ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ∼1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.HighlightsThe projection of FTE subtypes refines the molecular classification of serous OCComprehensive single-cell profiling of FTE cells identifies 6 molecular subtypesSubstantial non-genetic heterogeneity of HGSOC identified in 1700 tumorsA mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies.

Inactivation of p53 greatly contributes to serous ovarian cancer, while the role of the wild-type p53 induced phosphatase 1 (Wip1) is quite unclear. In this study, by silencing or overexpression of Wip1, we found that Wip1 suppressed ovarian cancer cell invasion, migration, epithelial to mesenchymal transition (EMT), and ovarian cancer metastasis in xenograft animal models. Mechanistic studies showed that Wip1 may block ovarian cancer metastasis through inhibition of Snail and p-Akt expression because silencing or overexpression of Wip1 either upregulated or downregulated the expression of Snail and p-Akt (Ser 473), while further knockdown of Snail by shRNA or inhibition of p-Akt by a chemical compound attenuated cell invasion, migration and EMT in Wip1 silencing cells. We also found that the phosphorylation of Akt at Ser 473 might be mediated through p-ATM (Ser 1981). Thus, Wip1 may suppress ovarian cancer metastasis through negative regulation of p-ATM, p-Akt, and Snail, which was also evidenced in the limited clinical specimens. Therefore, our data may provide a novel therapeutic indication for serous ovarian cancer based on the uncovered mechanism associated with the precise function of Wip1 independent of p53.

In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.

6001 Background: In China, secondary cytoreductive surgery (SCR) has been standard of care in some high volume cancer centers for ovarian cancer (OC) and most pts prefer surgery over the past two decades. Although GOG213 showed no OS benefit, the debate on selected pts and the conflict with certain local clinical care is still open. Methods: Pts with 1st relapsed OC after 6m+ platinum-free interval (PFI) were eligible if predicted to be a potential R0 by iMODEL score combined with PET-CT image and were randomized to SCR followed by chemotherapy (surgery arm) vs 2nd line chemotherapy alone (no surgery arm). Co-primary endpoint is PFS and OS. The 2nd endpoint is accumulated treatment-free survival (TFSa), which was defined as the overall survival time minus the time of surgery and chemotherapy after randomization. We report analysis of PFS and interim analysis of TFSa. Results: 357 pts were randomized 2012-2019. 6.3% of 175 pts were operated in no surgery arm and cross-over rate was 36.9% in 2nd+ relapsed pts of no surgery arm. 97% and 96% of pts received a platinum-containing 2nd line therapy. Complete resection (R0) rate was 76.7% in overall and 61.1% in pts with iMODEL> 4.7. 60 d mortality rates were 0 % in both surgery and no surgery arm. Postoperative 30 d complication rate with ≥ grade 3 was 5.2%. The median follow-up was 36.0 m. Median PFS was 17.4 m and 11.9 m in surgery and no surgery arm, respectively (HR 0.58, 95% CI 0.45-0.74, p < 0.001). Median time to start of first subsequent therapy (TFST) was 18.1 m vs 13.6 m in favor of the surgery arm (HR 0.59, 95%CI 0.46-0.76). 1.1% and 10.1% of pts underwent Bevacizumab and PARPi maintenance in the 2nd line therapy. The OS and TFSa was immatured. The median TFSa was unreached and 39.5 m in R0 subgroup and no surgery arm, respectively (HR0.59, 95%CI 0.38-0.91). TFSa in surgery arm showed a better long-term survival than that in no surgery group (restricted mean survival time from 60 to 72m: 6.2m vs 4.2m). Conclusions: SCR in selected pts resulted in a dramatically significant extension of PFS. The interim analysis of TFSa indicate that SCR might contribute to long-term survival.

The Asian Society of Gynecologic Oncology International Workshop 2018 on gynecologic oncology was held in the Ajou University Hospital, Suwon, Korea on the 24th to 25th August 2018. The workshop was an opportunity for Asian doctors to discuss the latest findings of gynecologic cancer, including cervical, ovarian, and endometrial cancers, as well as the future of fertility-sparing treatments, minimally invasive/radical/debulking surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Clinical guidelines and position statement of Asian countries were presented by experts. Asian clinical trials for gynecologic cancers were reviewed and experts emphasized the point that original Asian study is beneficial for Asian patients. In Junior session, young gynecologic oncologists presented their latest research on gynecologic cancers.

