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| Open AccessTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Cancer cells can employ aberrant glycosylation patterns to evade the host immune response. Here the authors report that inhibition of branched N-glycans sensitizes homologous recombination (HR)-proficient, but not HR-deficient, epithelial ovarian cancer to immune checkpoint inhibitors.
- Hao Nie
- , Pratima Saini
- & Rugang Zhang
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessTertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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Article
| Open AccessComprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation
The benefit of hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer remains controversial. Here, the authors perform a multi-omics analysis of hyperthermia-treated ovarian cancer cells, show that CDK1 becomes hyperactivated and regulates signalling upon hyperthermia, and identify WEE1 as a synergistic therapeutic target for hyperthermic intraperitoneal therapy.
- Xiaohang Yang
- , Xingyuan Hu
- & Chaoyang Sun
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Article
| Open AccessBevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group
Prognosis for patients diagnosed with advanced stage ovarian cancer remains poor. Here the authors report the results of a phase 2 study of a triple combination of the PARP inhibitor olaparib in combination with durvalumab (anti-PD1) and bevacizumab (antiVEGF) in advanced ovarian cancer.
- Gilles Freyer
- , Anne Floquet
- & Michele Lamuraglia
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Article
| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li
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Article
| Open AccessResidual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway
An important contribution of cancer associated fibroblasts (CAFs) in regulating chemoresistance has been reported. Here the authors investigate the impact of chemotherapy on CAF subsets in patients with high-grade serous ovarian cancer, suggesting that residual ANTXR1+ myofibroblasts are associated with inhibition of anti-tumor immunity.
- Monika Licaj
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessTracing back primed resistance in cancer via sister cells
Transcriptional cell states can drive treatment resistance in cancer. Here, the authors develop ReSisTrace to predict cell states that are primed to resist ovarian cancer treatment and validate their findings using small molecule inhibitors.
- Jun Dai
- , Shuyu Zheng
- & Anna Vähärautio
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Article
| Open AccessProteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes
The molecular phenotypic features of epithelial ovarian cancer (EOC) remain elusive. Here, the authors perform mass spectrometry-based proteomic profiling for 269 EOC patients and reveal molecularly distinct features and potential therapeutic targets among the histological subtypes of EOC.
- Ting-Ting Gong
- , Shuang Guo
- & Qi-Jun Wu
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Article
| Open AccessDetection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer
Long-read single-cell RNA sequencing is capable of detecting isoform-level gene expression and genomic alterations such as mutations and gene fusions, thereby providing cell-specific genotype-phenotype information. Here, the authors use long-read scRNA-seq on metastatic ovarian cancer samples and detect cell-type specific isoforms and gene fusions that may otherwise be misclassified in short-read data.
- Arthur Dondi
- , Ulrike Lischetti
- & Niko Beerenwinkel
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Article
| Open AccessRepression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51
Here, the authors identify lysine-specific demethylase 1 is a homologous recombination (HR) regulator. Its inhibitor induces HR deficiency and sensitizes HR-proficient ovarian cancer cells to PARP inhibitors, which expand the use of PARP inhibitors.
- Lei Tao
- , Yue Zhou
- & Yinglan Zhao
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Article
| Open AccessUnlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering
Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.
- Derek Lee
- , Zachary Spencer Dunn
- & Lili Yang
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Article
| Open AccessSpatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles
Extracellular vesicles (EVs) are known to be heterogeneous intravitally. Here, we present cellulose nanofiber sheets which capture EVs with high purity from trace volumes of biofluids and enable analysis of location-dependent heterogeneity to enhance understanding of pathological mechanisms and enable diagnostic readouts.
- Akira Yokoi
- , Kosuke Yoshida
- & Takao Yasui
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Article
| Open AccessIntegrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer
Response to treatment in high grade serous ovarian carcinoma (HGSOC) is highly variable. Here, the authors leverage a radiogenomic model to predict neoadjuvant chemotherapy response in HGSOC, including clinical data, medical imaging, and blood-based biomarkers such as CA-125 and ctDNA features.
- Mireia Crispin-Ortuzar
- , Ramona Woitek
- & James D. Brenton
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Article
| Open AccessMolecular landscape and functional characterization of centrosome amplification in ovarian cancer
The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- , James A. Hall
- & James D. Brenton
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Article
| Open AccessTriplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4
Even in patients who are initially sensitive, patients treated with platinum-based therapies often go on to relapse and have limited treatment options. Here, the authors report the efficacy and safety of a phase II trial investigating olaparib, pembrolizumab and bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer.
