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2. DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers

Author

Gull, Nicole, Jones, Michelle R, Peng, Pei-Chen, Coetzee, Simon G, Silva, Tiago C, Plummer, Jasmine T, Reyes, Alberto Luiz P, Davis, Brian D, Chen, Stephanie S, Lawrenson, Kate, Lester, Jenny, Walsh, Christine, Rimel, Bobbie J, Li, Andrew J, Cass, Ilana, Berg, Yonatan, Govindavari, John-Paul B, Rutgers, Joanna KL, Berman, Benjamin P, Karlan, Beth Y, and Gayther, Simon A

Subjects
Human Genome, Genetics, Ovarian Cancer, Clinical Research, Cancer, Rare Diseases, Orphan Drug, Aetiology, 2.1 Biological and endogenous factors, DNA Methylation, Drug Resistance, Neoplasm, Female, Humans, Neoplasm Recurrence, Local, Ovarian Neoplasms, Transcriptome, High grade serous ovarian cancer, Methylation, Chemoresistance, Epigenetics, Whole genome bisulfite sequencing, Computational methods, Translational research, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundLittle is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC).MethodsWe performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations.ResultsLandscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers.ConclusionThese findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

Published
2022

3. Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes

Author

Bolton, Kelly L, Chen, Denise, de la Fuente, Rosario I Corona, Fu, Zhuxuan, Murali, Rajmohan, K�bel, Martin, Tazi, Yanis, Cunningham, Julie M, Chan, Irenaeus CC, Wiley, Brian J, Moukarzel, Lea A, Winham, Stacey J, Armasu, Sebastian M, Lester, Jenny, Elishaev, Esther, Laslavic, Angela, Kennedy, Catherine J, Piskorz, Anna, Sekowska, Magdalena, Brand, Alison H, Chiew, Yoke-Eng, Pharoah, Paul, Elias, Kevin M, Drapkin, Ronny, Churchman, Michael, Gourley, Charlie, DeFazio, Anna, Karlan, Beth, Brenton, James D, Weigelt, Britta, Anglesio, Michael S, Huntsman, David, Gayther, Simon A, Konner, Jason, Modugno, Francesmary, Lawrenson, Kate, Goode, Ellen L, and Papaemmanuil, Elli

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Human Genome, Genetics, Rare Diseases, Cancer, Biotechnology, Cancer Genomics, Precision Medicine, Clinical Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Female, Humans, Ovarian Neoplasms, Adenocarcinoma, Clear Cell, Mutation, Endometriosis, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeTo identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental designWe profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.ResultsWe detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.ConclusionsOur study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Published
2022

4. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Author

Dareng, Eileen O., Coetzee, Simon G., Tyrer, Jonathan P., Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian D., Dezem, Felipe Segato, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto L., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Bandera, Elisa V., Beane Freeman, Laura E., Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bolton, Kelly L., Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda S., DeFazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Ene, Gabrielle, Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham G., Goodman, Marc T., Gronwald, Jacek, Haiman, Christopher A., Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huang, Ruea-Yea, Jensen, Allan, Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony N., Kelemen, Linda E., Kennedy, Catherine J., Khusnutdinova, Elza K., Kiemeney, Lambertus A., Kjaer, Susanne K., Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa C., Le, Nhu D., Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey R., Matsuo, Keitaro, May, Taymaa, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro N., Moysich, Kirsten B., Narod, Steven A., Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N. Charlotte, Park, Sue K., Pejovic, Tanja, Permuth, Jennifer B., Piskorz, Anna, Prokofyeva, Darya, Riggan, Marjorie J., Risch, Harvey A., Rodríguez-Antona, Cristina, Rossing, Mary Anne, Sandler, Dale P., Setiawan, V. Wendy, Shan, Kang, Song, Honglin, Southey, Melissa C., Steed, Helen, Sutphen, Rebecca, Swerdlow, Anthony J., Teo, Soo Hwang, Terry, Kathryn L., Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Webb, Penelope M., Weinberg, Clarice R., Weise, Rayna Matsuno, Wentzensen, Nicolas, White, Emily, Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zeinomar, Nur, Zheng, Wei, Ziogas, Argyrios, Berchuck, Andrew, Goode, Ellen L., Huntsman, David G., Pearce, Celeste L., Ramus, Susan J., Sellers, Thomas A., Freedman, Matthew L., Lawrenson, Kate, Schildkraut, Joellen M., Hazelett, Dennis, Plummer, Jasmine T., Kar, Siddhartha, Jones, Michelle R., Pharoah, Paul D.P., and Gayther, Simon A.

Published
2024
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5. Author Correction: A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus

Author

Spisak, Sandor, Tisza, Viktoria, Nuzzo, Pier Vitale, Seo, Ji-Heui, Pataki, Balint, Ribli, Dezso, Sztupinszki, Zsofia, Bell, Connor, Rohanizadegan, Mersedeh, Stillman, David R., Alaiwi, Sarah Abou, Bartels, Alan H., Papp, Marton, Shetty, Anamay, Abbasi, Forough, Lin, Xianzhi, Lawrenson, Kate, Gayther, Simon A., Pomerantz, Mark, Baca, Sylvan, Solymosi, Norbert, Csabai, Istvan, Szallasi, Zoltan, Gusev, Alexander, and Freedman, Matthew L.

Published
2023
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6. A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus

Author

Spisak, Sandor, Tisza, Viktoria, Nuzzo, Pier Vitale, Seo, Ji-Heui, Pataki, Balint, Ribli, Dezso, Sztupinszki, Zsofia, Bell, Connor, Rohanizadegan, Mersedeh, Stillman, David R., Alaiwi, Sarah Abou, Bartels, Alan H., Papp, Marton, Shetty, Anamay, Abbasi, Forough, Lin, Xianzhi, Lawrenson, Kate, Gayther, Simon A., Pomerantz, Mark, Baca, Sylvan, Solymosi, Norbert, Csabai, Istvan, Szallasi, Zoltan, Gusev, Alexander, and Freedman, Matthew L.