Objective An improved nerve-sparing radical hysterectomy (NSRH), which is based on the paravesico-vaginal space, has been recently introduced in a phase II, prospective clinical trial by our team. This study aims to report the surgical and oncological outcomes of this improved NSRH. Methods One hundred seventy-seven consecutive patients were enrolled in our study and underwent the improved NSRH. The proportion of successful catheter removal and postvoid residual urine volume (PVR) of 50 mL or less at postoperative day 7 or day 4 was used to assess surgical outcomes. The local control rate (LCR), disease free survival (DFS), and overall survival (OS) were used to assess oncological outcomes. Results Postoperative 30-day complications occurred in 27/177 (15.3%) patients. The rate of successful catheter removal and PVR of 50 mL or less were 85.2% (23/27) and 66.7% (18/27) at postoperative day 7, and 73.3% (110/150) and 35.3% (53/150) at postoperative day 4. A total of 13 (7.9%) patients showed recurrence after a median follow-up time of 39.2 months (range 3.2–68.1 months). The estimated 2-year and 5-year DFS rates were 92.2% and 91.1%, respectively. Seven (4.2%) patients presented local recurrence, and five (3.0%) patients were dead at the end of the follow-up period. The estimated 5-year LCR and OS were 95.1% and 96.2%, respectively. In univariate analysis, International Federation of Gynecology and Obstetrics (FIGO) stage, lymphovascular space invasion (LVSI), and lymph node metastasis were found to be the prognostic risk factors of DFS. Patients with LVSI were associated with a worse DFS according to the multivariate analysis. Conclusions The improved NSRH in our study may provide better surgical outcomes without compromising the survival in patients with early cervical cancer.

The kinesin-like factor 1 B (KIF1B) gene plays an important role in the process of apoptosis and the transformation and progression of malignant cells. Genetic variations in KIF1B may contribute to risk of epithelial ovarian cancer (EOC). In this study of 1,324 EOC patients and 1,386 cancer-free female controls, we investigated associations between two potentially functional single nucleotide polymorphisms in KIF1B and EOC risk by the conditional logistic regression analysis. General linear regression model was used to evaluate the correlation between the number of variant alleles and KIF1B mRNA expression levels. We found that the rs17401966 variant AG/GG genotypes were significantly associated with a decreased risk of EOC (adjusted odds ratio (OR) = 0.81, 95 % confidence interval (CI) = 0.68-0.97), compared with the AA genotype, but no associations were observed for rs1002076. Women who carried both rs17401966 AG/GG and rs1002076 AG/AA genotypes of KIF1B had a 0.82-fold decreased risk (adjusted 95 % CI = 0.69-0.97), compared with others. Additionally, there was no evidence of possible interactions between about-mentioned co-variants. Further genotype-phenotype correlation analysis indicated that the number of rs17401966 variant G allele was significantly associated with KIF1B mRNA expression levels (P for GLM = 0.003 and 0.001 in all and Chinese subjects, respectively), with GG carriers having the lowest level of KIF1B mRNA expression. Taken together, the rs17401966 polymorphism likely regulates KIF1B mRNA expression and thus may be associated with EOC risk in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.

