21 results on '"Anthe, Stylianou"'
Search Results
2. Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer
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Lea A. Moukarzel, Lorenzo Ferrando, Anthe Stylianou, Stephanie Lobaugh, Michelle Wu, Silvana Pedra Nobre, Alexia Iasonos, Gabriele Zoppoli, Dilip D. Giri, Nadeem R. Abu‐Rustum, Vance A. Broach, Neil M. Iyengar, Britta Weigelt, and Vicky Makker
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Inflammation ,Metabolic Syndrome ,Cancer Research ,Oncology ,Adipose Tissue, White ,Tumor Microenvironment ,Humans ,Female ,Obesity ,Biomarkers ,Endometrial Neoplasms - Abstract
A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC.Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods.WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p .05). WAT inflammation was associated with greater body mass index (p .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue.WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.
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- 2022
3. Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues
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Lea A. Moukarzel, Lorenzo Ferrando, Higinio Dopeso, Anthe Stylianou, Thais Basili, Fresia Pareja, Arnaud Da Cruz Paula, Gabriele Zoppoli, Nadeem R. Abu-Rustum, Jorge S. Reis-Filho, Kara Long Roche, William P. Tew, Dennis S. Chi, Yukio Sonoda, Dmitriy Zamarin, Carol Aghajanian, Roisin E. O'Cearbhaill, Oliver Zivanovic, and Britta Weigelt
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Ovarian Neoplasms ,Obstetrics and Gynecology ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,Hyperthermic Intraperitoneal Chemotherapy ,Combined Modality Therapy ,Article ,Carboplatin ,Oncology ,Humans ,RNA ,Female ,Transcriptome ,Heat-Shock Proteins - Abstract
OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4,231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value
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- 2022
4. Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases
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Fresia Pareja, Pier Selenica, Edaise M da Silva, Jason A. Konner, Daniel J Fix, Jennifer J. Mueller, E. Smith, Britta Weigelt, Karen Cadoo, Nadeem R. Abu-Rustum, Jorge S. Reis-Filho, Kay J. Park, Anthe Stylianou, Ahmet Zehir, Sarah H. Kim, Lorenzo Ferrando, Arnaud Da Cruz Paula, and Ana Paula Martins Sebastiao
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Adult ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Genital Neoplasms, Female ,Ovary ,Chromosome 9 ,medicine.disease_cause ,Article ,Pathology and Forensic Medicine ,Mesonephric duct ,03 medical and health sciences ,0302 clinical medicine ,Mesonephroma ,Carcinoma ,medicine ,Humans ,PTEN ,Chromosome 12 ,Aged ,biology ,Histology ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,KRAS - Abstract
Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher’s exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.
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- 2021
5. Acquisition of APOBEC Mutagenesis and Microsatellite Instability Signatures in the Development of Brain Metastases in Low-Grade, Early-Stage Endometrioid Endometrial Carcinoma
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Arnaud Da Cruz Paula, Jorge S. Reis-Filho, Nadeem R. Abu-Rustum, Amir Farmanbar, Kimberly Dessources, Britta Weigelt, Anthe Stylianou, Fresia Pareja, Sarat Chandarlapaty, Paulina Cybulska, and Jennifer J. Mueller
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APOBEC ,Cancer Research ,Oncology ,business.industry ,Carcinoma ,medicine ,Cancer research ,Mutagenesis (molecular biology technique) ,Microsatellite instability ,Case Reports ,Stage (cooking) ,medicine.disease ,business - Published
- 2020
6. Ovarian cancer mutational processes drive site-specific immune evasion
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Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L. P. Lim, Michelle Wu, Neeman Mohibullah, Juliana Niyazov, Arvin Eric B. Ruiz, Kevin M. Boehm, Viktoria Bojilova, Christopher J. Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M. Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J. Williams, Allen W. Zhang, Vance Broach, Dennis S. Chi, Arnaud Da Cruz Paula, Ginger J. Gardner, Sarah H. Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Fatemeh N. Derakhshan, Luke Geneslaw, Shirin Issa Bhaloo, Ana Maroldi, Rahelly Nunez, Fresia Pareja, Anthe Stylianou, Mahsa Vahdatinia, Yonina Bykov, Rachel N. Grisham, Ying L. Liu, Yulia Lakhman, Ines Nikolovski, Daniel Kelly, Jianjiong Gao, Andrea Schietinger, Travis J. Hollmann, Samuel F. Bakhoum, Robert A. Soslow, Lora H. Ellenson, Nadeem R. Abu-Rustum, Carol Aghajanian, Claire F. Friedman, Andrew McPherson, Britta Weigelt, Dmitriy Zamarin, and Sohrab P. Shah
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Multidisciplinary - Abstract
High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.