Published
2023
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7. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma

Author

Nassar, Amin H., Abou Alaiwi, Sarah, Baca, Sylvan C., Adib, Elio, Corona, Rosario I., Seo, Ji-Heui, Fonseca, Marcos A. S., Spisak, Sandor, El Zarif, Talal, Tisza, Viktoria, Braun, David A., Du, Heng, He, Monica, Flaifel, Abdallah, Alchoueiry, Michel, Denize, Thomas, Matar, Sayed G., Acosta, Andres, Shukla, Sachet, Hou, Yue, Steinharter, John, Bouchard, Gabrielle, Berchuck, Jacob E., O’Connor, Edward, Bell, Connor, Nuzzo, Pier Vitale, Mary Lee, Gwo-Shu, Signoretti, Sabina, Hirsch, Michelle S., Pomerantz, Mark, Henske, Elizabeth, Gusev, Alexander, Lawrenson, Kate, Choueiri, Toni K., Kwiatkowski, David J., and Freedman, Matthew L.

Published
2023
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8. The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17.

Author

Chaves-Moreira, Daniele, Mitchell, Marilyn, Arruza, Cristina, Rawat, Priyanka, Sidoli, Simone, Nameki, Robbin, Reddy, Jessica, Corona, Rosario, Afeyan, Lena, Klein, Isaac, Ma, Sisi, Winterhoff, Boris, Konecny, Gottfried, Garcia, Benjamin, Brady, Donita, Lawrenson, Kate, Morin, Patrice, and Drapkin, Ronny

Subjects
Animals, Fallopian Tubes, Female, HMGB Proteins, Humans, Mice, Neoplasm Grading, Ovarian Neoplasms, PAX8 Transcription Factor, SOXF Transcription Factors, Transcription Factors
Abstract

PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non-cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

Published
2022

9. A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Author

Mortlock, Sally, Corona, Rosario I, Kho, Pik Fang, Pharoah, Paul, Seo, Ji-Heui, Freedman, Matthew L, Gayther, Simon A, Siedhoff, Matthew T, Rogers, Peter AW, Leuchter, Ronald, Walsh, Christine S, Cass, Ilana, Karlan, Beth Y, Rimel, BJ, Consortium, International Endometriosis Genetics Consortium Ovarian Cancer Association, Montgomery, Grant W, Lawrenson, Kate, and Kar, Siddhartha P

Subjects
Endometriosis, Genetics, Cancer, Rare Diseases, Human Genome, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium, Mendelian randomization, endometriosis, epithelial ovarian cancer, genetic association, genetic correlation, genetic risk, histotype, meta-analysis
Abstract

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

Published
2022

10. Sex differences in microRNA expression in first and third trimester human placenta†.

Author

Flowers, Amy E, Gonzalez, Tania L, Joshi, Nikhil V, Eisman, Laura E, Clark, Ekaterina L, Buttle, Rae A, Sauro, Erica, DiPentino, Rosemarie, Lin, Yayu, Wu, Di, Wang, Yizhou, Santiskulvong, Chintda, Tang, Jie, Lee, Bora, Sun, Tianyanxin, Chan, Jessica L, Wang, Erica T, Jefferies, Caroline, Lawrenson, Kate, Zhu, Yazhen, Afshar, Yalda, Tseng, Hsian-Rong, Williams, John, and Pisarska, Margareta D

Subjects
Placenta, Humans, MicroRNAs, Epigenesis, Genetic, Pregnancy, Pregnancy Trimester, First, Pregnancy Trimester, Third, Sex Characteristics, Female, Male, chorionic villous sampling, developmental epigenetics, human transcriptome, miRNome, microRNA, placenta sex differences, pregnancy, sexually dimorphic normative miRNA atlas, stable miRNAs, Biotechnology, Human Genome, Perinatal Period - Conditions Originating in Perinatal Period, Genetics, Pediatric, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Reproductive health and childbirth, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Obstetrics & Reproductive Medicine
Abstract

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR 10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

Published
2022

13. DNA Methylation Profiles of Ovarian Clear Cell Carcinoma

Author

Cunningham, Julie M, Winham, Stacey J, Wang, Chen, Weiglt, Britta, Fu, Zhuxuan, Armasu, Sebastian M, McCauley, Bryan M, Brand, Alison H, Chiew, Yoke-Eng, Elishaev, Esther, Gourley, Charlie, Kennedy, Catherine J, Laslavic, Angela, Lester, Jenny, Piskorz, Anna, Sekowska, Magdalena, Brenton, James D, Churchman, Michael, DeFazio, Anna, Drapkin, Ronny, Elias, Kevin M, Huntsman, David G, Karlan, Beth Y, Köbel, Martin, Konner, Jason, Lawrenson, Kate, Papaemmanuil, Elli, Bolton, Kelly L, Modugno, Francesmary, and Goode, Ellen L

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Ovarian Cancer, Rare Diseases, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Clear Cell, Adult, Aged, Aged, 80 and over, Aneuploidy, Class I Phosphatidylinositol 3-Kinases, CpG Islands, DNA Methylation, DNA-Binding Proteins, Disease Progression, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Mutation, Neoplasm Staging, Ovarian Neoplasms, Prognosis, Transcription Factors, Tumor Suppressor Protein p53, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundOvarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC.MethodsWe interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways.ResultsTwo approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10-6).ConclusionsDNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.ImpactThis work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Published
2022

14. In vivo discovery of RNA proximal proteins via proximity-dependent biotinylation

Author

Lin, Xianzhi, Fonseca, Marcos AS, Breunig, Joshua J, Corona, Rosario I, and Lawrenson, Kate

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Human Genome, Genetics, Lung, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Ascorbate Peroxidases, Biotinylation, CRISPR-Associated Proteins, CRISPR-Cas Systems, HEK293 Cells, Humans, Poly A, RNA, RNA, Guide, Kinetoplastida, RNA, Small Nuclear, RNA-Binding Proteins, Recombinant Fusion Proteins, Staining and Labeling, Type VI Crispr-Cas, engineered soybean ascorbate peroxidase APEX2, proximity-dependent biotinylation, RNA proximity labelling, RNA proximal proteins, RNA-centric method, RRNA&#8211, proteininteractions, poly(A) tail, RNA binding proteins, U1 snRNA RBPS, noncoding RNAs, RRNA–proteininteractions, Developmental Biology, Biochemistry and cell biology
Abstract

RNA molecules function as messenger RNAs (mRNAs) that encode proteins and noncoding transcripts that serve as adaptor molecules, structural components, and regulators of genome organization and gene expression. Their function and regulation are largely mediated by RNA binding proteins (RBPs). Here we present RNA proximity labelling (RPL), an RNA-centric method comprising the endonuclease-deficient Type VI CRISPR-Cas protein dCas13b fused to engineered ascorbate peroxidase APEX2. RPL discovers target RNA proximal proteins in vivo via proximity-based biotinylation. RPL applied to U1 identified proteins involved in both U1 canonical and noncanonical functions. Profiling of poly(A) tail proximal proteins uncovered expected categories of RBPs and provided additional evidence for 5'-3' proximity and unexplored subcellular localizations of poly(A)+ RNA. Our results suggest that RPL allows rapid identification of target RNA binding proteins in native cellular contexts, and is expected to pave the way for discovery of novel RNA-protein interactions important for health and disease.

