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279 results on '"Hazelett, Dennis"'

1. MotifbreakR v2: extended capability and database integration

Author

Coetzee, Simon G. and Hazelett, Dennis J.

Subjects
Quantitative Biology - Genomics, Quantitative Biology - Quantitative Methods
Abstract

MotifbreakR is a software tool that scans genetic variants against position weight matrices of transcription factors (TF) to determine the potential for the disruption of TF binding at the site of the variant. It leverages the Bioconductor suite of software packages and annotations to operate across a diverse array of genomes and motif databases. Initially developed to interrogate the effect of single nucleotide variants (common and rare SNVs) on potential TF binding sites, in motifbreakR v2, we have updated the functionality. New features include the ability to query other types of more complex genetic variants, such as short insertions and deletions (indels). This function allows modeling a more extensive array of variants that may have more significant effects on TF binding. Additionally, while TF binding is based partly on sequence preference, predictions of TF binding based on sequence preference alone can indicate many more potential binding events than observed. Adding information from DNA-binding sequencing datasets lends confidence to motif disruption prediction by demonstrating TF binding in cell lines and tissue types. Therefore, motifbreakR implements querying the ReMap2022 database for evidence that a TF matching the disrupted motif binds over the disrupting variant. Finally, in motifbreakR, in addition to the existing interface, we have implemented an R/Shiny graphical user interface to simplify and enhance access to researchers with different skill sets., Comment: 4 pages of text, 1 figure with 2 panels, 12 total pages. Source code, documentation, and tutorials are available on Bioconductor at https://bioconductor.org/packages/release/bioc/html/motifbreakR.html and GitHub at https://github.com/Simon-Coetzee/motifBreakR

Published
2024

2. POLE-Mutant Colon Cancer Treated with PD-1 Blockade Showing Clearance of Circulating Tumor DNA and Prolonged Disease-Free Interval.

Author

Bikhchandani, Mihir, Amersi, Farin, Hendifar, Andrew, Gangi, Alexandra, Osipov, Arsen, Zaghiyan, Karen, Atkins, Katelyn, Cho, May, Aguirre, Francesca, Hazelett, Dennis, Alvarez, Rocio, Zhou, Lisa, Hitchins, Megan, and Gong, Jun

Subjects
Humans, Colonic Neoplasms, Neoplasm Recurrence, Local, Mutation, Programmed Cell Death 1 Receptor, Circulating Tumor DNA, MSS, POLE, checkpoint inhibitor, colon cancer, high tumor mutation burden, immunotherapy, Digestive Diseases, Immunization, Genetics, Vaccine Related, Colo-Rectal Cancer, Cancer, Good Health and Well Being
Abstract

Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab. Treatment with immunotherapy in this patient also led to the clearance of circulating tumor DNA (ctDNA). ctDNA is beginning to emerge as a marker for minimal residual disease in many solid malignancies, including colon cancer. Its clearance with treatment suggests that the selection of pembrolizumab on the basis of identifying a POLE mutation on next-generation sequencing may increase disease-free survival in this patient.

Published
2023

3. Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS

Author

Vogelaar, Ingrid P, Greer, Stephanie, Wang, Fan, Shin, GiWon, Lau, Billy, Hu, Yajing, Haraldsdottir, Sigurdis, Alvarez, Rocio, Hazelett, Dennis, Nguyen, Peter, Aguirre, Francesca P, Guindi, Maha, Hendifar, Andrew, Balcom, Jessica, Leininger, Anna, Fairbank, Beth, Ji, Hanlee, and Hitchins, Megan P

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Genetics, Colo-Rectal Cancer, Clinical Research, Prevention, Digestive Diseases, Cancer, Biotechnology, Genetic Testing, Aetiology, 2.1 Biological and endogenous factors, Lynch syndrome, multicancer gene panel test, splice variants, Oncology and carcinogenesis
Abstract

Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.

Published
2022

4. Circulating tumor DNA dynamics and response to immunotherapy in colorectal cancer

Author

Gong, Jun, Aguirre, Francesca, Hazelett, Dennis, Alvarez, Rocio, Zhou, Lisa, Hendifar, Andrew, Osipov, Arsen, Zaghiyan, Karen, Cho, May, Gangi, Alexandra, and Hitchins, Megan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunization, Colo-Rectal Cancer, Cancer, Digestive Diseases, Vaccine Related, Good Health and Well Being, colorectal cancer, circulating tumor DNA, immunotherapy, microsatellite stable, microsatellite instability high, Biochemistry and Cell Biology, Medical Biotechnology, Oncology and carcinogenesis
Abstract