Background/Aims: Prognostic value of germline BRCA1 or BRCA2 (gBRCA1/2) mutations in epithelial ovarian cancer (EOC) remains controversial, especially in the estimation of long-term survival. We previously reported the largest study of gBRCA1/2 mutation prevalence in Chinese EOC patients. The aim of this study is to further illustrate the correlation of residual disease and survival in BRCA-associated EOC in China. Methods: In the current cohort consisting of 615 cases from the Chinese EOC genome-wide association study, we evaluated the association between gBRCA1/2 mutation and clinical outcomes. Results: Overall, we did not find any significant difference between gBRCA1/2 mutation carriers and non-carriers in both progression-free survival (PFS) and overall survival (OS) (19.3 vs. 18.1 months and 77.2 vs. 73.2 months, P=0.528 and 0.147, HR 0.93 and 0.79, 95%CI 0.74-1.17 and 0.57-1.09, respectively). However, within three years after diagnosis, mutation carriers showed a longer OS than non-carriers (P=0.018, HR 0.53, 95%CI 0.31-0.90). Such a survival advantage decreased along with the extension of follow-up time. Quite interestingly, in the subgroup of patients with gross residual disease, mutation carriers had a longer survival than non-carriers (18.5 vs. 15.1 months and 68.5 vs. 54.3 months, P=0.046 and 0.038, HR 0.74 and 0.65, 95% CI 0.55-1.00 and 0.43-0.98, for PFS and OS respectively). Conclusions: Our findings provided the evidence that gBRCA1/2 mutation was not associated with survival in Chinese EOC patients, which possibly attributed to more than 37% of the patients without gross residual disease. Survival benefit of gBRCA1/2 mutation was prominent in ovarian cancer patients with gross residual disease.

Background We assessed the efficacy of adding intraperitoneal (IP) chemotherapy to standard first-line intravenous (IV) chemotherapy in epithelial ovarian cancer (EOC) patients. Methods Patients with stage IIIC-IV EOC who underwent optimal debulking surgery were randomly assigned to four cycles of weekly IP chemotherapy with cisplatin (50 mg/m2) and etoposide (100 mg/m2) followed by six cycles of IV chemotherapy every 3 weeks (IP/IV arm), or were administered IV chemotherapy alone (IV arm). The primary endpoint for this study was the 12-month non-progression rate (NPR). Results Between 4/2009 and 9/2015, 218 patients were randomised, of whom 215 initiated treatment. In the IP/IV arm, 90.6% of patients completed 4 cycles of IP chemotherapy. The 12-month NPRs were 81.9% and 64.2% in the IP/IV and IV groups, respectively (HR 0.48 (95% CI 0.27–0.82)). The median progression-free survival (PFS) was increased in the IP/IV arm compared with that in the IV arm (22.4 vs. 16.8 months; HR 0.66 (0.48–0.91)) and in a subgroup with no gross cytoreduction (31.1 vs. 16.8 months; HR 0.46 (0.26–0.82)). Similar findings were detected with regard to time to first subsequent anticancer therapy (TFST) (25.9 vs. 18.0 months; P = 0.009) and time to second subsequent anticancer therapy (TSST) (40.8 vs. 30.1 months; P = 0.042). Grade 3/4 leukopenia, anaemia and gastrointestinal events were more common in the IP/IV arm, but the treatment burden was considered acceptable. Conclusions IP chemotherapy prior to IV chemotherapy was associated with an increased 12-month NPR and a longer TSST than IV alone in patients with EOC, albeit with acceptable toxic effects. Long-term follow-up is warranted to identify the effects of IP therapy on overall survival.

// Min He 1,4 , Xin Hu 1 , Li Chen 1,4 , A-Yong Cao 1 , Ke-Da Yu 1 , Ting-Yan Shi 2 , Xia-Ying Kuang 1,4 , Wen-Biao Shi 1 , Hong Ling 1 , Shan Li 1 , Feng Qiao 1 , Ling Yao 1 , Qingyi Wei 3,5 , Gen-Hong Di 1,4 and Zhi-Ming Shao 1,3,4 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China 3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 5 Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States of America Correspondence: Zhi-Ming Shao, email: // Xin Hu, email: // Keywords : XRCC4, homozygous variant, nuclear localization, susceptibility, breast cancer Received : September 07, 2014 Accepted : October 22, 2014 Published : October 22, 2014 Abstract XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non- BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4 A247S mutant, thus compensating for the impaired localization of XRCC4 A247S . This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non- BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non- BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.

