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1. Sexually dimorphic DNA methylation and gene expression patterns in human first trimester placenta

Author

Tania L. Gonzalez, Bryn E. Willson, Erica T. Wang, Kent D. Taylor, Allynson Novoa, Akhila Swarna, Juanita C. Ortiz, Gianna J. Zeno, Caroline A. Jefferies, Kate Lawrenson, Jerome I. Rotter, Yii-Der Ida Chen, John Williams, Jinrui Cui, Mark O. Goodarzi, and Margareta D. Pisarska

Subjects
Placenta, Early pregnancy, Healthy pregnancy, Fetal sex, DNA methylation, Total RNA-seq, Medicine, Physiology, QP1-981
Abstract

Abstract Background Fetal sex and placental development impact pregnancy outcomes and fetal–maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies. Methods Pregnant subjects were recruited in late first trimester (weeks 10–14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas. Results Methylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate

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

Author

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

Subjects
Science
Abstract

Abstract To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

Published
2023
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3. KRAS mutations and endometriosis burden of disease

Author

Natasha L Orr, Arianne Albert, Yang Doris Liu, Amy Lum, JooYoon Hong, Catalina L Ionescu, Janine Senz, Tayyebeh M Nazeran, Anna F Lee, Heather Noga, Kate Lawrenson, Catherine Allaire, Christina Williams, Mohamed A Bedaiwy, Michael S Anglesio, and Paul J Yong

Subjects
classification, endometrioma, endometriosis, ethnicity, fertility, gene, Pathology, RB1-214
Abstract

Abstract The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.

Published
2023
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4. Fallopian tube single cell analysis reveals myeloid cell alterations in high-grade serous ovarian cancer

Author

Joshua Brand, Marcela Haro, Xianzhi Lin, B.J. Rimel, Stephanie M. McGregor, Kate Lawrenson, and Huy Q. Dinh

Subjects
Microenvironment, Immunology, Cancer, Transcriptomics, Science
Abstract

Summary: Most high-grade serous ovarian cancers (HGSCs) likely initiate from fallopian tube (FT) epithelia. While epithelial subtypes have been characterized using single-cell RNA-sequencing (scRNA-Seq), heterogeneity of other compartments and their involvement in tumor progression are poorly defined. Integrated analysis of human FT scRNA-Seq and HGSC-related tissues, including tumors, revealed greater immune and stromal transcriptional diversity than previously reported. We identified abundant monocytes in FTs across two independent cohorts. The ratio of macrophages to monocytes is similar between benign FTs, ovaries, and adjacent normal tissues but significantly greater in tumors. FT-defined monocyte and macrophage signatures, cell-cell communication, and gene set enrichment analyses identified monocyte- and macrophage-specific interactions and functional pathways in paired tumors and adjacent normal tissues. Further reanalysis of HGSC scRNA-Seq identified monocyte and macrophage subsets associated with neoadjuvant chemotherapy. Taken together, our work provides data that an altered FT myeloid cell composition could inform the discovery of early detection markers for HGSC.

Published
2024
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5. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma

Author

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

Subjects
Science
Abstract

The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.

Published
2023
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6. circCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment

Author

Roberta Piras, Emily Y. Ko, Connor Barrett, Marco De Simone, Xianzhi Lin, Marina T. Broz, Fernando H. G. Tessaro, Mireia Castillo-Martin, Carlos Cordon-Cardo, Helen S. Goodridge, Dolores Di Vizio, Mona Batish, Kate Lawrenson, Y. Grace Chen, Keith Syson Chan, and Jlenia Guarnerio

Subjects
Science
Abstract

Circular RNAs can contribute to tumour progression. Here the authors show that two circular RNAs, circCsnk1g3 and circAnkib1 promote sarcoma growth by controlling the expression of interferon related genes and pro-inflammatory factors in sarcoma cells

Published
2022
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7. DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers

Author

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

Subjects
High grade serous ovarian cancer, Methylation, Chemoresistance, Epigenetics, Whole genome bisulfite sequencing, Computational methods, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). Methods We 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. Results Landscapes 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. Conclusion These 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
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8. 50 Therapeutic opportunities in the master transcription factor circuitries of clear cell carcinomas

Author

Nolan J. Kinne, Soledad Ochoa, Marla Scott, Forough Abbasi, Pak Hin Yu, Marcela Haro, BJ Rimel, and Kate Lawrenson