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- 2021
7. Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes
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Allen W. Zhang, Mahsa Vahdatinia, Christopher J. Fong, Anthe Stylianou, Agnes Viale, Yonina Bykov, Arnaud Da Cruz Paula, Matthew Lennon, Fatemeh Derakhshan, Ignacio Vázquez-García, Tyler Funnell, M. Wu, Hongyu Shi, Rachel N. Grisham, Ana Maroldi, Nicole Rusk, Kevin M. Boehm, Ginger J. Gardner, Rahelly Nunez, Samuel F. Bakhoum, Neeman Mohibullah, Ying L Liu, Vance Broach, Arfath Pasha, Andrea Schietinger, Maryam Pourmaleki, Nadeem R. Abu-Rustum, Ines Nikolovski, Andrew McPherson, Dennis S. Chi, Daniel Kelly, Kara Long Roche, Oliver Zivanovic, Travis J. Hollmann, Claire F. Friedman, Luke Geneslaw, Rami Vanguri, Marc J Williams, Yukio Sonoda, Britta Weigelt, Nicholas Ceglia, Diljot Grewal, Florian Uhlitz, Carol Aghajanian, Robert A. Soslow, Sohrab P. Shah, Druv M. Patel, Ritika Kundra, Yulia Lakhman, Arvin Ruiz, Jianjiong Gao, Dmitriy Zamarin, Fresia Pareja, Viktoria Bojilova, Lora H. Ellenson, Jamie L. P. Lim, Eliyahu Havasov, Sarah H. Kim, and Samantha Leung
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Genome instability ,Tumor microenvironment ,Immune system ,Immunoediting ,Cancer cell ,medicine ,Cancer research ,Cancer ,Human leukocyte antigen ,Biology ,medicine.disease ,Ovarian cancer - Abstract
High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, intratumoral heterogeneity and intraperitoneal spread. We investigated determinants of immune recognition and evasion in HGSOC to elucidate co- evolutionary processes underlying malignant progression and tumor immunity. Mutational processes and anatomic sites of tumor foci were key determinants of tumor microenvironment cellular phenotypes, inferred from whole genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive HGSOC patients. Homologous recombination-deficient (HRD)-Dup (BRCA1 mutant-like) and HRD- Del (BRCA2 mutant-like) tumors harbored increased neoantigen burden, inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly- differentiated dysfunctional CD8+ T cells. Foldback inversion (FBI, non-HRD) tumors exhibited elevated TGFβ signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies.HIGHLIGHTSMulti-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancerAnatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypesTumor mutational processes impact mechanisms of immune control and immune evasionSpatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypes
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- 2021
8. Genetic characterization of adult primary pleomorphic uterine rhabdomyosarcoma and comparison with uterine carcinosarcoma
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Andrea Gazzo, Jorge S. Reis-Filho, Lorenzo Ferrando, Paul Weisman, Rodrigo Gularte-Mérida, Sarah Chiang, Ana Paula Martins Sebastiao, Darya Buehler, Britta Weigelt, David N Brown, Fresia Pareja, Nadeem R. Abu-Rustum, Charles W. Ashley, Anthe Stylianou, and Arnaud Da Cruz Paula