5514 Background: Dose-dense early postoperative intraperitoneal chemo (DD-EPIC) had been carried out in advanced ovarian cancer (OC) pts in China over the past three decades but it was not proved by a prospective study. This trial was designed to confirm the benefit of DD-EPIC in delaying progression and improving survival. Methods: In a multicenter, phase 2 trial, pts with FIGO IIIC-IV OC and optimal debulking surgery (residual disease ≤1cm) were randomly allocated to receive 4 doses of weekly DD-EPIC with cisplatin (50mg/m2) and etoposide (100mg/m2) followed by 6 cycles of intravenous (iv) chemo with carboplatin and taxane every 3 weeks (DD-EPIC group), or standard iv chemo alone (iv group). (ClinicalTrials.gov, NCT01669226). Results: Between 2009 and 2015, 218 pts were randomized, of whom 215 initiated treatment (106 to DD-EPIC and 109 to iv; for efficacy analyses). Totally, 36 pts (16·7%) were received neoadjuvant chemo. With a median of 61·9 mos follow-up, 122 pts died (54 in DD-EPIC and 68 in iv group). Remarkable OS benefit of DD-EPIC was recorded (67·5 mos for DD-EPIC vs. 46·3 mos for iv; HR 0·70, 95% CI 0·49-1·00, P=0·047). Pts in DD-EPIC had a significantly increased median PFS compared with those in iv group (21·7 vs. 16·8 mos; HR 0·64, 95% CI 0·47-0·86, P=0·003). Median TFST was 25·1 vs. 18·0 mos in favor of DD-EPIC (HR 0·62, 95%CI 0·46-0·83, P=0·002). Similar findings were detected in TSST (42·2 vs. 29·3 mos; HR 0·66, 95%CI 0·47-0·94, P=0·019). Grade 3 and 4 Leucopenia (53·8% vs. 35·2%), anemia (23·6% vs. 5·6%) and gastrointestinal events (10·4% vs. 1·9%) were more common in DD-EPIC ( P=0·006, P

The atypical protein kinase C (aPKCι), encoded by the PRKCI gene, has been recently found to be a unique human oncoprotein, compared with some other diverse PKC isozymes. Genetic variations in PRKCI have also been reported to be associated with prostate cancer (PCa) risk in Caucasian populations, but no similar studies have been reported for Chinese populations. We genotyped two well-described PRKCI single nucleotide polymorphisms (SNPs) rs546950 and rs4955720 in 1015 PCa patients and 1044 cancer-free controls of Eastern Chinese men. SNPs in the vicinity of those two variants of PRKCI were evaluated using the in silico analysis. Logistic regression was then used to estimate their associations with and interactions in PCa risk. Although no significant main effects were found for the two tested SNPs in the single locus analysis, individuals carrying homozygote wide-type form of these two SNPs had slightly reduced PCa risk (adjusted OR = 0.63, 95% CI = 0.40–0.99, P = 0.045), compared with those carrying any of heterozygous or homozygous variant genotypes. Our results indicated that the two PRKCI SNPs were jointly associated with PCa risk in an Eastern Chinese population. Larger studies with multiethnic groups are warranted to confirm these findings and to explore the role of PRKCI SNPs in the etiology of PCa. © 2014 Wiley Periodicals, Inc.

Introduction Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that functions as a key regulator of gene transcription, protein translation, and autophagy. No studies have assessed associations between functional single nucleotide polymorphisms (SNPs) in mTORC1 genes and risk of esophageal squamous cell carcinoma (ESCC). Methods In a case–control study of 1126 ESCC patients and 1131 cancer-free controls, we genotyped eight SNPs in mTORC1 ( mTOR rs1883965 G>A and rs2536 T>C, mLST8 rs3160 C>T and rs26865 G>A, RPTOR rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A) and assessed their associations with risk of ESCC. Results In the single-locus analyses, we found a significantly altered risk of ESCC associated with mTOR rs1883965 A variant genotypes (adjusted OR=1.27 and 1.26; 95% confidence interval=1.01–1.60 and 1.01–1.58 for GA and GA/AA, respectively, compared with GG) but not with other SNPs. In the combined analysis of the eight SNPs, we found individuals with two or more unfavorable genotypes exhibited an increased risk for ESCC (adjusted OR=1.35; 95% confidence interval=1.20–1.62), compared with those with less than two unfavorable genotypes. Such a cumulative effect was dose-dependent ( p trend = 0.004). In the multiple dimension reduction analysis, mTOR rs1883965 was consistently suggested as the strongest individual factor for ESCC risk, and the model including all SNPs yielded the lowest prediction error of 17.66% for model validation. Conclusions These findings suggest that functional SNPs of mTORC1 genes may individually or collectively contribute to ESCC risk. Further validation of these findings is warranted.