Subjects
Gynecology and obstetrics, RG1-991, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Objectives: Transcription factors are emerging as targets for novel therapeutics for the treatment of malignancies. We sought to evaluate functions of PAX8 and HNF1B in both clear cell ovarian cancer (CCOC) and clear cell renal cell carcinoma (ccRCC) to ask whether these factors control tissue-specific or shared molecular functions and to assess their candidacy for targeted therapy. Methods: We used two prototypic human cell lines for each cell type. We determined differential expression of PAX8 and HNF1B byquantification of protein in western blots. HNF1B and PAX8 expression was depleted using siRNA and the Incucyte® Live-Cell Analysis System to monitor continuous growth of cells grown as monolayers and as three-dimensional spheroids. RNA-sequencing and CUT&RUN was performed to determine the transcriptional targets and binding sites of these factors. Results: PAX8 was found to be more highly expressed in CCOC than ccRCC however there was no difference in expression of HNF1B. Knockdown of PAX8 caused decrease in expression of HNF1B in both cell lines but no change in expression of two other factors ETS2 and EPAS1. Knockdown of HNF1B did not affect expression of the other transcription factors tested. The knockdown of HNF1B and PAX8 caused a significant decrease in growth rate of both cell lines in monolayer culture and had heterogeneous effects on spheroid growth. Depletion of these factors resulted in varying degrees of global transcriptional repression or activation, with evidence of a hierarchy dominated by HNF1B and PAX8, and negative crosstalk between ETS2 and EPAS1. Key downstream pathways include immune signaling, PDGF signaling and autophagy. Conclusions: PAX8 is more highly expressed in CCOC than ccRCC. PAX8, HNF1B, ETS2 and EPAS1 exhibit a strong degree of connectedness, suggesting they form a core regulatory circuit in both CCOC and ccRCC. Critically PAX8 and HNF1B are required for normal cellular proliferation in both CCOC and ccRCC in both monolayer and spheroid culture. Ongoing integrated multi-omic analyses have identified the autophagy pathway as a novel therapeutic opportunity in PAX8 and HNF1B-driven clear cell tumors.

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

Author

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

Subjects
Science
Published
2023
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11. PAX8 and MECOM are interaction partners driving ovarian cancer

Author

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

Subjects
Science
Abstract

Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.

Published
2021
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12. Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Author

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

Subjects
Science
Abstract

The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.

Published
2021
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13. Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer

Author

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

Subjects
Science
Abstract

The role of non-coding somatic mutations in ovarian cancer is unclear. Here, the authors integrate genomic and epigenomic data from patient samples to show that these mutations frequently converge on the PAX8 transcriptional network.

Published
2020
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14. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Author

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

Subjects
breast cancer, ovarian cancer, pleiotropy, GWAS, transcriptome-wide association study, Genetics, QH426-470
Abstract

Summary: 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
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15. GENAVi: a shiny web application for gene expression normalization, analysis and visualization

Author

Alberto Luiz P. Reyes, Tiago C. Silva, Simon G. Coetzee, Jasmine T. Plummer, Brian D. Davis, Stephanie Chen, Dennis J. Hazelett, Kate Lawrenson, Benjamin P. Berman, Simon A. Gayther, and Michelle R. Jones

Subjects
Next generation sequencing, RNA-seq, Shiny, GUI, Differential expression, Visualization, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The development of next generation sequencing (NGS) methods led to a rapid rise in the generation of large genomic datasets, but the development of user-friendly tools to analyze and visualize these datasets has not developed at the same pace. This presents a two-fold challenge to biologists; the expertise to select an appropriate data analysis pipeline, and the need for bioinformatics or programming skills to apply this pipeline. The development of graphical user interface (GUI) applications hosted on web-based servers such as Shiny can make complex workflows accessible across operating systems and internet browsers to those without programming knowledge. Results We have developed GENAVi (Gene Expression Normalization Analysis and Visualization) to provide a user-friendly interface for normalization and differential expression analysis (DEA) of human or mouse feature count level RNA-Seq data. GENAVi is a GUI based tool that combines Bioconductor packages in a format for scientists without bioinformatics expertise. We provide a panel of 20 cell lines commonly used for the study of breast and ovarian cancer within GENAVi as a foundation for users to bring their own data to the application. Users can visualize expression across samples, cluster samples based on gene expression or correlation, calculate and plot the results of principal components analysis, perform DEA and gene set enrichment and produce plots for each of these analyses. To allow scalability for large datasets we have provided local install via three methods. We improve on available tools by offering a range of normalization methods and a simple to use interface that provides clear and complete session reporting and for reproducible analysis. Conclusion The development of tools using a GUI makes them practical and accessible to scientists without bioinformatics expertise, or access to a data analyst with relevant skills. While several GUI based tools are currently available for RNA-Seq analysis we improve on these existing tools. This user-friendly application provides a convenient platform for the normalization, analysis and visualization of gene expression data for scientists without bioinformatics expertise.