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0301 basic medicine ,Genome instability ,Adult ,medicine.medical_specialty ,Pathology ,Histology ,DNA Copy Number Variations ,Somatic cell ,Biology ,Article ,Genomic Instability ,Pathology and Forensic Medicine ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Molecular genetics ,Rhabdomyosarcoma ,medicine ,Cluster Analysis ,Humans ,Gene ,Massive parallel sequencing ,Sequence Analysis, RNA ,Gene Amplification ,High-Throughput Nucleotide Sequencing ,General Medicine ,Sequence Analysis, DNA ,medicine.disease ,Genes, p53 ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Uterine Neoplasms ,Female ,Gene Fusion - Abstract
AIMS To characterise the genetic alterations in adult primary uterine rhabdomyosarcomas (uRMSs) and to investigate whether these tumours are genetically distinct from uterine carcinosarcomas (UCSs). METHODS AND RESULTS Three tumours originally diagnosed as primary adult pleomorphic uRMS were subjected to massively parallel sequencing targeting 468 cancer-related genes and RNA-sequencing. Mutational profiles were compared with those of UCSs (n = 57) obtained from The Cancer Genome Atlas. Sequencing data analyses were performed using validated bioinformatic approaches. Pathogenic TP53 mutations and high levels of genomic instability were detected in the three cases. uRMS1 harboured a likely pathogenic YTHDF2-FOXR1 fusion. uRMS2 harboured a PPP2R1A hotspot mutation and amplification of multiple genes, including WHSC1L1, FGFR1, MDM2, and CCNE1, whereas uRMS3 harboured an FBXW7 hotspot mutation and an ANKRD11 homozygous deletion. Hierarchical clustering of somatic mutations and copy number alterations revealed that these tumours initially diagnosed as pleomorphic uRMSs and UCSs were similar. Subsequent comprehensive pathological re-review of the three uRMSs revealed previously unidentified minute pan-cytokeratin-positive atypical glands in one case (uRMS3), favouring its reclassification as UCS with extensive rhabdomyosarcomatous overgrowth. CONCLUSIONS Adult pleomorphic uRMSs harbour TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.
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- 2021
9. Mutant FOXL2C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors
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Carol Aghajanian, Robert A. Soslow, Simone Sidoli, Toshihiko Yanase, Jesper Christensen, Ole N. Jensen, Akira Iwase, Britta Weigelt, Faizaan Mohammad, Paul A. C. Cloos, Tomoko Nakamura, Richard Koche, Arnaud Da Cruz Paula, Daniela Kleine-Kohlbrecher, Kristian Helin, Anthe Stylianou, Nadeem R. Abu-Rustum, Stine Emilie Weis-Banke, and Mads Lerdrup
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0301 basic medicine ,Cancer Research ,Ovarian Granulosa Cell ,Chemistry ,Mutant ,medicine.disease_cause ,Cell biology ,Chromatin ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Transcription (biology) ,Mutant protein ,030220 oncology & carcinogenesis ,medicine ,Sequence motif ,Carcinogenesis ,Gene - Abstract
The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition. Significance: FOXL2C134W hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2C134W and the TGFβ pathway therapeutic targets in this condition.