XPC polymorphisms may alter DNA repair capacity, thus leading to genetic instability and carcinogenesis. Numerous studies have investigated the associations of XPC Lys939Gln (rs2228001) and Ala499Val (rs2228000) polymorphisms with cancer susceptibility; however, the findings are inconclusive. We searched literature from MEDLINE and EMBASE for eligible publications that assessed the associations between these two polymorphisms and cancer risk. We also assessed genotype-mRNA expression correlation data from HapMap for rs2228001 and rs2228000 in normal cell lines derived from 270 subjects with different ethnicities. The final analysis included 62 published studies of 25,708 cases and 30,432 controls for the Lys939Gln and 34 studies with 14,877 cases and 17,888 controls for the Ala499Val. Overall, Lys939Gln was significantly associated with an increased overall cancer risk (Gln/Gln vs. Lys/Lys: OR = 1.16, 95% CI = 1.07 − 1.25, p

Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions, and genetic variations in this complex may affect cancer risk. In this study, we examined the associations between eight potential functional single nucleotide polymorphisms in the mTORC1 genes (rs2536T>C and rs1883965G>A for mTOR, rs3160T>C, and rs26865A>G for mLST8, rs3751934C>A, rs1062935T>C, rs3751932T>C, and rs12602885G>A for Raptor, not included in published gastric cancer genome-wide association studies) and gastric cancer risk in 1125 gastric cancer cases and 1196 cancer-free controls. We performed conditional logistic regression and multifactor dimensionality reduction (MDR) analyses to assess their associations with gastric cancer risk. We also used false-positive report probabilities (FPRP) for assessing significant findings. We found that only the rs1883965A variant genotypes were associated with an increased risk of gastric cancer (AG vs. GG: adjusted odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.00–1.59; AA vs. GG: adjusted OR = 1.85, 95% CI = 0.67–5.16 and dominant model: adjusted OR = 1.28, 95% CI = 1.03–1.61). Patients with ≥1 risk genotypes of mTOR had significant increased risk (adjusted OR = 1.25, 95% CI = 1.04–1.49), compared with those having zero risk genotypes. In the stratified analysis, the risk effect of the rs1883965 AG/AA genotypes was evident in subgroups of ever-smokers, non-gastric cardia adenocarcinoma and clinical stage I + II, which were noteworthy findings as evaluated by FPRP. The MDR analysis identified smoking status and rs1883965 as the strongest two-factors for gastric cancer risk. These data support the hypothesis that functional polymorphisms of mTOR may contribute to gastric cancer risk. Clearly, our results require validation in larger studies with different ethnic populations. © 2013 Wiley Periodicals, Inc.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is an anti apoptotic and pro-oncogenic signaling molecule involved in the process of immunity, carcinogenesis and tumor progression. Single nucleotide polymorphisms (SNPs) at microRNA-binding sites may change messenger RNA target gene function, thus leading to cancer susceptibility and tumor progression. In this study of 1584 cervical cancer cases and 1394 cancer-free female controls, we investigated associations between three potentially functional SNPs in TNFAIP8 family genes and cervical cancer risk as well as platinum resistance and clinical outcomes in Eastern Chinese women. We found that the TNFAIP8-rs11064 variant GG genotype was associated with an increased risk of cervical cancer compared with AA/AG genotypes (adjusted odds ratio = 2.16, 95% confidence interval = 1.16-4.03, P = 0.015). Further in vitro and ex vivo functional experiments demonstrated that the TNFAIP8-rs11064 variant G allele weakened the binding affinity of miR-22 to the TNFAIP8 3'-untranslated region (UTR) in four cancer cell lines, resulting in increased production of the TNFAIP8 protein in the patients' cervical tissues. In the survival subset, the high TNFAIP8 protein expression was significantly associated with both resistance to cisplatin and nedaplatin, recurrence and death from cervical cancer. Taken together, in the absence of information on human papillomavirus (HPV) infection, the TNFAIP8-rs11064 SNP may function by affecting the affinity of miR-22 binding to the 3'-UTR of TNFAIP8 and regulating TNFAIP8 expression, thus contributing to cervical cancer risk. Additionally, the increased TNFAIP8 protein expression may predict platinum resistance and clinical outcomes in cervical cancer patients. Larger, prospective studies with detailed HPV infection data are warranted to validate our findings.