Published
2021

15. Predicting master transcription factors from pan-cancer expression data

Author

Reddy, Jessica, Fonseca, Marcos AS, Corona, Rosario I, Nameki, Robbin, Segato Dezem, Felipe, Klein, Isaac A, Chang, Heidi, Chaves-Moreira, Daniele, Afeyan, Lena K, Malta, Tathiane M, Lin, Xianzhi, Abbasi, Forough, Font-Tello, Alba, Sabedot, Thais, Cejas, Paloma, Rodríguez-Malavé, Norma, Seo, Ji-Heui, Lin, De-Chen, Matulonis, Ursula, Karlan, Beth Y, Gayther, Simon A, Pasaniuc, Bogdan, Gusev, Alexander, Noushmehr, Houtan, Long, Henry, Freedman, Matthew L, Drapkin, Ronny, Young, Richard A, Abraham, Brian J, and Lawrenson, Kate

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Ovarian Cancer, Human Genome
Abstract

Critical developmental “master transcription factors” (MTFs) can be subverted during tumorigenesis to control oncogenic transcriptional programs. Current approaches to identifying MTFs rely on ChIP-seq data, which is unavailable for many cancers. We developed the CaCTS (Cancer Core Transcription factor Specificity) algorithm to prioritize candidate MTFs using pan-cancer RNA sequencing data. CaCTS identified candidate MTFs across 34 tumor types and 140 subtypes including predictions for cancer types/subtypes for which MTFs are unknown, including e.g. PAX8, SOX17, and MECOM as candidates in ovarian cancer (OvCa). In OvCa cells, consistent with known MTF properties, these factors are required for viability, lie proximal to superenhancers, co-occupy regulatory elements globally, co-bind loci encoding OvCa biomarkers, and are sensitive to pharmacologic inhibition of transcription. Our predictions of MTFs, especially for tumor types with limited understanding of transcriptional drivers, pave the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

Published
2021

16. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Author

Kar, Siddhartha P, Considine, Daniel PC, Tyrer, Jonathan P, Plummer, Jasmine T, Chen, Stephanie, Dezem, Felipe S, Barbeira, Alvaro N, Rajagopal, Padma S, Rosenow, Will T, Moreno, Fernando, Bodelon, Clara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, deFazio, Anna, Dörk, Thilo, Ekici, Arif B, Ewing, Ailith, Fountzilas, George, Goode, Ellen L, Hartman, Mikael, Heitz, Florian, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Huzarski, Tomasz, Jensen, Allan, Karlan, Beth Y, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Li, Jingmei, Liebrich, Clemens, May, Taymaa, Olsson, Håkan, Permuth, Jennifer B, Peterlongo, Paolo, Radice, Paolo, Ramus, Susan J, Riggan, Marjorie J, Risch, Harvey A, Saloustros, Emmanouil, Simard, Jacques, Szafron, Lukasz M, Titus, Linda, Thompson, Cheryl L, Vierkant, Robert A, Winham, Stacey J, Zheng, Wei, Doherty, Jennifer A, Berchuck, Andrew, Lawrenson, Kate, Im, Hae Kyung, Manichaikul, Ani W, Pharoah, Paul DP, Gayther, Simon A, and Schildkraut, Joellen M

Subjects
Biotechnology, Genetics, Prevention, Cancer, Breast Cancer, Human Genome, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Published
2021

17. Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube

Author

Dinh, Huy Q, Lin, Xianzhi, Abbasi, Forough, Nameki, Robbin, Haro, Marcela, Olingy, Claire E, Chang, Heidi, Hernandez, Lourdes, Gayther, Simon A, Wright, Kelly N, Aspuria, Paul-Joseph, Karlan, Beth Y, Corona, Rosario I, Li, Andrew, Rimel, BJ, Siedhoff, Matthew T, Medeiros, Fabiola, and Lawrenson, Kate

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Rare Diseases, Cancer, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Cell Differentiation, Cell Line, Tumor, Core Binding Factor Alpha 3 Subunit, Endometriosis, Epithelial Cells, Epithelial-Mesenchymal Transition, Fallopian Tubes, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leiomyoma, Middle Aged, PAX8 Transcription Factor, SOXF Transcription Factors, Signal Transduction, Single-Cell Analysis, Transcriptome, PAX8, RUNX3, SOX17, ciliated epithelial cells, fallopian tube, microenvironment, ovarian cancer, scRNA-seq, secretory epithelial cells, transcription factor, Medical Physiology, Biological sciences
Abstract

The human fallopian tube harbors the cell of origin for the majority of high-grade serous "ovarian" cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We perform single-cell transcriptomic profiling of around 53,000 individual cells from 12 primary fallopian specimens to map their major cell types. We identify 10 epithelial subpopulations with diverse transcriptional programs. Based on transcriptional signatures, we reconstruct a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of advanced HGSCs identifies the "early secretory" population as a likely precursor state for the majority of HGSCs. Its signature comprises both epithelial and mesenchymal features and is enriched in mesenchymal-type HGSCs (p = 6.7 × 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

Published
2021

18. Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer.