Published
2019
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16. Super-Enhancer-Associated LncRNA UCA1 Interacts Directly with AMOT to Activate YAP Target Genes in Epithelial Ovarian Cancer

Author

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

Subjects
Science
Abstract

Summary: 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. : Cancer Systems Biology; Omics; Proteomics; Systems Biology Subject Areas: Cancer Systems Biology, Omics, Proteomics, Systems Biology

Published
2019
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17. Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube

Author

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

Subjects
fallopian tube, scRNA-seq, SOX17, PAX8, ovarian cancer, secretory epithelial cells, Biology (General), QH301-705.5
Abstract

Summary: 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
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18. Validity and prognostic significance of sperm protein 17 as a tumor biomarker for epithelial ovarian cancer: a retrospective study

Author

Laurie L. Brunette, Paulette Y. Mhawech-Fauceglia, Lingyun Ji, Joseph G. Skeate, Heike E. Brand, Kate Lawrenson, Saloni Walia, Maurizio Chiriva-Internati, Susan Groshen, Lynda D. Roman, W. Martin Kast, and Diane M. Da Silva

Subjects
Epithelial ovarian cancer, Borderline ovarian tumor, Sperm protein 17, Ovarian biomarker, Serous, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Prior small studies have shown increased expression of sperm protein 17 (Sp17) in epithelial ovarian cancer (EOC) tissue and suggest Sp17 as a potential biomarker for EOC. However, how Sp17 expression varies with histology, grade, and stage of EOC and its expression in other ovarian neoplasms has not been defined. It is unknown whether patients with EOC have elevated serum Sp17 levels or if Sp17 expression is associated with survival outcomes. Methods The study included 982 patients with benign, borderline, and malignant ovarian neoplasms and normal ovary. There were 878 patients with tissue only, 39 with serum only, and 65 with matching serum and tissue. Immunohistochemical (IHC) staining with anti-Sp17 antibody was performed on tissue specimens and the intensity scored as weak, moderate, or strong. A sandwich enzyme-linked immunosorbent assay (ELISA) was performed to measure Sp17 sera concentrations. Results Sp17 expression was most commonly seen in serous cystadenomas (83%) and serous borderline tumors (100%). Of the 773 EOC specimens, 223 (30%) expressed Sp17. Grade and histology were significantly associated with Sp17 expression among EOC specimens (p

Published
2018
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19. A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Author

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

Subjects
Biology (General), QH301-705.5
Abstract

Summary: 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. : Lawrenson et al. profile gene expression and active chromatin in ∼200 ovarian and fallopian epithelial isolates and implement machine learning to demonstrate that most high-grade serous ovarian cancers (HGSOCs) derive from fallopian tube epithelial cells, but a subset may originate from ovarian epithelia. SOX18 induces mesenchymal features to drive early neoplasia in fallopian tube precursors. Keywords: high-grade serous ovarian cancer, ovarian surface epithelial cell, fallopian tube secretory epithelial cell, super enhancers, transcription factors, SOX18, single-cell RNA-seq, RNA-seq, machine learning, one-class logistic regression models, dual origins

Published
2019
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20. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Author

Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, GEMO Study Collaborators, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, EMBRACE, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, KConFab Investigators, Australian Ovarian Cancer Study Group, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, and Simon A. Gayther

Subjects
Science
Abstract

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Published
2016
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21. Optimizing exosomal RNA isolation for RNA-Seq analyses of archival sera specimens.