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- 2020
10. Whole-Exome Sequencing Analysis of the Progression from Non-Low Grade Ductal Carcinoma In Situ to Invasive Ductal Carcinoma
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Ju Youn Lee, Jorge S. Reis-Filho, James W. Hicks, Anthe Stylianou, Edaise M da Silva, Pier Selenica, Mahsa Vahdatinia, Felipe C Geyer, Andrea Gazzo, Arnaud Da Cruz Paula, Fresia Pareja, Hannah Y Wen, David N Brown, Britta Weigelt, Lorenzo Ferrando, and Rui Bi
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Adult ,Cancer Research ,DNA Copy Number Variations ,Class I Phosphatidylinositol 3-Kinases ,DNA Mutational Analysis ,Breast Neoplasms ,Biology ,Article ,Neoplasms, Multiple Primary ,Genetic Heterogeneity ,Breast cancer ,Exome Sequencing ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Breast ,skin and connective tissue diseases ,Gene ,neoplasms ,Exome sequencing ,Aged ,Neoplasm Grading ,Massive parallel sequencing ,Genetic heterogeneity ,Carcinoma, Ductal, Breast ,Ductal carcinoma ,Middle Aged ,medicine.disease ,body regions ,Carcinoma, Intraductal, Noninfiltrating ,Oncology ,Cancer research ,Disease Progression ,Female - Abstract
Purpose: Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease. Experimental Design: Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods. Results: DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed. Conclusions: Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
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- 2020
11. Mutant FOXL2
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Stine E, Weis-Banke, Mads, Lerdrup, Daniela, Kleine-Kohlbrecher, Faizaan, Mohammad, Simone, Sidoli, Ole N, Jensen, Toshihiko, Yanase, Tomoko, Nakamura, Akira, Iwase, Anthe, Stylianou, Nadeem R, Abu-Rustum, Carol, Aghajanian, Robert, Soslow, Arnaud, Da Cruz Paula, Richard P, Koche, Britta, Weigelt, Jesper, Christensen, Kristian, Helin, and Paul A C, Cloos
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Forkhead Box Protein L2 ,Epithelial-Mesenchymal Transition ,Smad Proteins ,Smad2 Protein ,Article ,Gene Expression Regulation, Neoplastic ,Cell Line, Tumor ,Mutation ,Humans ,Female ,Smad3 Protein ,Cells, Cultured ,Granulosa Cell Tumor ,Smad4 Protein - Abstract
The mutant protein FOXL2(C134W) is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2(C134W) contributes to tumorigenesis is not known. Here we show that mutant FOXL2(C134W) acquires the ability to bind SMAD4, forming a FOXL2(C134W)/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2(C134W) mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2(C134W) also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2(C134W) binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2(C134W). Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2(C134W) and its interaction with SMAD4 as potential therapeutic targets to this condition.
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- 2020
12. Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene
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Caterina Marchiò, Fresia Pareja, Britta Weigelt, Sarah H. Kim, Mauro Papotti, Thais Basili, Higinio Dopeso, Ana Maroldi, José Roberto Lapa e Silva, Lorenzo Ferrando, Anthe Stylianou, Arnaud Da Cruz Paula, Brian P. Rubin, Carlos Gil Ferreira, Edaise M da Silva, and Jorge S. Reis-Filho
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Cancer Research ,Oncogene Proteins, Fusion ,Cyclopamine ,Carcinogenesis ,Thyroid Gland ,Mice, Nude ,Follicular cell ,Article ,thyroid ,Fusion gene ,Mice ,PAX8 Transcription Factor ,03 medical and health sciences ,chemistry.chemical_compound ,sonic hedgehog pathway ,0302 clinical medicine ,Cell Movement ,Animals ,Humans ,Hedgehog Proteins ,Thyroid Neoplasms ,Sonic hedgehog ,Clonogenic assay ,Cell Proliferation ,biology ,fusion gene ,hyalinizing trabecular tumor ,Oncogenes ,Hedgehog signaling pathway ,DNA-Binding Proteins ,Repressor Proteins ,HEK293 Cells ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Trans-Activators ,Cancer research ,biology.protein ,Heterografts ,Female ,Smoothened ,PAX8 ,Signal Transduction - Abstract
Hyalinizing trabecular tumors (HTTs) of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In this study we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human non-malignant thyroid (Nthy-ori 3–1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3–1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.
