ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear ...cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.
Cancer-Associated Mutations in Endometriosis without Cancer Anglesio, Michael S; Papadopoulos, Nickolas; Ayhan, Ayse ...
New England journal of medicine/The New England journal of medicine,
05/2017, Letnik:
376, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic ...lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis.
We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations.
Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions.
We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Ovarian cancer is the fifth cause of cancer-related death in women and comprises a histologically and genetically broad range of tumours, including those of epithelial, sex cord-stromal and germ cell ...origin. Recent evidence indicates that high-grade serous ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma primarily arise from tissues that are not normally present in the ovary. These histogenetic pathways are informing risk-reduction strategies for the prevention of ovarian and ovary-associated cancers and have highlighted the importance of the seemingly unique ovarian microenvironment.
Objective The purpose of this study was to assess the uptake and perioperative safety of bilateral salpingectomy (BS) as an ovarian cancer risk-reduction strategy in low-risk women after a regional ...initiative that was aimed at general gynecologists in the province of British Columbia, Canada. Study Design This population-based retrospective cohort study evaluated 43,931 women in British Columbia from 2008-2011 who underwent hysterectomy that was performed with and without BS or bilateral salpingo-oophorectomy or who underwent surgical sterilization by means of BS or tubal ligation. Parameters that were examined include patient age, operating time, surgical approach, indication, length of hospital stay, and perioperative complications. Results There was an increase in the uptake of hysterectomy with BS (5-35%; P < .001) and BS for sterilization (0.5-33%; P < .001) over the study period, particularly in women <50 years old. Minimal additional surgical time is required for hysterectomy with BS (16 minutes; P < .001) and BS for sterilization (10 minutes; P < .001) compared with hysterectomy alone or tubal ligation, respectively. No significant differences were observed in the risks of hospital readmission or blood transfusions in women who underwent hysterectomy with BS (adjusted odds ratio aOR, 0.91; 95% confidence interval CI, 0.75–1.10; and aOR, 0.86; 95% CI, 0.67–1.10, respectively) or BS for sterilization (aOR, 0.8; 95% CI, 0.56–1.21; and aOR, 0.75; 95% CI, 0.32–1.73, respectively). From 2008-2011 the proportion of hysterectomies with BS performed by open laparotomy decreased from 77-44% with uptake in laparoscopic, vaginal, and combined procedures ( P < .001). Conclusion After our 2010 educational initiative, there has been a shift in surgical paradigm in our province. This cancer prevention approach does not increase the risk of operative/perioperative complications and appears both feasible and safe.
The SWI SNF (mating type
SWIt
ch Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. ...These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.
OVARIAN CARCINOMAS CONSIST OF AT LEAST FIVE DISTINCT DISEASES: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a ...more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies.
We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 "ovarian cancer" cell lines has been classified into histotypes using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis.
Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements.
As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histotype of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic "ovarian carcinoma" cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma.
Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations ...in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.
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