Author

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

Subjects
Medicine, Science
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
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22. Microcell-Mediated Chromosome Transfer Identifies EPB41L3 as a Functional Suppressor of Epithelial Ovarian Cancers

Author

Dimitra Dafou, Barbara Grun, John Sinclair, Kate Lawrenson, Elizabeth C. Benjamin, Estrid Hogdall, Susanne Kruger-Kjaer, Lise Christensen, Heidi M. Sowter, Ahmed Al-Attar, Richard Edmondson, Stephen Darby, Andrew Berchuck, Peter W. Laird, C. Leigh Pearce, Susan J. Ramus, Ian J. Jacobs, and Simon A. Gayther

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

We used a functional complementation approach to identify tumor-suppressor genes and putative therapeutic targets for ovarian cancer. Microcell-mediated transfer of chromosome 18 in the ovarian cancer cell line TOV21 G induced in vitro and in vivo neoplastic suppression. Gene expression microarray profiling in TOV21 +19 hybrids identified 14 candidate genes on chromosome 18 that were significantly overexpressed and therefore associated with neoplastic suppression. Further analysis of messenger RNA and protein expression for these genes in additional ovarian cancer cell lines indicated that EPB41L3 (erythrocyte membrane protein band 4.1-like 3, alternative names DAL-1 and 4.1 B) was a candidate ovarian cancer-suppressor gene. Immunoblot analysis showed that EPB41L3 was activated in TOV21 +18 hybrids, expressed in normal ovarian epithelial cell lines, but was absent in 15 (78%) of 19 ovarian cancer cell lines. Using immunohistochemistry, 66% of 794 invasive ovarian tumors showed no EPB41L3 expression compared with only 24% of benign ovarian tumors and 0% of normal ovarian epithelial tissues. EPB41L3 was extersively methylated it ovarian cancer cell Hires and primary ovarian tumors compared with normal tissues (P = 00004), suggesting this may be the mechanism of gene inactivation it ovarian cancers. Constitutive reexpressior of EPB41L3 it a three-dimensional multicellular spheroid model of ovarian cancer caused significant growth suppressior and induced apoptosis. Transmission and scanning electron microscopy demonstrated many similarities between EPB41L3-expressing cells and chromosome 18 donor-recipient hybrids, suggesting that EPB41L3 is the gene responsible for reoplastic suppression after chromosome 18 transfer. Finally, ar irducible model of EPB41L3 expression it three-dimersioral spheroids confirmed that reexpression of EPB41L3 induces extensive apoptotic cell death it ovarian cancers.

Published
2010
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23. Senescent Fibroblasts Promote Neoplastic Transformation of Partially Transformed Ovarian Epithelial Cells in a Three-dimensional Model of Early Stage Ovarian Cancer

Author

Kate Lawrenson, Barbara Grun, Elizabeth Benjamin, Ian J. Jacobs, Dimitra Dafou, and Simon A. Gayther

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Most epithelial ovarian cancers are diagnosed postmenopausally, although the well-established epidemiological risk factors (parity, oral contraceptive use) are premenopausal. We hypothesized that accumulation of senescent fibroblasts, together with concomitant loss of presenescent fibroblasts within the ovarian cortex, promotes initiation and early development of ovarian cancer from ovarian surface epithelial (OSE) cells. To test this, we established immortalized OSE (IOSE) cell lines that mimic early neoplastic transformation by overexpressing the CMYC oncogene (IOSECMYC) and normal ovarian presenescent (PSN) and senescent (SEN) fibroblast cell lines. We then evaluated the ability of PSN and SEN fibroblasts to transform IOSE and IOSECMYC after coculture. SEN fibroblasts significantly enhanced neoplastic development of IOSECMYC cells; there was an up to 15-fold increase in migration of IOSECMYC cells cocultured with SEN fibroblasts compared with PSN fibroblasts. Conditioned medium from SEN fibroblasts promoted anchorage-independent growth of IOSECMYC cells. We studied fibroblast-epithelial cell interactions in heterotypic three-dimensional spheroid models. Dual immunohistochemical staining of spheroids for a proliferation marker (MIB-1) and cytokeratin-18 indicated that SEN fibroblasts induce approximately a five-fold increase in proliferation of IOSECMYC cells relative to cocultures with PSN fibroblasts. SEN, but not PSN fibroblasts, also induced nuclear atypia in epithelial cells in three-dimensional spheroids. These data suggest for the first time that the accumulation of senescent, or loss of presenescent fibroblasts, can promote neoplastic development of partially transformed OSE cells in vitro and illustrates the power of using three-dimensional heterotypic modeling to gain better insights into the etiology underlying the development of epithelial ovarian cancer.