Author

Baca, Sylvan C, Takeda, David Y, Seo, Ji-Heui, Hwang, Justin, Ku, Sheng Yu, Arafeh, Rand, Arnoff, Taylor, Agarwal, Supreet, Bell, Connor, O'Connor, Edward, Qiu, Xintao, Alaiwi, Sarah Abou, Corona, Rosario I, Fonseca, Marcos AS, Giambartolomei, Claudia, Cejas, Paloma, Lim, Klothilda, He, Monica, Sheahan, Anjali, Nassar, Amin, Berchuck, Jacob E, Brown, Lisha, Nguyen, Holly M, Coleman, Ilsa M, Kaipainen, Arja, De Sarkar, Navonil, Nelson, Peter S, Morrissey, Colm, Korthauer, Keegan, Pomerantz, Mark M, Ellis, Leigh, Pasaniuc, Bogdan, Lawrenson, Kate, Kelly, Kathleen, Zoubeidi, Amina, Hahn, William C, Beltran, Himisha, Long, Henry W, Brown, Myles, Corey, Eva, and Freedman, Matthew L

Subjects
Cell Line, Tumor, Animals, Humans, Neuroendocrine Tumors, Adenocarcinoma, Prostatic Neoplasms, Disease Progression, Receptors, Androgen, Gene Expression Regulation, Neoplastic, RNA Interference, Mutation, Male, Hepatocyte Nuclear Factor 3-alpha, Epigenomics, Cell Line, Tumor, Receptors, Androgen, Gene Expression Regulation, Neoplastic
Abstract

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.

Published
2021

19. Single-cell transcriptomic analysis of endometriosis

Author

Fonseca, Marcos A. S., Haro, Marcela, Wright, Kelly N., Lin, Xianzhi, Abbasi, Forough, Sun, Jennifer, Hernandez, Lourdes, Orr, Natasha L., Hong, Jooyoon, Choi-Kuaea, Yunhee, Maluf, Horacio M., Balzer, Bonnie L., Fishburn, Aaron, Hickey, Ryan, Cass, Ilana, Goodridge, Helen S., Truong, Mireille, Wang, Yemin, Pisarska, Margareta D., Dinh, Huy Q., EL-Naggar, Amal, Huntsman, David G., Anglesio, Michael S., Goodman, Marc T., Medeiros, Fabiola, Siedhoff, Matthew, and Lawrenson, Kate

Published
2023
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20. Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Author

Pomerantz, Mark M, Qiu, Xintao, Zhu, Yanyun, Takeda, David Y, Pan, Wenting, Baca, Sylvan C, Gusev, Alexander, Korthauer, Keegan D, Severson, Tesa M, Ha, Gavin, Viswanathan, Srinivas R, Seo, Ji-Heui, Nguyen, Holly M, Zhang, Baohui, Pasaniuc, Bogdan, Giambartolomei, Claudia, Alaiwi, Sarah A, Bell, Connor A, O’Connor, Edward P, Chabot, Matthew S, Stillman, David R, Lis, Rosina, Font-Tello, Alba, Li, Lewyn, Cejas, Paloma, Bergman, Andries M, Sanders, Joyce, van der Poel, Henk G, Gayther, Simon A, Lawrenson, Kate, Fonseca, Marcos AS, Reddy, Jessica, Corona, Rosario I, Martovetsky, Gleb, Egan, Brian, Choueiri, Toni, Ellis, Leigh, Garraway, Isla P, Lee, Gwo-Shu Mary, Corey, Eva, Long, Henry W, Zwart, Wilbert, and Freedman, Matthew L

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Aging, Human Genome, Urologic Diseases, Cancer, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Cell Line, Cell Line, Tumor, Disease Progression, Epigenomics, Gene Expression Regulation, Neoplastic, HEK293 Cells, Hepatocyte Nuclear Factor 3-alpha, Humans, Male, Prostate, Prostatic Neoplasms, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Published
2020

21. Identification of novel epithelial ovarian cancer loci in women of African ancestry

Author

Manichaikul, Ani, Peres, Lauren C, Wang, Xin‐Qun, Barnard, Mollie E, Chyn, Deanna, Sheng, Xin, Du, Zhaohui, Tyrer, Jonathan, Dennis, Joseph, Schwartz, Ann G, Cote, Michele L, Peters, Edward, Moorman, Patricia G, Bondy, Melissa, Barnholtz‐Sloan, Jill S, Terry, Paul, Alberg, Anthony J, Bandera, Elisa V, Funkhouser, Ellen, Wu, Anna H, Pearce, Celeste Leigh, Pike, Malcom, Setiawan, Veronica Wendy, Haiman, Christopher A, Consortium, the African American Breast Cancer, Consortium, the African Ancestry Prostate Cancer, Palmer, Julie R, LeMarchand, Loic, Wilkens, Lynne R, Berchuck, Andrew, Doherty, Jennifer A, Modugno, Francesmary, Ness, Roberta, Moysich, Kirsten, Karlan, Beth Y, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Lawrenson, Kate, Gayther, Simon, Sellers, Thomas A, Pharoah, Paul, Schildkraut, Joellen M, and Consortium, the African American Cancer Epidemiology Study and the Ovarian Cancer Association

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Cancer, Prevention, Ovarian Cancer, Rare Diseases, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Aldo-Keto Reductase Family 1 Member C3, Antigens, Neoplasm, Black People, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Follistatin, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasm Proteins, Polymorphism, Single Nucleotide, United States, White People, ovarian cancer, African ancestry, genome wide association study, gene expression, eQTLs, African American Breast Cancer Consortium, African Ancestry Prostate Cancer Consortium, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p

Published
2020

22. Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer.

Author

Corona, Rosario I, Seo, Ji-Heui, Lin, Xianzhi, Hazelett, Dennis J, Reddy, Jessica, Fonseca, Marcos AS, Abassi, Forough, Lin, Yvonne G, Mhawech-Fauceglia, Paulette Y, Shah, Sohrab P, Huntsman, David G, Gusev, Alexander, Karlan, Beth Y, Berman, Benjamin P, Freedman, Matthew L, Gayther, Simon A, and Lawrenson, Kate

Subjects
Ovary, Humans, Ovarian Neoplasms, Muscle Proteins, DNA-Binding Proteins, Transcription Factors, Repressor Proteins, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Binding Sites, Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Kruppel-Like Transcription Factors, Gene Regulatory Networks, Enhancer Elements, Genetic, Gene Knockout Techniques, Epigenomics, PAX8 Transcription Factor, Whole Genome Sequencing, Carcinoma, Ovarian Epithelial, Chromatin Immunoprecipitation Sequencing, RNA-Seq
Abstract

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.