Circulating tumor DNA (ctDNA) is increasingly being investigated as a tool to detect minimal residual disease in resected, stage I-III colorectal cancer. Recent ctDNA studies have indicated that detection of ctDNA following surgery for resectable colorectal cancer confers a significantly higher risk of recurrence than those with negative ctDNA postoperatively. In those with postoperative ctDNA positivity, clearance of minimal residual disease with adjuvant chemotherapy is a positive prognostic indicator. Lastly, ctDNA has demonstrated superior sensitivity to the conventional blood tumor marker carcinoembryonic antigen (CEA) and can offer median lead times of up to 11 months for radiographic detection of recurrence during the surveillance of resected, stage I-III colorectal cancer. In metastatic colorectal cancer (mCRC), there is growing evidence to suggest that plasma ctDNA can be used to monitor tumor response to conventional chemotherapy as well. The present case series demonstrated that plasma ctDNA is a predictor of tumor response to immunotherapy in patients with mCRC that are microsatellite stable or microsatellite instability high. Plasma ctDNA could serve as a dynamic marker of immunotherapy response even in colorectal tumors that were CEA non-producers. Overall, these findings add to ongoing efforts to establish the role of plasma ctDNA in monitoring response to immunotherapy in CRC.

Published
2022

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

Author

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

Published
2024
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6. Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer.

Author

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

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

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

Published
2020

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

Author

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

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

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

Published
2019

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

Author

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

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

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

Published
2019

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

Author

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

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

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

Published
2019

10. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Author

Rotinen, Mirja, You, Sungyong, Yang, Julie, Coetzee, Simon G, Reis-Sobreiro, Mariana, Huang, Wen-Chin, Huang, Fangjin, Pan, Xinlei, Yáñez, Alberto, Hazelett, Dennis J, Chu, Chia-Yi, Steadman, Kenneth, Morrissey, Colm M, Nelson, Peter S, Corey, Eva, Chung, Leland WK, Freedland, Stephen J, Di Vizio, Dolores, Garraway, Isla P, Murali, Ramachandran, Knudsen, Beatrice S, and Freeman, Michael R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Genetics, Biotechnology, Cancer, Urologic Diseases, Adenocarcinoma, Androgens, Animals, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Homeodomain Proteins, Humans, Male, Mice, Neuroendocrine Tumors, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Signal Transduction, Transcription Factors, Xenograft Model Antitumor Assays, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

Published
2018

12. Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry

Author

Conti, David V, Wang, Kan, Sheng, Xin, Bensen, Jeannette T, Hazelett, Dennis J, Cook, Michael B, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Stanford, Janet L, Zheng, Wei, Sanderson, Maureen, John, Esther M, Park, Jong Y, Xu, Jianfeng, Stevens, Victoria L, Berndt, Sonja I, Huff, Chad D, Wang, Zhaoming, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Sellers, Thomas A, Yamoah, Kosj, Murphy, Adam B, Crawford, Dana C, Gapstur, Susan M, Bush, William S, Aldrich, Melinda C, Cussenot, Olivier, Petrovics, Gyorgy, Cullen, Jennifer, Neslund-Dudas, Christine, Stern, Mariana C, Jarai, Zsofia-Kote, Govindasami, Koveela, Chokkalingam, Anand P, Hsing, Ann W, Goodman, Phyllis J, Hoffmann, Thomas, Drake, Bettina F, Hu, Jennifer J, Clark, Peter E, Van Den Eeden, Stephen K, Blanchet, Pascal, Fowke, Jay H, Casey, Graham, Hennis, Anselm JM, Han, Ying, Lubwama, Alexander, Thompson, Ian M, Leach, Robin, Easton, Douglas F, Schumacher, Fredrick, Van den Berg, David J, Gundell, Susan M, Stram, Alex, Wan, Peggy, Xia, Lucy, Pooler, Loreall C, Mohler, James L, Fontham, Elizabeth TH, Smith, Gary J, Taylor, Jack A, Srivastava, Shiv, Eeles, Rosalind A, Carpten, John, Kibel, Adam S, Multigner, Luc, Parent, Marie-Elise, Menegaux, Florence, Cancel-Tassin, Geraldine, Klein, Eric A, Brureau, Laurent, Stram, Daniel O, Watya, Stephen, Chanock, Stephen J, Witte, John S, Blot, William J, Henderson, Brian E, and Haiman, Christopher A

Subjects
Aging, Human Genome, Cancer, Prevention, Prostate Cancer, Biotechnology, Clinical Research, Genetics, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Blacks, Case-Control Studies, Checkpoint Kinase 2, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 22, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, PRACTICAL/ELLIPSE Consortium, Black People, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