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- 2020
13. Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary
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Kristian Helin, Higinio Dopeso, Robert A. Soslow, Zhen Sun, Anqi Li, Wesley R Samore, Yonina Bykov, Arnaud Da Cruz Paula, Dmitriy Zamarin, Fresia Pareja, Edaise M da Silva, Sarah H. Kim, Esther Oliva, Thais Basili, Rui Bi, Anthe Stylianou, Charles W. Ashley, Achim A. Jungbluth, Lorenzo Ferrando, Rodrigo Gularte-Mérida, Ana Paula Martins Sebastiao, Britta Weigelt, Sho Fujisawa, Pier Selenica, Catarina Silveira, Nadeem R. Abu-Rustum, Jorge S. Reis-Filho, and Caitlin G. Smith
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0301 basic medicine ,Oncogene Proteins, Fusion ,Gene Dosage ,General Physics and Astronomy ,Muscle Proteins ,Fusion gene ,0302 clinical medicine ,DNA sequencing ,Sonic hedgehog ,lcsh:Science ,Ovarian Neoplasms ,Multidisciplinary ,Nuclear Proteins ,RNA sequencing ,Middle Aged ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Cell signalling ,Adult ,Stromal cell ,animal structures ,Adolescent ,Science ,LIM-Homeodomain Proteins ,Ovary ,Biology ,Zinc Finger Protein Gli2 ,Gene dosage ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Young Adult ,Ovarian cancer ,GLI2 ,Exome Sequencing ,medicine ,Humans ,Sex Cord-Gonadal Stromal Tumors ,Hedgehog Proteins ,Sclerosis ,Cancer ,General Chemistry ,medicine.disease ,FHL2 ,030104 developmental biology ,Mutation ,Cancer research ,biology.protein ,Next-generation sequencing ,lcsh:Q ,Stromal Cells ,Transcription Factors - Abstract
Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic–phenotypic correlation in ovarian neoplasms., 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.
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- 2020
14. Abstract P4-05-11: Methylation profiling of mucinous breast cancer
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Britta Weigelt, Matjia Snuderl, Fresia Pareja, Edaise M da Silva, Larry Norton, Jorge S. Reis-Filho, Anthe Stylianou, Pier Selenica, Lorenzo Ferrando, Hong Zhang, David N Brown, Hannah Y Wen, Jonathan Serrano, Arnaud Da Cruz Paula, and Edi Brogi
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Cancer Research ,Estrogen receptor ,Cancer ,Biology ,medicine.disease ,Phenotype ,Fusion gene ,Germline mutation ,Breast cancer ,Oncology ,Cancer research ,medicine ,Mucinous carcinoma ,Epigenetics - Abstract
Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer characterized by tumor cells floating in lakes of mucin. As compared to invasive ductal carcinoma of no special type (IDC-NST), we have recently shown that MCBs harbor a lower frequency of PIK3CA mutations and lack concurrent 1q gains and 16q losses, hallmark genetic alterations of ER-positive breast cancer. Despite their distinctive phenotype and previous efforts to characterize their genomic landscape by whole-genome, whole-exome and RNA-sequencing, no pathognomonic somatic mutation or fusion gene underpinning MCBs or the mucinous phenotype have been identified. In this study we sought to determine whether MCBs would be defined by specific epigenetic changes. Materials and methods: Thirty-six MCBs were subjected to DNA methylation profiling using Infinium MethylationEPIC arrays. Following quantile normalization, low quality probe filtering, and data background and dye bias correction using the ‘noob’ algorithm, methylation profiling data of MCBs were compared to those of ER-positive/HER2-negative IDC-NSTs from The Cancer Genome Atlas (TCGA) lacking concurrent 1q gains/16q losses or PIK3CA hotspot mutations and matched according to age and menopausal status at a 1:2 ratio (n=72). An enrichment analysis of the differentially methylated targets in gene promoters and enhancers was conducted using Minfi and MethylGSEA R packages. A subset of 12 MCBs of this cohort was subjected to RNA-sequencing and compared to age, menopausal status and molecular features-matched ER-positive/HER2-negative IDC-NSTs from TCGA (1:2 ratio; n=24) using gene set enrichment analysis (GSEA). Results: Enrichment analysis of differentially methylated probes revealed a significant enrichment of targets in promoters and enhancers of mucin-encoding genes and in genes of the mTOR signaling pathway between MCBs and matched IDC-NSTs from TCGA (P Conclusions: Taken together, our data suggest that MCBs display a high expression of mucin-encoding genes, due to hypomethylation of promoters and enhancers and could provide the basis for their distinctive phenotype. Moreover, our findings suggest that despite the lack of genetic alterations affecting genes of the PI3K/mTOR signaling pathway in MCBs, mTOR signaling might be constitutively active in these tumors via epigenetic mechanisms, supporting the notion that, in the absence of pathognomonic genetic alterations, a disruption of the epigenetic landscape is a critical driver in the development of this rare breast cancer type. Citation Format: Fresia Pareja, Lorenzo Ferrando, Edaise M da Silva, Arnaud Da Cruz Paula, Anthe Stylianou, David N Brown, Pier Selenica, Jonathan Serrano, Hannah Y Wen, Hong Zhang, Edi Brogi, Larry Norton, Matjia Snuderl, Jorge S Reis-Filho, Britta Weigelt. Methylation profiling of mucinous breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-11.