Published
2020

23. A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Author

Lawrenson, Kate, Fonseca, Marcos AS, Liu, Annie Y, Dezem, Felipe Segato, Lee, Janet M, Lin, Xianzhi, Corona, Rosario I, Abbasi, Forough, Vavra, Kevin C, Dinh, Huy Q, Gill, Navjot Kaur, Seo, Ji-Heui, Coetzee, Simon, Lin, Yvonne G, Pejovic, Tanja, Mhawech-Fauceglia, Paulette, Rowat, Amy C, Drapkin, Ronny, Karlan, Beth Y, Hazelett, Dennis J, Freedman, Matthew L, Gayther, Simon A, and Noushmehr, Houtan

Subjects
Biological Sciences, Rare Diseases, Ovarian Cancer, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Cell Line, Cell Line, Tumor, Epithelial Cells, Epithelial-Mesenchymal Transition, Fallopian Tubes, Female, Gene Expression Regulation, Neoplastic, Humans, Machine Learning, Middle Aged, Ovarian Neoplasms, Ovary, RNA-Seq, SOXF Transcription Factors, Single-Cell Analysis, Transcriptome, RNA-seq, SOX18, dual origins, fallopian tube secretory epithelial cell, high-grade serous ovarian cancer, machine learning, one-class logistic regression models, ovarian surface epithelial cell, single-cell RNA-seq, super enhancers, transcription factors, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10-4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10-4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10-16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs.

Published
2019

24. Super-Enhancer-Associated LncRNA UCA1 Interacts Directly with AMOT to Activate YAP Target Genes in Epithelial Ovarian Cancer

Author

Lin, Xianzhi, Spindler, Tassja J, de Souza Fonseca, Marcos Abraão, Corona, Rosario I, Seo, Ji-Heui, Dezem, Felipe Segato, Li, Lewyn, Lee, Janet M, Long, Henry W, Sellers, Thomas A, Karlan, Beth Y, Noushmehr, Houtan, Freedman, Matthew L, Gayther, Simon A, and Lawrenson, Kate

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Ovarian Cancer, Genetics, Rare Diseases, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Cancer Systems Biology, Omics, Proteomics, Systems Biology
Abstract

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis, and yet their mechanistic roles remain challenging to characterize. Here, we integrate functional proteomics with lncRNA-interactome profiling to characterize Urothelial Cancer Associated 1 (UCA1), a candidate driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 activates transcription coactivator YAP and its target genes. In vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as a direct binding partner. Loss-of-function experiments show that AMOT mediates YAP activation by UCA1, as UCA1 enhances the AMOT-YAP interaction to promote YAP dephosphorylation and nuclear translocation. Together, we characterize UCA1 as a lncRNA regulator of Hippo-YAP signaling and highlight the UCA1-AMOT-YAP signaling axis in ovarian cancer development.

Published
2019

25. Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

Author

Lawrenson, Kate, Song, Fengju, Hazelett, Dennis J, Kar, Siddhartha P, Tyrer, Jonathan, Phelan, Catherine M, Corona, Rosario I, Rodríguez-Malavé, Norma I, Seo, Ji-Hei, Adler, Emily, Coetzee, Simon G, Segato, Felipe, Fonseca, Marcos AS, Amos, Christopher I, Carney, Michael E, Chenevix-Trench, Georgia, Choi, Jiyeob, Doherty, Jennifer A, Jia, Weihua, Jin, Gang J, Kim, Byoung-Gie, Le, Nhu D, Lee, Juyeon, Li, Lian, Lim, Boon K, Adenan, Noor A, Mizuno, Mika, Park, Boyoung, Pearce, Celeste L, Shan, Kang, Shi, Yongyong, Shu, Xiao-Ou, Sieh, Weiva, Group, The Australian Ovarian Cancer Study, Thompson, Pamela J, Wilkens, Lynne R, Wei, Qingyi, Woo, Yin L, Yan, Li, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Goode, Ellen L, Berchuck, Andrew, Sellers, Thomas A, Teo, Soo-Hwang, Zheng, Wei, Matsuo, Keitaro, Park, Sue, Chen, Kexin, Pharoah, Paul DP, Gayther, Simon A, and Goodman, Marc T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Human Genome, Ovarian Cancer, Genetics, Prevention, Clinical Research, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Asian People, Base Sequence, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-wide association study, Asian ancestry, Epithelial ovarian cancer, Enhancer, eQTL, Gene regulation, Australian Ovarian Cancer Study Group, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

ObjectiveGenome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.MethodsGenotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.ResultsAt chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP

Published
2019

26. A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants

Author

Gusev, Alexander, Lawrenson, Kate, Lin, Xianzhi, Lyra, Paulo C, Kar, Siddhartha, Vavra, Kevin C, Segato, Felipe, Fonseca, Marcos AS, Lee, Janet M, Pejovic, Tanya, Liu, Gang, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Monteiro, Alvaro N, Pharoah, Paul DP, Pasaniuc, Bogdan, and Gayther, Simon A

Subjects
Biological Sciences, Genetics, Clinical Research, Prevention, Biotechnology, Human Genome, Ovarian Cancer, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Alternative Splicing, Carcinoma, Ovarian Epithelial, Cell Cycle Proteins, Cell Line, Tumor, Databases, Genetic, Endosomal Sorting Complexes Required for Transport, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Models, Genetic, Nuclear Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Transcriptome, Ovarian Cancer Association Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.

Published
2019

27. Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

Author

Buckley, Melissa A, Woods, Nicholas T, Tyrer, Jonathan P, Mendoza-Fandiño, Gustavo, Lawrenson, Kate, Hazelett, Dennis J, Najafabadi, Hamed S, Gjyshi, Anxhela, Carvalho, Renato S, Lyra, Paulo C, Coetzee, Simon G, Shen, Howard C, Yang, Ally W, Earp, Madalene A, Yoder, Sean J, Risch, Harvey, Chenevix-Trench, Georgia, Ramus, Susan J, Phelan, Catherine M, Coetzee, Gerhard A, Noushmehr, Houtan, Hughes, Timothy R, Sellers, Thomas A, Goode, Ellen L, Pharoah, Paul D, Gayther, Simon A, and Monteiro, Alvaro NA

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Prevention, Human Genome, Cancer, Rare Diseases, Biotechnology, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Base Sequence, Carcinoma, Ovarian Epithelial, Cell Cycle Proteins, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 9, Cystadenocarcinoma, Serous, DNA, Neoplasm, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HEK293 Cells, Humans, Linkage Disequilibrium, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Ovarian Cancer Association Consortium, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