- Yoo-Na Kim
- , Boram Park
- & Jung-Yun Lee
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Article
| Open AccessThe copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
‘Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status.
- Philip Smith
- , Thomas Bradley
- & Iain A. McNeish
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Article
| Open AccessExtracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis
Although remodelling of the extracellular matrix (ECM) is associated with the establishment of an immunosuppressive tumour microenvironment, whether the ECM can educate tumor-associated macrophage phenotypes is not known. Here, the authors examine this question using decellularized tissue models of omental metastasis from patient biopsies.
- E. H. Puttock
- , E. J. Tyler
- & O. M. T. Pearce
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Article
| Open AccessAnalysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.
- Jennifer B. Shah
- , Dana Pueschl
- & Katherine L. Nathanson
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Article
| Open AccessClonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.
- Filipe Correia Martins
- , Dominique-Laurent Couturier
- & James D. Brenton
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Article
| Open AccessSerine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD+ and PARP activity upregulation.
- Tom Van Nyen
- , Mélanie Planque
- & Frédéric Amant
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Article
| Open AccessA multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Super-enhancers and their associated transcription factor networks have been shown to influence ovarian cancer biology. Here, based on an integrated set of genomic and epigenomic datasets, the authors identify clinically relevant super-enhancers amplified in ovarian cancer patients and functionally validate their activity.
- Michael R. Kelly
- , Kamila Wisniewska
- & Hector L. Franco
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Article
| Open AccessRevealing the human mucinome
Mucin-domain glycoproteins are densely O-glycosylated proteins with unique secondary structure that imparts a large influence on cellular environments. Here, the authors develop a technique to selectively enrich and characterize mucin-domain glycoproteins from cell lysate and patient biofluids.
- Stacy A. Malaker
- , Nicholas M. Riley
- & Carolyn R. Bertozzi
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Article
| Open AccessSingle-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer
The tumour microenvironment has not been fully characterised in high-grade serous ovarian cancers (HGSOC). Here, the authors use highly multiplexed imaging to analyse the HGSOC immune microenvironment at spatial and single-cell resolution, with clinically relevant findings for BRCA1/2-mutated tumours.
- I.-M. Launonen
- , N. Lyytikäinen
- & A. Färkkilä
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Article
| Open AccessThe DNA methylome of cervical cells can predict the presence of ovarian cancer
Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
- James E. Barrett
- , Allison Jones
- & Martin Widschwendter
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Article
| Open AccessA Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer
A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib.
- Panagiotis A. Konstantinopoulos
- , Alexandre André B. A. da Costa
- & Geoffrey I. Shapiro
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Article
| Open AccessClinically translatable quantitative molecular photoacoustic imaging with liposome-encapsulated ICG J-aggregates
Photoacoustic imaging is limited by a lack of contrast agents which can enable combined molecular and physiological imaging at depth. Here the authors address these limitations by developing and validating a contrast agent based on targeted liposomes loaded with J-aggregated indocyanine green dye.
- Cayla A. Wood
- , Sangheon Han
- & Richard R. Bouchard
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Article
| Open AccessTargeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer
The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.
- Jianhuang Lin
- , Heng Liu
- & Rugang Zhang
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Article
| Open AccessExtracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness
Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.
- Huijing Yin
- , Jingshu Wang
- & Gong Yang
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Article
| Open AccessCo-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance
Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.
- Elina A. Pietilä
- , Jordi Gonzalez-Molina
- & Kaisa Lehti
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Article
| Open AccessEvolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
High-grade serous ovarian cancer (HGSOC) is prone to developing resistance to treatment. Here, the authors use single-cell RNA-seq and an analysis of archetypes, and find that shifts in metabolism and proliferation are associated with the response to treatment and clonal heterogeneity in HGSOC.
- Aritro Nath
- , Patrick A. Cosgrove
- & Andrea H. Bild
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Article
| Open AccessMolecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
- Elizabeth M. Swisher
- , Tanya T. Kwan
- & Iain A. McNeish
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Article
| Open AccessTransient commensal clonal interactions can drive tumor metastasis
Cooperative interactions among tumor cells may have important implications for metastasis. Here, the authors examined the spatio-temporal nature of interactions among clonal populations of ovarian carcinoma cells and found that transient interactions cells can promote metastases via commensal interactions.