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- 2020
15. GENETIC HETEROGENEITY OF OVARIAN SEX CORD-STROMAL TUMORS
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Britta Weigelt, Jorge S Reis-Filho, Robert A. Soslow, Nadeem R. Abu-Rustum, Anthe Stylianou, Edaise M. da Silva, Sarah Kim, and Arnaud Da Cruz Paula
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- 2019
16. 229 Genetic heterogeneity of ovarian sex cord-stromal tumors
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Sarah H. Kim, Jorge S. Reis-Filho, Robert A. Soslow, E M Da Silva, Britta Weigelt, A Da Cruz Paula, Nadeem R. Abu-Rustum, and Anthe Stylianou
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Mutation ,medicine.anatomical_structure ,Somatic cell ,Genetic heterogeneity ,medicine ,Cancer research ,Missense mutation ,Ovary ,Epigenetics ,Biology ,medicine.disease_cause ,Chromosome 12 ,Frameshift mutation - Abstract
Objectives Sertoli-Leydig and granulosa cell tumors are sex cord-stromal tumors of the ovary that primarily impact young women. Adult-type granulosa cell tumors (aGCTs) are characterized by pathognomonic somatic FOXL2 mutations, whilst 30–60% of Sertoli-Leydig cell tumors (SLCTs) harbor DICER1 mutations. A comprehensive assessment of the repertoire of genomic alterations of sex cord-stromal tumors has yet to be performed. Methods Primary SLCTs (n=2), juvenile (j)GCTs (n=2) and a primary and matched mixed SLCT/aGCT recurrence (n=2) were subjected to whole-exome sequencing. Somatic mutations and copy number alterations were defined using state-of-the-art bioinformatics algorithms. Results Ovarian sex cord-stromal tumors displayed a low mutational burden, with a median of 22 (range 13–82) somatic mutations. Mutational analysis revealed the presence of a DICER1 p.R293lfs*4 frameshift mutation in the pure SLCT. A FOXL2 p.C134W hotpot mutation was identified in the primary and recurrent mixed SLCT/aGCT; in addition, LAMA5, ZNF837, and HCFC1 missense mutations and an UBR2 splice-site mutation were present only in the mixed recurrence but absent in the primary mixed SLCT/aGCT. Neither of the two jGCTs harbored FOXL2 or DICER1 mutations, and none of the identified somatic mutations and copy number alterations were shared between the two jGCTs. jGCT1 harbored GATA4 p.L281M/Q missense mutations and copy number gains of chromosomes 4 and 8, whereas jGCT2 displayed a TOPAZ1 p.K335R missense mutation and chromosome 12 and 18 gains. Conclusions Sex cord-stromal tumors are a genetically heterogeneous group of rare ovarian neoplasms. Larger studies to assess whether jGCTs harbor recurrent genetic/epigenetic alterations are warranted.