On June 18, 2016, the 5th Shanghai Gynecologic Oncology Group (SGOG)-Korean Gynecologic Oncology Group (KGOG) Joint Meeting was held in Zhongshan Hospital, Fudan University, Shanghai, China. Rongyu Zang (chairman of SGOG, KGOG-SGOG coordinator) from Zhongshan Hospital, Fudan University hosted this meeting. Total 21 KGOG members including Byoung-Gie Kim (president of KGOG, SGOG-KGOG coordinator), Yong-Man Kim (vice president of KGOG), Jae-Weon Kim (chair of ovarian-fallopian tube tumor site committee of KGOG, SGOG-KGOG coordinator), and Taek Sang Lee (secretary general of KGOG) attended the 5th joint meeting. Eight young fellows were included in 21 KGOG attendees (Table 1, Fig. 1).

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21% and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy.

Hui Zhang,1,5,* Mengyun Wang,2,5,* Tingyan Shi,2,5 Lijun Shen,1,5 Ji Zhu,1,5 Menghong Sun,3,5 Yun Deng,1,5 Liping Liang,1,5 Guichao Li,1,5 Yongxin Wu,1,5 Ming Fan,1,5 Qingyi Wei,2,4 Zhen Zhang1,5 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 4Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; 5Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Plasminogen activator inhibitor type 1 (PAI-1) and protease-activated receptor-1 (PAR-1) are crucial mediators of the intestinal microenvironment and are involved in radiation-induced acute and chronic injury. To evaluate whether genetic polymorphisms of PAI-1 and PAR-1 were predictors of radiation-induced injury in patients with rectal cancer, we retrospectively evaluated 356 rectal cancer patients who had received pelvic radiotherapy and analyzed the association of genetic polymorphisms of PAI-1 and PAR-1 with acute toxicities after radiotherapy. Acute adverse events were scored, including dermatitis, fecal incontinence (anal toxicity), hematological toxicity, diarrhea, and vomiting. The patients were grouped into grade ≥2 and grade 0–1 toxicity groups to analyze the acute toxicities. Genotyping of six single nucleotide polymorphisms (SNPs) of PAI-1 and PAR-1 was performed using TaqMan assays. Alogistic regression model was used to estimate the odds ratios and 95% confidence intervals. Of the 356 individuals, 264 (72.5%) had grade ≥2 total toxicities; within this group, there were 65 (18.3%) individuals who reached grade ≥3 toxicities. There were 19.5% (69/354) and 36.9% (130/352) patients that developed grade ≥2 toxicities for diarrhea and fecal incontinence, respectively. The variant genotype GG of rs1050955 in PAI-1 was found to be negatively associated with the risk of diarrhea and incontinence (P

Objective The aim of this study was to determine the impact of neoadjuvant chemotherapy (NACT) on survival in patients with bulky stage IIIC and IV epithelial ovarian cancer. Methods Between January 2009 and December 2012, 408 patients with ovarian cancer with extensive upper abdominal disease were reviewed. On the basis of the cycle number of NACT, patients were divided into 2 groups, namely, primary debulking surgery (PDS) group, which included the patients who received no more than 1 cycle of NACT; and neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) group, which included the patients who received more than 1 cycle of NACT. All patients underwent cytoreductive surgery with the goal of optimal outcome (⩽1 cm). Progression-free survival and overall survival were evaluated. Results There was no difference in surgical outcomes between PDS and NACT-IDS group, which was evaluated with either complete cytoreduction (41/376, 10.9% vs 6/32, 18.8%) or optimal cytoreduction (201/376, 53.5% vs 18/32, 56.2%). The median survival was 43.0 and 27.3 months in the PDS group and NACT-IDS group, with an estimated 5-year survival of 36% and 31%, respectively (P = 0.032; hazard ratio, 0.59; 95% confidence interval, 0.36–0.95). Complete cytoreduction, without bowel mesenteric carcinomatosis, and no more than 1 cycle of NACT were associated with lengthened survival by the multivariate analysis (P = 0.012, 0.025, and 0.036, respectively). Conclusions Neoadjuvant chemotherapy was associated with poor survival of patients with bulky stage IIIC and IV ovarian cancer. A well-designed randomized trial with a better quality control of surgical procedures is needed to confirm the results.