Published
2019

28. A scalable filtration method for high throughput screening based on cell deformability

Author

Gill, Navjot Kaur, Ly, Chau, Nyberg, Kendra D, Lee, Linus, Qi, Dongping, Tofig, Bobby, Reis-Sobreiro, Mariana, Dorigo, Oliver, Rao, JianYu, Wiedemeyer, Ruprecht, Karlan, Beth, Lawrenson, Kate, Freeman, Michael R, Damoiseaux, Robert, and Rowat, Amy C

Subjects
Engineering, Bioengineering, Rare Diseases, Breast Cancer, Biotechnology, Cancer, Ovarian Cancer, Cell Line, Tumor, Cell Separation, Cell Shape, High-Throughput Screening Assays, Humans, Single-Cell Analysis, Chemical Sciences, Analytical Chemistry, Chemical sciences
Abstract

Cell deformability is a label-free biomarker of cell state in physiological and disease contexts ranging from stem cell differentiation to cancer progression. Harnessing deformability as a phenotype for screening applications requires a method that can simultaneously measure the deformability of hundreds of cell samples and can interface with existing high throughput facilities. Here we present a scalable cell filtration device, which relies on the pressure-driven deformation of cells through a series of pillars that are separated by micron-scale gaps on the timescale of seconds: less deformable cells occlude the gaps more readily than more deformable cells, resulting in decreased filtrate volume which is measured using a plate reader. The key innovation in this method is that we design customized arrays of individual filtration devices in a standard 96-well format using soft lithography, which enables multiwell input samples and filtrate outputs to be processed with higher throughput using automated pipette arrays and plate readers. To validate high throughput filtration to detect changes in cell deformability, we show the differential filtration of human ovarian cancer cells that have acquired cisplatin-resistance, which is corroborated with cell stiffness measurements using quantitative deformability cytometry. We also demonstrate differences in the filtration of human cancer cell lines, including ovarian cancer cells that overexpress transcription factors (Snail, Slug), which are implicated in epithelial-to-mesenchymal transition; breast cancer cells (malignant versus benign); and prostate cancer cells (highly versus weekly metastatic). We additionally show how the filtration of ovarian cancer cells is affected by treatment with drugs known to perturb the cytoskeleton and the nucleus. Our results across multiple cancer cell types with both genetic and pharmacologic manipulations demonstrate the potential of this scalable filtration device to screen cells based on their deformability.

Published
2019

29. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

Kang, Eun Young, Millstein, Joshua, Popovic, Gordana, Meagher, Nicola S., Bolithon, Adelyn, Talhouk, Aline, Chiu, Derek S., Anglesio, Michael S., Leung, Betty, Tang, Katrina, Lambie, Neil, Pavanello, Marina, Da-anoy, Annalyn, Lambrechts, Diether, Loverix, Liselore, Olbrecht, Siel, Bisinotto, Christiani, Garcia-Donas, Jesus, Ruiz-Llorente, Sergio, Yagüe-Fernandez, Monica, Edwards, Robert P., Elishaev, Esther, Olawaiye, Alexander, Taylor, Sarah, Ataseven, Beyhan, du Bois, Andreas, Harter, Philipp, Lester, Jenny, Høgdall, Claus K., Armasu, Sebastian M., Huang, Yajue, Vierkant, Robert A., Wang, Chen, Winham, Stacey J., Heublein, Sabine, Kommoss, Felix K. F., Cramer, Daniel W., Sasamoto, Naoko, van-Wagensveld, Lilian, Lycke, Maria, Mateoiu, Constantina, Joseph, Janine, Pike, Malcolm C., Odunsi, Kunle, Tseng, Chiu-Chen, Pearce, Celeste L., Bilic, Sanela, Conrads, Thomas P., Hartmann, Arndt, Hein, Alexander, Jones, Michael E., Leung, Yee, Beckmann, Matthias W., Ruebner, Matthias, Schoemaker, Minouk J., Terry, Kathryn L., El-Bahrawy, Mona A., Coulson, Penny, Etter, John L., LaVigne-Mager, Katherine, Andress, Juergen, Grube, Marcel, Fischer, Anna, Neudeck, Nina, Robertson, Greg, Farrell, Rhonda, Barlow, Ellen, Quinn, Carmel, Hettiaratchi, Anusha, Casablanca, Yovanni, Erber, Ramona, Stewart, Colin J. R., Tan, Adeline, Yu, Yu, Boros, Jessica, Brand, Alison H., Harnett, Paul R., Kennedy, Catherine J., Nevins, Nikilyn, Morgan, Terry, Fasching, Peter A., Vergote, Ignace, Swerdlow, Anthony J., Candido dos Reis, Francisco J., Maxwell, G. Larry, Neuhausen, Susan L., Barquin-Garcia, Arantzazu, Modugno, Francesmary, Moysich, Kirsten B., Crowe, Philip J., Hirasawa, Akira, Heitz, Florian, Karlan, Beth Y., Goode, Ellen L., Sinn, Peter, Horlings, Hugo M., Høgdall, Estrid, Sundfeldt, Karin, Kommoss, Stefan, Staebler, Annette, Wu, Anna H., Cohen, Paul A., DeFazio, Anna, Lee, Cheng-Han, Steed, Helen, Le, Nhu D., Gayther, Simon A., Lawrenson, Kate, Pharoah, Paul D. P., Konecny, Gottfried, Cook, Linda S., Ramus, Susan J., Kelemen, Linda E., and Köbel, Martin

Published
2022
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30. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.

Published
2022
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32. Optimizing exosomal RNA isolation for RNA-Seq analyses of archival sera specimens.