- Suha Naffar-Abu Amara
- , Hendrik J. Kuiken
- & Joan S. Brugge
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Article
| Open AccessTh17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients
The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.
- Matthew S. Block
- , Allan B. Dietz
- & Martin J. Cannon
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Article
| Open AccessMolecular stratification of endometrioid ovarian carcinoma predicts clinical outcome
The molecular classification of endometroid ovarian carcinomas (EnOC) has not been established, preventing the development of stratified therapeutic approaches. Here the authors characterise the molecular landscape of EnOC by whole exome sequencing, identifying clinically distinct disease subtypes.
- Robert L. Hollis
- , John P. Thomson
- & C. Simon Herrington
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Article
| Open AccessCombining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.
- Hyoung Kim
- , Haineng Xu
- & Fiona Simpkins
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Article
| Open AccessITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment
Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.
- Chi-Lam Au-Yeung
- , Tsz-Lun Yeung
- & Samuel C. Mok
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Article
| Open AccessmiR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling
The majority of high grade serous ovarian cancers originate from fallopian tube secretory epithelial cells (FTSECs). Here the authors show that miR-181a drives oncogenic transformation in FTSECs through the cooperative inhibition of the tumor suppressor RB1 and of STING, resulting in genomic instability and suppression of intrinsic interferon signaling.
- Matthew Knarr
- , Rita A. Avelar
- & Analisa DiFeo
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Article
| Open AccessAssessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.
- Kadi Lõhmussaar
- , Oded Kopper
- & Hans Clevers
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Article
| Open AccessHigh-throughput functional evaluation of BRCA2 variants of unknown significance
Many germline variants are found in the BRCA2 gene, some of which pre-dispose women to breast and ovarian cancer. Here, the authors develop a method to determine the functional significance of BRCA2 variants and show that it is comparable to the IARC system of classifying variants.
- Masachika Ikegami
- , Shinji Kohsaka
- & Hiroyuki Mano
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Article
| Open AccessNon-coding somatic mutations converge on the PAX8 pathway in ovarian cancer
The role of non-coding somatic mutations in ovarian cancer is unclear. Here, the authors integrate genomic and epigenomic data from patient samples to show that these mutations frequently converge on the PAX8 transcriptional network.
- Rosario I. Corona
- , Ji-Heui Seo
- & Kate Lawrenson
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Article
| Open AccessRXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression
Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs.
- María Casanova-Acebes
- , María Piedad Menéndez-Gutiérrez
- & Mercedes Ricote
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Article
| Open AccessExome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.
- Deepak N. Subramanian
- , Magnus Zethoven
- & Ian G. Campbell
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Comment
| Open AccessWhy the dual origins of high grade serous ovarian cancer matter
Utilising identical genetic aberrations but targeting different cells, Zhang and colleagues seek to uncover how the cell of origin influences high-grade serous ovarian cancer biology, metastasis and response to treatment.
- Emily K. Colvin
- & Viive M. Howell
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Article
| Open AccessIdentification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary
Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.
- Sarah H. Kim
- , Arnaud Da Cruz Paula
- & Britta Weigelt
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Article
| Open AccessBRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance
BRCA1 mutations located within the BRCT domain result in proteasomal degradation and sensitivity to PARP inhibitors (PARPi). Here, the authors report genetic rearrangements in the BRCA1 gene that generate a BRCT-less BRCA1 protein isoform, which avoids degradation and leads to PARPi resistance.
- Yifan Wang
- , Andrea J. Bernhardy
- & Neil Johnson
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Article
| Open AccessZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer
High-grade serous ovarian cancers (HGSOCs) have defects in homologous recombination despite a lack of BRCA1/2 mutations. Here, the authors show that ZC3H18 positively regulates BRCA1 transcription and its loss causes BRCA1 promoter methylation and increased HR deficiency in HGSOCs.
- Arun Kanakkanthara
- , Catherine J. Huntoon
- & Larry M. Karnitz
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Article
| Open AccessARID1A promotes genomic stability through protecting telomere cohesion
Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number.
- Bo Zhao
- , Jianhuang Lin
- & Rugang Zhang
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Article
| Open AccessThe molecular origin and taxonomy of mucinous ovarian carcinoma
Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.
- Dane Cheasley
- , Matthew J. Wakefield
- & Kylie L. Gorringe