Polymorphisms in Caspase-7 (CASP7) may modulate the programmedcell death and thus contribute to cervical cancer risk. In this case-controlstudy of 1,486 cervical cancer cases and 1,301 controls, we investigated associationsbetween four potentially functional polymorphisms in CASP7 and cervicalcancer risk and evaluated their locus-locus interaction effects on the risk.The genotype-phenotype correlation was performed by a generalized linear regressionmodel. We found that the rs4353229 polymorphism was associated with cervicalcancer risk (under a recessive model: crude OR = 1.20, 95% CI = 1.02–1.40).Compared with the TT genotype, the rs10787498GT genotype was associated withan increased cervical cancer risk (adjusted OR = 1.19, 95% CI = 1.00–1.41).Combination analysis showed that subjects with four putative risk genotypeshad a 1.54-fold increased cancer risk, compared with those who carried threeor less putative risk genotypes. We also observed significant locus-locusjoint effects on the risk, which may be mediated by the polymorphisms regulating CASP7mRNA expression. Subsequent multifactor dimensionality reduction and classificationand regression tree analyses indicated that the CASP7 genotypes mighthave a locus-locus interaction effect that modulated cervical cancer risk.Out data suggest that CASP7 polymorphisms may interact to modify cervicalcancer risk by a possible mechanism of regulating CASP7 mRNA expression.

1583 Background: BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, precise data of BRCA1/2mutations among Chinese epithelial ovarian cancer (EOC) pts. Methods: We performed a multicenter cohort study including 916 unselected consecutive EOC pts from eastern China, to screen for BRCA1/2mutations using the next-generation sequencing approach. Results: 153 EOC pts were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C>T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of EOC. Taken together, germline BRCA1/2mutations were common in Chinese EOC pts with distinct mutational spectrum compared to Western populations. Conclusions: Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2genetic testing to all Chinese women diagnosed with EOC in order to identify HBOC families, to provide genetic counselling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies. [Table: see text]

REV3L, the catalytic subunit of DNA Polymerase ζ (Polζ), plays a significant role in the DNA damage tolerance mechanism of translesion synthesis (TLS). The role of REV3L in chemosensitivity of cervical cancer needs exploration. In the present study, we evaluated the expression of the Polζ protein in paraffin-embedded tissues using immunohistochemistry and found that the expression of Polζ in cervical cancer tissues was higher than that in normal tissues. We then established some cervical cancer cell lines with REV3L suppression or overexpression. Depletion of REV3L suppresses cell proliferation and colony formation of cervical cancer cells through G1 arrest, and REV3L promotes cell proliferation and colony formation of cervical cancer cells by promoting G1 phase to S phase transition. The suppression of REV3L expression enhanced the sensitivity of cervical cancer cells to cisplatin, and the overexpression of REV3L conferred resistance to cisplatin as evidenced by the alteration of apoptosis rates, and significantly expression level changes of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax). Our data suggest that REV3L plays an important role in regulating cervical cancer cellular response to cisplatin, and thus targeting REV3L may be a promising way to alter chemosensitivity in cervical cancer patients.

Affiliations numbers 1 and 3 for multiple authors are incorrect. The correct affiliation number 1 is: Cancer Institute, Fudan University Cancer Center, Shanghai, China. The correct affiliation number 3 is: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Ovarian cancer is the leading cause of death from gynaecological malignancies worldwide. Here we perform a three-stage genome-wide association study (GWAS) in Han Chinese women to identify risk genetic variants for epithelial ovarian cancer (EOC). We scan 900,015 single-nucleotide polymorphisms (SNPs) in 1,057 EOC cases and 1,191 controls in stage I, and replicate 41 SNPs (P(meta)