Author

Prendergast, Emily N, de Souza Fonseca, Marcos Abraão, Dezem, Felipe Segato, Lester, Jenny, Karlan, Beth Y, Noushmehr, Houtan, Lin, Xianzhi, and Lawrenson, Kate

Subjects
Humans, Specimen Handling, Sequence Analysis, RNA, Exosomes, Transcriptome, Biomarkers, Cell-Free Nucleic Acids, Sequence Analysis, RNA, General Science & Technology
Abstract

Exosomes are endosome-derived membrane vesicles that contain proteins, lipids, and nucleic acids. The exosomal transcriptome mediates intercellular communication, and represents an understudied reservoir of novel biomarkers for human diseases. Next-generation sequencing enables complex quantitative characterization of exosomal RNAs from diverse sources. However, detailed protocols describing exosome purification for preparation of exosomal RNA-sequence (RNA-Seq) libraries are lacking. Here we compared methods for isolation of exosomes and extraction of exosomal RNA from human cell-free serum, as well as strategies for attaining equal representation of samples within pooled RNA-Seq libraries. We compared commercial precipitation with ultracentrifugation for exosome purification and confirmed the presence of exosomes via both transmission electron microscopy and immunoblotting. Exosomal RNA extraction was compared using four different RNA purification methods. We determined the minimal starting volume of serum required for exosome preparation and showed that high quality exosomal RNA can be isolated from sera stored for over a decade. Finally, RNA-Seq libraries were successfully prepared with exosomal RNAs extracted from human cell-free serum, cataloguing both coding and non-coding exosomal transcripts. This method provides researchers with strategic options to prepare RNA-Seq libraries and compare RNA-Seq data quantitatively from minimal volumes of fresh and archival human cell-free serum for disease biomarker discovery.

Published
2018

33. Abstract A004: Patterns of lncRNA-regulated gene expression in high-grade serous ovarian carcinomas

Author

Reid, Brett M., primary, Chen, Ann, additional, Chen, Zhihua, additional, Karreth, Florian A., additional, Kanetsky, Peter, additional, Permuth, Jennifer B., additional, Saglam, Ozlen, additional, Teer, Jamie K., additional, Yu, Xiaoqing, additional, Gayther, Simon, additional, Goode, Ellen, additional, Pharoah, Paul, additional, Sellers, Thomas A., additional, Lawrenson, Kate, additional, and Tyrer, Jonathan, additional

Published
2024
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35. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja KH, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, AOCS study group, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, and Dorfling, Cecilia M

Subjects
AOCS study group, EMBRACE Study, GEMO Study Collaborators, HEBON Study, KConFab Investigators, OPAL study group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Telomere-Binding Proteins, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Mutation, Polymorphism, Single Nucleotide, Alleles, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Carcinoma, Ovarian Epithelial, Genetics, Cancer, Human Genome, Rare Diseases, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017

38. MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

Author

German, Beatriz, primary, Singh, Jagpreet N., additional, Fonseca, Marcos AdS, additional, Burkhart, Deborah L., additional, Sheahan, Anjali, additional, Bergom, Hannah, additional, Morel, Katherine L., additional, Beltran, Himisha, additional, Hwang, Justin H., additional, Lawrenson, Kate, additional, and Ellis, Leigh, additional

Published
2024
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39. α‐Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus

Author

Montano, Erica N., primary, Bose, Moumita, additional, Huo, Lihong, additional, Tumurkhuu, Gantsetseg, additional, De Los Santos, Gabriela, additional, Simental, Brianna, additional, Stotland, Aleksandr B., additional, Wei, Janet, additional, Bairey Merz, C. Noel, additional, Suda, Jo, additional, Martins, Gislaine, additional, Lalani, Sarfaraz, additional, Lawrenson, Kate, additional, Wang, Yizhou, additional, Parker, Sarah, additional, Venuturupalli, Swamy, additional, Ishimori, Mariko, additional, Wallace, Daniel J., additional, and Jefferies, Caroline A., additional

Published
2024
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40. A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.

Author

Jia, Dongyu, Liu, Zhenqiu, Deng, Nan, Tan, Tuan Zea, Huang, Ruby Yun-Ju, Taylor-Harding, Barbie, Cheon, Dong-Joo, Lawrenson, Kate, Wiedemeyer, Wolf R, Walts, Ann E, Karlan, Beth Y, and Orsulic, Sandra

Subjects
Cell Line, Tumor, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Collagen Type I, Actins, Neoplasm Staging, Disease-Free Survival, Coculture Techniques, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Time Factors, Databases, Genetic, Kaplan-Meier Estimate, Myofibroblasts, Tumor Microenvironment, Neoplasm Grading, Transcriptome, Biomarkers, Tumor, Cancer-Associated Fibroblasts, Carcinoma, Ovarian Epithelial, Cancer-associated fibroblasts, Pan-cancer, Therapeutic targets, Tumor microenvironment, Cell Line, Tumor, Neoplasms, Glandular and Epithelial, Gene Expression Regulation, Neoplastic, Databases, Genetic, Biomarkers, Carcinoma, Ovarian Epithelial, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs. Our analyses uncovered COL11A1 as a highly specific biomarker of activated CAFs. Using COL11A1 as a 'seed', we identified co-expressed genes in 13 types of primary carcinoma in The Cancer Genome Atlas. We demonstrated that a molecular signature of activated CAFs is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, suggesting that targeting fibroblast activation should be effective in multiple cancers. We prioritized several potential pan-cancer therapeutic targets that are likely to have high specificity for activated CAFs and minimal toxicity in normal tissues.

Published
2016

42. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Olama, Ali Amin Al, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, Investigators, ABCTB, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, Study, AOCS Study Group amp Australian Cancer, BioResource, APCB, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Aging, Urologic Diseases, Prostate Cancer, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Signal Transduction, ABCTB Investigators, AOCS Study Group & Australian Cancer Study, APCB BioResource, kConFab Investigators, NBCS Investigators, GENICA Network, PRACTICAL consortium, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Published
2016

43. Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer

Author

Beach, Jessica A, Aspuria, Paul-Joseph P, Cheon, Dong-Joo, Lawrenson, Kate, Agadjanian, Hasmik, Walsh, Christine S, Karlan, Beth Y, and Orsulic, Sandra

Subjects
Cancer, Ovarian Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Animals, Apoptosis, Blotting, Western, Cell Differentiation, Cell Movement, Cell Proliferation, Cystadenocarcinoma, Serous, Female, Fibroblasts, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Lysophospholipids, Mice, Mice, Knockout, Myofibroblasts, Neoplasm Grading, Ovarian Neoplasms, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Prognosis, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Lysosphingolipid, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sphingosine, Survival Rate, Transforming Growth Factor beta, Tumor Cells, Cultured, sphingosine kinase 1, cancer-associated fibroblast, transforming growth factor-beta 1, sphingosine-1-phosphate, microenvironment, Oncology and Carcinogenesis
Abstract

Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-β-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-β signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.