Published
2010
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24. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Author

Ganna Chornokur, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ernest K Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S L Jim, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Linda E Kelemen, Mellissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Robert A Vierkant, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N Hasmad, Andrew Berchuck, Georgia Chenevix-Trench, AOCS management group, Edwin S Iversen, Joellen M Schildkraut, Susan J Ramus, Ellen L Goode, Alvaro N A Monteiro, Simon A Gayther, Steven A Narod, Paul D P Pharoah, Thomas A Sellers, and Catherine M Phelan

Subjects
Medicine, Science
Abstract

BACKGROUND:Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS:In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q

Published
2015
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25. Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium.

Author

Kate Lawrenson, Elham Pakzamir, Biao Liu, Janet M Lee, Melissa K Delgado, Kara Duncan, Simon A Gayther, Song Liu, Lynda Roman, and Paulette Mhawech-Fauceglia

Subjects
Medicine, Science
Abstract

The molecular biology and cellular origins of mixed type endometrial carcinomas (MT-ECs) are poorly understood, and a Type II component of 10 percent or less may confer poorer prognoses.We studied 10 cases of MT-EC (containing endometrioid and serous differentiation), 5 pure low-grade endometrioid adenocarcinoma (EAC) and 5 pure uterine serous carcinoma (USC). Endometrioid and serous components of the MT-ECs were macrodissected and the expression of 60 candidate genes compared between MT-EC, pure USC and pure EAC. We found that four genes were differentially expressed when MT-ECs were compared to pure low-grade EAC: CDKN2A (P = 0.006), H19 (P = 0.010), HOMER2 (P = 0.009) and TNNT1 (P = 0.006). Also while we found that even though MT-ECs closely resembled the molecular profiles of pure USCs, they also exhibit lower expression of PAX8 compared to all pure cases combined (P = 0.035).Our data suggest that MT-EC exhibits the closest molecular and epidemiological similarities to pure USC and supports clinical observations that suggest patients with MT-EC should receive the same treatment as patients with pure serous carcinoma. Novel specific markers of MT-EC could be of diagnostic utility and could represent novel therapeutic targets in the future.

Published
2015
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27. Single-cell transcriptomic analysis of endometriosis

Author

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

Subjects
Genetics
Published
2023
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28. Rewiring of master transcription factor cistromes during high-grade serous ovarian cancer development

Author

Robbin A. Nameki, Heidi Chang, Pak Yu, Forough Abbasi, Xianzhi Lin, Jessica Reddy, Marcela Haro, Marcos AS Fonseca, Matthew L. Freedman, Ronny Drapkin, Rosario I. Corona, and Kate Lawrenson

Abstract

The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous ‘ovarian’ cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors incisandtrans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.

Published
2023
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29. Supplementary Grant Support from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Grant Support

Published
2023
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30. Supplementary Methods, Figures S1 - S3 from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.

Published
2023
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31. Supplementary Tables S1 - S10 from 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

Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar

Abstract

Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.

Published
2023
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32. Supplementary Tables 1 - 4 from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author

Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau

Abstract

PDF file - 157K, Supplemental Table 1. Regulatory T cell genes included in this study (N=25). Supplemental Table 2. Regulatory T cell SNPs included in this study. Supplemental Table 3. Participating invasive epithelial ovarian cancer studies. Supplemental Table 4. Association between clinical variables and overall survival.

Published
2023
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33. Data from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author

Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau

Abstract

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Published
2023
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34. Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

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

Abstract

Purpose:To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental Design:We 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.Results:We 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.Conclusions:Our 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
2023
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35. Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

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

Abstract

Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Published
2023
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36. Functional analysis of the 1p34.3 risk locus implicates GNL2 in high-grade serous ovarian cancer

Author

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

Subjects
DNA Copy Number Variations, Quantitative Trait Loci, Polymorphism, Single Nucleotide, Article, White People, Mice, GTP-Binding Proteins, Cell Line, Tumor, Odds Ratio, Genetics, Animals, Humans, Genetic Predisposition to Disease, Gene Silencing, Alleles, Genetic Association Studies, Genetics (clinical), Ovarian Neoplasms, Gene Expression Profiling, Prognosis, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplastic, Alternative Splicing, Disease Models, Animal, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Chromosomes, Human, Pair 1, Chromatin Immunoprecipitation Sequencing, Heterografts, Female, Neoplasm Grading, Transcriptome, Genome-Wide Association Study
Abstract