BACKGROUND: Caspase 7 (CASP7) is an important regulator and executioner in the apoptosis pathway and plays a crucial role in cancer development and progression. However, few studies have evaluated associations between functional single nucleotide polymorphisms (SNPs) in the 3' untranslational region (UTR) of CASP7 and risk of gastric cancer. METHODS: In a case-control study of 1117 patients with gastric cancer and 1146 cancer-free controls with frequency matching on age and sex, we genotyped four potentially functional SNPs (rs4353229T>C, rs10787498T>G, rs1127687G>A and rs12247479G>A) located in the microRNA binding sites of the CASP7 3' UTR by using Taqman assays and evaluated their associations with risk of gastric cancer by using logistic regression analyses as well as multifactorial dimension reduction (MDR) analysis. RESULTS: In the single-locus analysis, only the CASP7 rs4353229 TT genotype was associated with 0.83-fold decreased risk (95% confidence interval [CI] = 0.70-0.98) of gastric cancer under a recessive model, compared with the CT/CC genotypes. In the combined analysis of all four SNPs, we found that the risk of gastric cancer decreased by 19% in those carrying any of the risk genotypes (adjusted odds ratio = 0.81, 95% CI = 0.68-0.96), compared with those carrying zero risk genotypes, and this risk was more evident in subgroups of younger age (

BACKGROUND: The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis. CONCLUSIONS/SIGNIFICANCES: In the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13-1.78), P = 0.003 and 1.29 (1.07-1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64-0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04-1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies.

markdownabstract__Background:__ Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site) and LEPR (Q223R, nonsynonymous SNP in exon 6) with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations. __Methods:__ We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A) and rs1137101 (Q223R) in normal cell lines derived from 270 subjects with different ethnicities. __Results:__ The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41). Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51) but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity. __Conclusions:__ Despite some limitations, this meta-analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies.

Background High risk human papillomavirus (HPV) infection is the major cause of cervical cancer. Several epidemiological studies have performed HPV screening in Chinese women, but no report was for Shanghai suburb women. Objectives To understand the prevalence of HPV infection and risk factors in Shanghai suburbs. Study design Between March 2011 and May 2011, 10,000 female volunteers lived in Fengxian District of Shanghai were recruited for the detection of 21 HPV types using PCR and fast flow hybridization of gene chip array. For the 508 HPV-positive patients, we performed the liquid-based ThinPrep cytology test (TCT) and histological examination for the diagnosis of local cervical lesions. The questionnaire surveyed demographic and behavioral indicators for the evaluation of risk factors of HPV infection. Results We found that the HPV-positive rate was 12.6%. The five top HPV types were as follows (in descending order): HPV52, 16, 58, 18 and 33. Moreover, HPV-positive rates were higher in women with older age, lower educational level, younger age of the first sexual intercourse, multiple sexual partners, no usage of condom for contraception, multiple deliveries, vaginal delivery, menopause, vaginal inflammation, cervical erosion and no regular cervical cytological examination. We also found that an HPV genotyping in combination with TCT and histological examination could improve early diagnosis for local cervical lesions. Conclusion HPV infection was associated with age, sexual behavior and chronic inflammation of the cervix and vagina. We recommend popularizing HPV genotyping in women with high risk factors for the early diagnosis and prevention of cervical cancer.

BACKGROUND: Transforming growth factor-beta 1 (TGF-β1) protein may be multifunctional and related to the development of fibrosis, induction of apoptosis, extracellular signaling and inhibition of proliferation in response to radiation-induced DNA damage. Several studies have investigated associations between single nucleotide polymorphisms (SNPs) in the TGFB1 gene and risk of late radiation-induced injury of normal tissue, but the conclusions remain controversial. METHODS: We searched three electronic databases (i.e., MEDLINE, EMBASE and EBSCO) for eligible publications and performed a meta-analysis assessing the association of three commonly studied SNPs in TGFB1 (i.e., rs1800469, rs1800470 and rs1800471) with risk of late radiation-induced injury of normal tissue. RESULTS: We finally included 28 case-only studies from 16 publications on aforementioned SNPs in TGFB1. However, we did not find statistical evidence of any significant association with overall risk of late radiotherapy toxicity in the pooled analysis or in further stratified analysis by cancer type, endpoint, ethnicity and sample size. CONCLUSIONS: This meta-analysis did not find statistical evidence for an association between SNPs in TGFB1 and risk of late radiation-induced injury of normal tissue, but this finding needs further confirmation by a single large study.