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Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer. We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model. We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months [95% CI 15–22]) and a low-risk group (90 patients; median progression-free survival 38 months [24–not estimable]; hazard ratio [HR] 1·85 [1·29–2·64], p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33–4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11–1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03–2·13, p=0·036; OC263: adjusted HR 3·09 [2·24–4·28], p<0·0001; and OC452: HR 1·41 [1·11–1·79], p=0·0047). MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay. AIRC and CARIPLO Foundation.

In this randomized trial, an antibody against vascular endothelial growth factor, bevacizumab, prolonged the time to progression of disease in patients with metastatic renal-cell cancer. There was no effect on survival. Positive effects from an antibody against vascular endothelial growth factor. Studies of the hereditary form of clear-cell renal carcinoma, which occurs in the von Hippel–Lindau syndrome, led to the identification of the von Hippel–Lindau tumor suppressor gene ( VHL ). The gene is mutated both in hereditary renal-cell carcinoma (where one mutation is a germ-line mutation) and in most cases of sporadic clear-cell renal carcinoma (where both alleles have acquired mutations or deletions). 1 , 2 One consequence of these mutations is the overproduction of vascular endothelial growth factor through a mechanism involving hypoxia-inducible factor α. 3 – 7 In addition, both VHL -deficient mice and vascular endothelial growth factor–knockout mice die in utero . . .

To investigate the role of the lncRNA growth arrest special 5 (GAS5) in ovarian clear cell carcinoma (OCCC), we measured the expression of GAS5 and miR‐31‐5p in OCCC tissue samples and OCCC cell lines using RT‐qPCR. MTT and colony formation assays were used to measure cell viability and colony formation ability. Cell invasion was determined by Transwell assays. The binding between GAS5 and miR‐31‐5p as well as miR‐31‐5p and ARID1A was determined by dual‐luciferase reporter assays. The ARID1A protein levels were detected using western blotting. Kaplan–Meier curves were used for the analysis of the 5‐year survival rate of patients with OCCC. GAS5 and ARID1A levels were significantly decreased, while miR‐31‐5p levels were strongly elevated in the OCCC tissues and cell lines. Patients with lower GAS5/ARID1A levels had shorter overall survival times. Overexpression of GAS5 or inhibition of miR‐31‐5p suppressed cell viability and invasion of OCCC cells and upregulated the protein levels of ARID1A. Moreover, overexpression of miR‐31‐5p reversed the effects of overexpression of GAS5. Cotransfection with pcDNA3.1‐GAS5 and miR‐31‐5p inhibitor led to the lowest cell viability and cell invasion rates. A dual‐luciferase reporter assay was performed to confirm the target relationship between GAS5 and miR‐31‐5p, as well as between miR‐31‐5p and ARID1A. LncRNA GAS5 inhibited cell viability and invasion of OCCC through activation of ARID1A by sponging miR‐31‐5p.

ObjectiveTo describe the pattern and frequency of oncogene mutations in white and African American women with endometrial cancer and to determine if racial differences in oncogene mutations exist among women with pathologically similar tumors.MethodsPatients with endometrial cancer from a large urban hospital were identified through medical records, and representative formalin-fixed paraffin-embedded tumor blocks were retrieved. The study sample included 150 patients (84 African Americans) who underwent total abdominal hysterectomy for endometrial cancer. The Sequenom MassARRAY system and the OncoCarta Assay version 1.0 (Sequenom) were used to test for 238 mutations in 19 common oncogenes. The χ2 test and the Fisher exact test were used to assess differences in distribution of variables by race and oncogene mutation status.ResultsThere were 20 mutations identified in 2 oncogenes (PIK3CA and KRAS) in tumors from 19 women (12.7%). Most of the mutations were found in PIK3CA (16/20). Thirteen percent of endometrioid tumors harbored mutations (11 PIK3CA and 2 KRAS) as did 29% of the malignant mixed Mullerian tumors (3 PIK3CA and 1 KRAS). There were no observed mutations in serous, clear cell, or mucinous tumor types. Among low-grade endometrioid cancers, tumors from African American patients were significantly associated with harboring either a KRAS or PIK3CA mutation (P = 0.04), with 7 PIK3CA mutations and all 4 KRAS mutations identified in African American women.ConclusionsThis study provides preliminary evidence that oncogene mutation frequency of some subtypes of histologically similar endometrial carcinoma differ by race. Additional studies are needed to further explore this phenomenon in patients with endometrial carcinoma.

Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis. ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.

In this study of ovarian clear-cell or endometrioid tumors, nearly half the samples had mutations in the ARID1A gene, which encodes a component of the SWI–SNF chromatin remodeling complex. Alterations in gene expression associated with abnormal chromatin remodeling may be linked with cancer. In the United States, ovarian cancer ranks as the fifth deadliest cancer among women. 1 Of the several subtypes of epithelial ovarian cancer, high-grade serous carcinomas are the most common, accounting for approximately 70% of all cases of epithelial ovarian cancer in North America. 2 Although ovarian clear-cell carcinoma is the second most common subtype in North America (accounting for 12% of cases and an even higher percentage in Japan 3 ) and is the second leading cause of death from ovarian cancer, 2 it is relatively understudied. Ovarian clear-cell carcinoma is defined on the basis of histopathological findings, including a predominance of clear . . .

Daphne Bell and colleagues report exome sequences of serous endometrial tumors, a clinically aggressive subtype of endometrial cancer. The authors identified recurrent somatic mutations in CHD4 , EP300 , ARID1A , TSPYL2 , FBXW7 , SPOP , MAP3K4 and ABCC9 . Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ∼74,000 deaths annually 1 . Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology 2 , 3 , 4 . We used whole-exome sequencing to comprehensively search for somatic mutations within ∼22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.

Different mutations found in endometrial and prostate tumors affecting the substrate-recognition domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al . and Dai et al ., highlights the divergent effects of recurrent mutations affecting different residues within the same functional domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations. It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer–associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP–CUL3 substrates that are preferentially degraded by endometrial cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

Identification of ARID1A/ATR synthetic lethality led to ATR inhibitor phase II trials in ovarian clear cell carcinoma (OCCC), a cancer of unmet need. Using multiple CRISPR-Cas9 mutagenesis and interference screens, we show that inactivation of protein phosphatase 2A (PP2A) subunits, including PPP2R1A, enhance ATRi sensitivity in ARID1A mutant OCCC. Analysis of a new OCCC cohort indicates that 52% possess oncogenic PPP2R1A p.R183 mutations and of these, one half possessed both ARID1A as well as PPP2R1A mutations. Using CRISPR-prime editing to generate new isogenic models of PPP2R1A mutant OCCC, we found that PPP2R1A p.R183W and p.R183P mutations cause ATRi-induced S phase stress, premature mitotic entry, genomic instability and ATRi sensitivity in OCCC tumour cells. p.R183 mutation also enhanced both in vitro and in vivo ATRi sensitivity in preclinical models of ARID1A mutant OCCC. These results argue for the assessment of PPP2R1A mutations as a biomarker of ATRi sensitivity.