The high-grade serous ovarian cancer (HGSOC) risk locus at chromosome 1p34.3 resides within a frequently amplified genomic region signifying the presence of an oncogene. Here, we integrate in silico variant-to-function analysis with functional studies to characterize the oncogenic potential of candidate genes in the 1p34.3 locus. Fine mapping of genome-wide association statistics identified candidate causal SNPs local to H3K27ac-demarcated enhancer regions that exhibit allele-specific binding for CTCF in HGSOC and normal fallopian tube secretory epithelium cells (FTSECs). SNP risk associations colocalized with eQTL for six genes (DNALI1, GNL2, RSPO1, SNIP1, MEAF6, and LINC01137) that are more highly expressed in carriers of the risk allele, and three (DNALI1, GNL2, and RSPO1) were upregulated in HGSOC compared to normal ovarian surface epithelium cells and/or FTSECs. Increased expression of GNL2 and MEAF6 was associated with shorter survival in HGSOC with 1p34.3 amplifications. Despite its activation of β-catenin signaling, RSPO1 overexpression exerted no effects on proliferation or colony formation in our study of ovarian cancer and FTSECs. Instead, GNL2, MEAF6, and SNIP1 silencing impaired in vitro ovarian cancer cell growth. Additionally, GNL2 silencing diminished xenograft tumor formation, whereas overexpression stimulated proliferation and colony formation in FTSECs. GNL2 influences 60S ribosomal subunit maturation and global protein synthesis in ovarian cancer and FTSECs, providing a potential mechanism of how GNL2 upregulation might promote ovarian cancer development and mediate genetic susceptibility of HGSOC.

Published
2022
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37. Supplementary Table 5 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

eQTL Associations from GTEx (Release V7 (dbGaP Accession phs000424.v7.p2). Contains single gene eQTLs for BNC2, CNTLN, c9orf92 and SH3GL2 in all tissues and single SNP eQTL for all 40 SNPs in the credible candidate set.

Published
2023
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38. Data from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar

Abstract

Background: Genome-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.Methods: We 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).Results: Gene 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.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

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2023
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39. Supplementary Figures 1-4 and extended methods from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

This file contains: Supplementary Figure 1 (Related to Figure 2): Haplotype frequency for tiles Enhancer Scanning times with multiple SNPs. Supplementary Figure 2 (Related to Figure 3): Conservation and S/MAR predicted sequences at the locus. Supplementary Figure 3: Study overview and Overlap between the set of 134 SNPs obtained through the LD-guided analysis and the set of 40 SNPs obtained through the fine mapping-guided approach. Supplementary Figure 4 (Related to Figure 5): BNC2 binds to its own promoter. Extended data and detailed methods (including QC metrics) for BNC2 ChIP-Seq.

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2023
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40. Supplementary Table 2 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

Genes selected for NanoString analysis. Contains the following tabs: (1) Nanostring gene set: final list for NanoString analysis. Gene Symbol, genes selected for nanostring analysis; Pathway, annotation from literature or from pathways in Tab 10; Cell line, cell line (FTE, iFTSEC283; OSE, iOSE11) in which the BNC2 ChIP-Seq peak was identified in proximity to the TSS. P-value, significance of expression changes using a nominal p-value {less than or equal to} 0.05 (indicated in green highlight); (2) 995 gene list: list of 995 genes/transcripts with TSS within 30 kb of the BNC2 ChIP-Seq peak centers found in both iOSE11 and iFTSEC283 cells; (3)-(9) Coordinates and annotation of BNC2 ChIP-seq peaks and genes with TSS within 30 kb of the BNC2 ChIP-seq peak centers from two replicates each of FTE (iFTSEC283) and OSE (iOSE11) cells, their overlaps; (10) Panther GO analysis results.

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2023
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41. Data from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

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

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2023
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42. Supplementary Table 1 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

Primers used in this study.

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2023
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43. Supplementary Table 4 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

Fine mapping association results. Contains univariate and conditional (conditioning on rs3814113) analysis.

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2023
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44. Supplementary Table 3 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

Abstract

List of 134 SNPs in linkage disequilibrium (r2 {greater than or equal to} 0.3) with rs3814113 (based on 1000GP v3), selected for functional analysis.