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- 2019
17. Compositional and architectural characterization of high-grade serous ovarian carcinomas using single cell technologies and multiplex microscopy
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S.H. Kim, Nadeem R. Abu-Rustum, Britta Weigelt, Mario M. Leitao, Linas Mazutis, Yonina Bykov, Travis J. Hollmann, Dana Pe'er, Rachel M. Fromme, Dennis S. Chi, Tyler Walther, C. Liu, Alejandro Jiménez-Sánchez, D. Zamarin, Aliya Holland, George Plitas, Anthe Stylianou, Oliver Zivanovic, and Yukio Sonoda
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Pathology ,medicine.medical_specialty ,Serous fluid ,medicine.anatomical_structure ,Oncology ,business.industry ,Cell ,Microscopy ,medicine ,Obstetrics and Gynecology ,Ovarian carcinomas ,Multiplex ,business - Published
- 2020
18. Identification of endometrial cancer mutations in pelvic washings using massively parallel sequencing: A pilot study
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Britta Weigelt, Anthe Stylianou, Pier Selenica, Kimberly Dessources, M. Wu, Simon Sk Lee, K. Long Roche, and Nadeem R. Abu-Rustum
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Massive parallel sequencing ,Oncology ,business.industry ,Endometrial cancer ,Obstetrics and Gynecology ,Medicine ,Identification (biology) ,Computational biology ,business ,medicine.disease - Published
- 2020
19. Immune and genomic profiling of small cell carcinomas of the ovary hypercalcemic type
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Kimberly Dessources, David M. Hyman, Britta Weigelt, J.D. Liu, Jorge S. Reis-Filho, Anthe Stylianou, Pier Selenica, Aliya Holland, Travis J. Hollmann, D. Zamarin, Simon Sk Lee, and M. Wu
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Immune system ,Genomic profiling ,medicine.anatomical_structure ,Oncology ,business.industry ,Cell ,medicine ,Cancer research ,Obstetrics and Gynecology ,Ovary ,business - Published
- 2020
20. Prospective study evaluating white adipose tissue inflammation and clinicopathologic features in endometrial cancer
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Vicky Makker, Nadeem R. Abu-Rustum, Silvana Pedra Nobre, M. Wu, Neil M. Iyengar, Vance Broach, Anthe Stylianou, Lea A. Moukarzel, Dilip Giri, and Britta Weigelt
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Endometrial cancer ,Cancer ,Retrospective cohort study ,Hematology ,medicine.disease ,Malignancy ,Oncology ,Internal medicine ,Biopsy ,medicine ,Progression-free survival ,business ,Prospective cohort study ,Dyslipidemia - Abstract
Background Obesity is a chief mediator of endometrial cancer (EC) and is responsible for the increasing incidence and mortality of this malignancy. Obesity induced chronic inflammation, creates a pro-neoplastic environment via local and systemic processes. In other obesity-related cancers, white adipose tissue inflammation (WATi) is an independent predictor of shortened cancer-specific survival. A retrospective study in advanced EC revealed that WATi is associated with shorter progression-free survival. The aim of this prospective study was to investigate the presence of WATi in EC and to evaluate the relationship between WATi and clinicopathologic factors in women with EC. Methods Patients who underwent primary surgical management of EC, regardless of stage or histology, had omental biopsies collected. WATi was detected by the presence of dead/dying adipocytes surrounded by CD68+ macrophages forming a crown-like structure (CLS). Clinicopathologic data were extracted from medical records. For association with WATi, Wilcoxon rank sum test was used for continuous variables, and the Fisher’s exact or χ2 test for categorical variables. Results A total of 101 EC patients who underwent primary surgical management between 2015 and 2019 were included. Of these, 46 (46%) had WATi. The presence of WATi was unaffected by race, histology, FIGO stage, smoking or menopausal state. In contrast, dyslipidemia (39% vs 13%, p = 0.002), hypertension (70% vs 35%, p 30kg/m2. Conclusions WATi was present in nearly 50% of newly diagnosed EC patients regardless of stage. There was an association between the presence and severity of WATi and BMI among patients with EC. Specifically, WATi was associated with hyperglycemia, hypertension, and diabetes mellitus. Further investigation into the impact of WATi on the tumor microenvironment and patient outcomes is ongoing. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
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- 2019
21. The amount of circulating cell-free DNA present in plasma of endometrial cancer patients is associated with surgical stage, histology and MRI-defined tumor volume
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Britta Weigelt, Mario M. Leitao, Yukio Sonoda, J. Nincevic, Charles W. Ashley, Yuliya Lakhman, Anthe Stylianou, Carol Aghajanian, Elizabeth L. Jewell, Karen Cadoo, and Nadeem R. Abu-Rustum
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Pathology ,medicine.medical_specialty ,Oncology ,Volume (thermodynamics) ,business.industry ,Endometrial cancer ,Obstetrics and Gynecology ,Medicine ,Histology ,Stage (cooking) ,business ,medicine.disease ,Circulating Cell-Free DNA - Published
- 2019
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