Published
2017

13. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Author

Rand, Kristin A, Song, Chi, Dean, Eric, Serie, Daniel J, Curtin, Karen, Sheng, Xin, Hu, Donglei, Huff, Carol Ann, Bernal-Mizrachi, Leon, Tomasson, Michael H, Ailawadhi, Sikander, Singhal, Seema, Pawlish, Karen, Peters, Edward S, Bock, Cathryn H, Stram, Alex, Van Den Berg, David J, Edlund, Christopher K, Conti, David V, Zimmerman, Todd, Hwang, Amie E, Huntsman, Scott, Graff, John, Nooka, Ajay, Kong, Yinfei, Pregja, Silvana L, Berndt, Sonja I, Blot, William J, Carpten, John, Casey, Graham, Chu, Lisa, Diver, W Ryan, Stevens, Victoria L, Lieber, Michael R, Goodman, Phyllis J, Hennis, Anselm JM, Hsing, Ann W, Mehta, Jayesh, Kittles, Rick A, Kolb, Suzanne, Klein, Eric A, Leske, Cristina, Murphy, Adam B, Nemesure, Barbara, Neslund-Dudas, Christine, Strom, Sara S, Vij, Ravi, Rybicki, Benjamin A, Stanford, Janet L, Signorello, Lisa B, Witte, John S, Ambrosone, Christine B, Bhatti, Parveen, John, Esther M, Bernstein, Leslie, Zheng, Wei, Olshan, Andrew F, Hu, Jennifer J, Ziegler, Regina G, Nyante, Sarah J, Bandera, Elisa V, Birmann, Brenda M, Ingles, Sue A, Press, Michael F, Atanackovic, Djordje, Glenn, Martha J, Cannon-Albright, Lisa A, Jones, Brandt, Tricot, Guido, Martin, Thomas G, Kumar, Shaji K, Wolf, Jeffrey L, Deming Halverson, Sandra L, Rothman, Nathaniel, Brooks-Wilson, Angela R, Rajkumar, S Vincent, Kolonel, Laurence N, Chanock, Stephen J, Slager, Susan L, Severson, Richard K, Janakiraman, Nalini, Terebelo, Howard R, Brown, Elizabeth E, De Roos, Anneclaire J, Mohrbacher, Ann F, Colditz, Graham A, Giles, Graham G, Spinelli, John J, Chiu, Brian C, Munshi, Nikhil C, Anderson, Kenneth C, Levy, Joan, Zonder, Jeffrey A, Orlowski, Robert Z, Lonial, Sagar, Camp, Nicola J, Vachon, Celine M, Ziv, Elad, Stram, Daniel O, and Hazelett, Dennis J

Subjects
Biomedical and Clinical Sciences, Cancer, Clinical Research, Genetics, Rare Diseases, Hematology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Black People, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Multiple Myeloma, Polycomb Repressive Complex 1, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Repressor Proteins, Transmembrane Activator and CAML Interactor Protein, White People, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundGenome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.MethodsWe performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.ResultsWe found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.ImpactA subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

Published
2016

14. Prostate Cancer Susceptibility in Men of African Ancestry at 8q24

Author

Han, Ying, Rand, Kristin A, Hazelett, Dennis J, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Stanford, Janet L, Zheng, Wei, Schumacher, Fredrick R, Berndt, Sonja I, Wang, Zhaoming, Xu, Jianfeng, Rohland, Nadin, Reich, David, Tandon, Arti, Pasaniuc, Bogdan, Allen, Alex, Quinque, Dominique, Mallick, Swapan, Notani, Dimple, Rosenfeld, Michael G, Jayani, Ranveer Singh, Kolb, Suzanne, Gapstur, Susan M, Stevens, Victoria L, Pettaway, Curtis A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, John, Esther M, Murphy, Adam B, Signorello, Lisa B, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anslem JM, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Zheng, S Lilly, Witte, John S, Casey, Graham, Lubwama, Alex, Pooler, Loreall C, Sheng, Xin, Coetzee, Gerhard A, Cook, Michael B, Chanock, Stephen J, Stram, Daniel O, Watya, Stephen, Blot, William J, Conti, David V, Henderson, Brian E, and Haiman, Christopher A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Prostate Cancer, Aging, Urologic Diseases, Human Genome, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Black or African American, Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 8, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostatic Neoplasms, RNA, Long Noncoding, United States, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