Published
2016

44. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

Author

Amankwah, Ernest K, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Chornokur, Ganna, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bruinsma, Fiona, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chen, Zhihua, Chen, Y Ann, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, du Bois, Andreas, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis N, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Jim, Heather, Kellar, Melissa, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lim, Boon Kiong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Ian, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, and Weber, Rachel Palmieri

Subjects
Georgia Chenevix-Trench on behalf of the AOCS management group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Risk, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Genome-Wide Association Study, Epithelial-Mesenchymal Transition, Carcinoma, Ovarian Epithelial, epithelial-mesenchymal transition, ovarian cancer, single-nucleotide polymorphisms, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Epidemiology, Public Health and Health Services, Genetics
Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

Published
2015

45. PAX8 and MECOM are interaction partners driving ovarian cancer

Author

Bleu, Melusine, Mermet-Meillon, Fanny, Apfel, Verena, Barys, Louise, Holzer, Laura, Bachmann Salvy, Marianne, Lopes, Rui, Amorim Monteiro Barbosa, Inês, Delmas, Cecile, Hinniger, Alexandra, Chau, Suzanne, Kaufmann, Markus, Haenni, Simon, Berneiser, Karolin, Wahle, Maria, Moravec, Ivana, Vissières, Alexandra, Poetsch, Tania, Ahrné, Erik, Carte, Nathalie, Voshol, Johannes, Bechter, Elisabeth, Hamon, Jacques, Meyerhofer, Marco, Erdmann, Dirk, Fischer, Matteo, Stachyra, Therese, Freuler, Felix, Gutmann, Sascha, Fernández, César, Schmelzle, Tobias, Naumann, Ulrike, Roma, Guglielmo, Lawrenson, Kate, Nieto-Oberhuber, Cristina, Cobos-Correa, Amanda, Ferretti, Stephane, Schübeler, Dirk, and Galli, Giorgio Giacomo

Published
2021
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46. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author

Lawrenson, Kate, Iversen, Edwin S, Tyrer, Jonathan, Weber, Rachel Palmieri, Concannon, Patrick, Hazelett, Dennis J, Li, Qiyuan, Marks, Jeffrey R, Berchuck, Andrew, Lee, Janet M, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Chen, Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Plisiecka-Halasa, Joanna, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Jakubowska, Anna, Paul, James, Jensen, Allan, Karlan, Beth Y, Kjaer, Susanne Kruger, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Cannioto, Rikki, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Nevanlinna, Heli, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Narod, Steven A, Nedergaard, Lotte, Ness, Roberta B, Azmi, Mat Adenan Noor, Odunsi, Kunle, and Olson, Sara H

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Biotechnology, Cancer, Human Genome, Ovarian Cancer, Prevention, Rare Diseases, Genetic Testing, Genetics, Aetiology, 2.1 Biological and endogenous factors, Carcinoma, Ovarian Epithelial, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Australian Cancer Study, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Published
2015

47. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Author

Kar, Siddhartha P, Tyrer, Jonathan P, Li, Qiyuan, Lawrenson, Kate, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjørge, Line, Bogdanova, Natalia, Brinton, Louise, Brooks-Wilson, Angela, Butzow, Ralf, Campbell, Ian, Carty, Karen, Chang-Claude, Jenny, Chen, Yian Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Easton, Douglas F, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus K, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Paul, James, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kjaer, Susanne K, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Narod, Steven A, Nedergaard, Lotte, Ness, Roberta B, Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H, and Orlow, Irene

Subjects
Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Genetic Predisposition to Disease, Nuclear Proteins, Transcription Factors, DNA, Neoplasm, Morbidity, Risk Factors, Gene Expression Regulation, Neoplastic, Genotype, Female, Genome-Wide Association Study, Global Health, Ovarian Cancer, Biotechnology, Cancer, Genetics, Rare Diseases, Prevention, Human Genome, 2.1 Biological and endogenous factors, Epidemiology, Medical and Health Sciences
Abstract

BackgroundGenome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.MethodsWe selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).ResultsGene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.ConclusionWe identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.ImpactNetwork analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Published
2015

48. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Author

Lawrenson, Kate, Li, Qiyuan, Kar, Siddhartha, Seo, Ji-Heui, Tyrer, Jonathan, Spindler, Tassja J, Lee, Janet, Chen, Yibu, Karst, Alison, Drapkin, Ronny, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Chen, Anne, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kruger Kjaer, Susanne, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Nevanlinna, Heli, McNeish, Ian, and Menon, Usha

Subjects
Australian Ovarian Cancer Study Group, Cell Line, Tumor, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Homeodomain Proteins, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Protein Binding, Quantitative Trait Loci, Female, Nuchal Cord, Genetic Association Studies, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Neoplasms, Glandular and Epithelial, Gene Expression Regulation, Neoplastic, Carcinoma, Ovarian Epithelial, Rare Diseases, Prevention, Ovarian Cancer, Biotechnology, Human Genome, Cancer, Genetics, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P

Published
2015

49. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

Author

Kelemen, Linda E, Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M, Seo, Ji-Heui, Phelan, Catherine M, Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chen, Y Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Doerk, Thilo, du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Engelholm, Svend Aage, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moysich, Kirsten B, Narod, Steven A, and Nedergaard, Lotte

Subjects
Developmental Biology, Medical and Health Sciences, Biological Sciences
Published
2015

50. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

Author

Coetzee, Simon G, Shen, Howard C, Hazelett, Dennis J, Lawrenson, Kate, Kuchenbaecker, Karoline, Tyrer, Jonathan, Rhie, Suhn K, Levanon, Keren, Karst, Alison, Drapkin, Ronny, Ramus, Susan J, Consortium, The Consortium of Investigators of Modifiers of BRCA1 2 The Ovarian Cancer Association, Couch, Fergus J, Offit, Kenneth, Chenevix-Trench, Georgia, Monteiro, Alvaro NA, Antoniou, Antonis, Freedman, Matthew, Coetzee, Gerhard A, Pharoah, Paul DP, Noushmehr, Houtan, Gayther, Simon A, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chen, Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Easton, Douglas F, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kjaer, Susanne Kruger, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, and Lissowska, Jolanta

Subjects
Biological Sciences, Genetics, Rare Diseases, Prevention, Human Genome, Ovarian Cancer, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Histones, Humans, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2, Medical and Health Sciences, Genetics & Heredity
Abstract

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.

Published
2015

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