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2023
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45. Supplemental Tables and Figures from Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

Author

Thomas A. Sellers, Simon A. Gayther, Jin Q. Cheng, Joellen M. Schildkraut, Mary Anne Rossing, Susan J. Ramus, Catherine M. Phelan, Paul D. Pharoah, Celeste L. Pearce, Kate Lawrenson, Edwin S. Iverson, Ellen L. Goode, Jennifer A. Doherty, Georgia Chenevix-Trench, Andrew Berchuck, Jonathan Tyrer, Zhihua Chen, Alvaro N.A. Monteiro, Jamie K. Teer, Y. Ann Chen, Jennifer B. Permuth, and Brett M. Reid

Abstract

Supplemental Figure S1. Flowchart for epigenomic annotation of lncRNAs. Supplemental Figure S2. Distribution of ovarian tissue histone marks in lncRNA genes. Supplemental Table S1. Study participants for GWAS meta-analysis of epithelial ovarian cancer. Supplemental Figure S3. Distribution of number of EOC risk SNPs for 10,000 permutations of lncRNA-sized regions. Supplemental Table S2. SNPs associated with risk for less common ovarian cancer subtypes are not enriched in lncRNAs. Supplemental Figure S4. Genomic coverage of GENCODE v19 lncRNA genes (n=13,442 with GWAS SNPs). Supplemental Table S3. Density of EOC-associated SNPs in lncRNA genes versus whole genome (All histologies). Supplemental Table S4. Density of EOC-associated SNPs in lncRNA genes by histologic subtype. Supplemental Table S5. Promoter and transcription factor motifs enriched in EOC-associated lncRNA regions. Supplemental Table S6. Biological processes of putative promoter and transcription factors enriched in 53 EOC-associated lncRNA. Supplemental Figure S5. Regional plots for five novel loci associated with EOC risk and expression of lncRNA genes.

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2023
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46. Supplementary Tables S1-6, Figures S1-2 from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar

Abstract

Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network

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2023
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47. Data from Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

Author

Thomas A. Sellers, Simon A. Gayther, Jin Q. Cheng, Joellen M. Schildkraut, Mary Anne Rossing, Susan J. Ramus, Catherine M. Phelan, Paul D. Pharoah, Celeste L. Pearce, Kate Lawrenson, Edwin S. Iverson, Ellen L. Goode, Jennifer A. Doherty, Georgia Chenevix-Trench, Andrew Berchuck, Jonathan Tyrer, Zhihua Chen, Alvaro N.A. Monteiro, Jamie K. Teer, Y. Ann Chen, Jennifer B. Permuth, and Brett M. Reid

Abstract

Background: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10−8). Most risk SNPs lie within non–protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets.Methods: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10−5 > P > 5 × 10−8) overlapping lncRNAs.Results: Of 5,294 EOC-associated SNPs (P < 1.0 × 10−5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10−4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression.Conclusions: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC.Impact: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116–25. ©2016 AACR.

Published
2023
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48. Supplemental Methods from Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci

Author

Thomas A. Sellers, Simon A. Gayther, Jin Q. Cheng, Joellen M. Schildkraut, Mary Anne Rossing, Susan J. Ramus, Catherine M. Phelan, Paul D. Pharoah, Celeste L. Pearce, Kate Lawrenson, Edwin S. Iverson, Ellen L. Goode, Jennifer A. Doherty, Georgia Chenevix-Trench, Andrew Berchuck, Jonathan Tyrer, Zhihua Chen, Alvaro N.A. Monteiro, Jamie K. Teer, Y. Ann Chen, Jennifer B. Permuth, and Brett M. Reid

Abstract

Density Measures of lncRNA Enrichment at Independent EOC-associated Regions

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2023
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49. <scp> KRAS </scp> mutations and endometriosis burden of disease

Author

Natasha L Orr, Arianne Albert, Yang Doris Liu, Amy Lum, JooYoon Hong, Catalina L Ionescu, Janine Senz, Tayyebeh M Nazeran, Anna F Lee, Heather Noga, Kate Lawrenson, Catherine Allaire, Christina Williams, Mohamed A Bedaiwy, Michael S Anglesio, and Paul J Yong

Subjects
Pathology and Forensic Medicine
Published
2023
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