Published
2016

15. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author

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

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

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

Published
2015

16. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Author

Han, Ying, Hazelett, Dennis J, Wiklund, Fredrik, Schumacher, Fredrick R, Stram, Daniel O, Berndt, Sonja I, Wang, Zhaoming, Rand, Kristin A, Hoover, Robert N, Machiela, Mitchell J, Yeager, Merideth, Burdette, Laurie, Chung, Charles C, Hutchinson, Amy, Yu, Kai, Xu, Jianfeng, Travis, Ruth C, Key, Timothy J, Siddiq, Afshan, Canzian, Federico, Takahashi, Atsushi, Kubo, Michiaki, Stanford, Janet L, Kolb, Suzanne, Gapstur, Susan M, Diver, W Ryan, Stevens, Victoria L, Strom, Sara S, Pettaway, Curtis A, Olama, Ali Amin Al, Kote-Jarai, Zsofia, Eeles, Rosalind A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, Isaacs, William B, Chen, Constance, Lindstrom, Sara, Le Marchand, Loic, Giovannucci, Edward L, Pomerantz, Mark, Long, Henry, Li, Fugen, Ma, Jing, Stampfer, Meir, John, Esther M, Ingles, Sue A, Kittles, Rick A, Murphy, Adam B, Blot, William J, Signorello, Lisa B, Zheng, Wei, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Nemesure, Barbara, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anselm JM, Rybicki, Benjamin A, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Zheng, S Lilly, Witte, John S, Casey, Graham, Riboli, Elio, Li, Qiyuan, Freedman, Matthew L, Hunter, David J, Gronberg, Henrik, Cook, Michael B, Nakagawa, Hidewaki, Kraft, Peter, Chanock, Stephen J, Easton, Douglas F, Henderson, Brian E, Coetzee, Gerhard A, Conti, David V, and Haiman, Christopher A

Subjects
Cancer, Human Genome, Biotechnology, Genetics, Urologic Diseases, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Asian People, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Linkage Disequilibrium, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Published
2015

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

Author

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

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

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

Published
2015

18. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Author

Kuchenbaecker, Karoline B, Ramus, Susan J, Tyrer, Jonathan, Lee, Andrew, Shen, Howard C, Beesley, Jonathan, Lawrenson, Kate, McGuffog, Lesley, Healey, Sue, Lee, Janet M, Spindler, Tassja J, Lin, Yvonne G, Pejovic, Tanja, Bean, Yukie, Li, Qiyuan, Coetzee, Simon, Hazelett, Dennis, Miron, Alexander, Southey, Melissa, Terry, Mary Beth, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Neuhausen, Susan L, Ding, Yuan Chun, Hansen, Thomas VO, Jønson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, Barrowdale, Daniel, Dennis, Joe, Benitez, Javier, Osorio, Ana, Garcia, Maria Jose, Komenaka, Ian, Weitzel, Jeffrey N, Ganschow, Pamela, Peterlongo, Paolo, Bernard, Loris, Viel, Alessandra, Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Radice, Paolo, Papi, Laura, Ottini, Laura, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Frost, Debra, Perkins, Jo, Platte, Radka, Ellis, Steve, EMBRACE, Godwin, Andrew K, Schmutzler, Rita Katharina, Meindl, Alfons, Engel, Christoph, Sutter, Christian, Sinilnikova, Olga M, GEMO Study Collaborators, Damiola, Francesca, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Claes, Kathleen, De Leeneer, Kim, Kirk, Judy, Rodriguez, Gustavo C, Piedmonte, Marion, O'Malley, David M, de la Hoya, Miguel, Caldes, Trinidad, Aittomäki, Kristiina, Nevanlinna, Heli, Collée, J Margriet, Rookus, Matti A, Oosterwijk, Jan C, Breast Cancer Family Registry, Tihomirova, Laima, Tung, Nadine, Hamann, Ute, Isaccs, Claudine, Tischkowitz, Marc, Imyanitov, Evgeny N, Caligo, Maria A, Campbell, Ian G, Hogervorst, Frans BL, HEBON, Olah, Edith, Diez, Orland, Blanco, Ignacio, Brunet, Joan, Lazaro, Conxi, Pujana, Miquel Angel, Jakubowska, Anna, Gronwald, Jacek, Lubinski, Jan, and Sukiennicki, Grzegorz

Subjects
EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, KConFab Investigators, Australian Cancer Study, Australian Ovarian Cancer Study Group, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Quantitative Trait Loci, Adolescent, Adult, Female, Genome-Wide Association Study, Young Adult, Carcinoma, Ovarian Epithelial, Human Genome, Rare Diseases, Genetics, Cancer, Prevention, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Published
2015

19. Supplementary Methods and Tables from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Amos, Christopher I., primary, Dennis, Joe, primary, Wang, Zhaoming, primary, Byun, Jinyoung, primary, Schumacher, Fredrick R., primary, Gayther, Simon A., primary, Casey, Graham, primary, Hunter, David J., primary, Sellers, Thomas A., primary, Gruber, Stephen B., primary, Dunning, Alison M., primary, Michailidou, Kyriaki, primary, Fachal, Laura, primary, Doheny, Kimberly, primary, Spurdle, Amanda B., primary, Li, Yafang, primary, Xiao, Xiangjun, primary, Romm, Jane, primary, Pugh, Elizabeth, primary, Coetzee, Gerhard A., primary, Hazelett, Dennis J., primary, Bojesen, Stig E., primary, Caga-Anan, Charlisse, primary, Haiman, Christopher A., primary, Kamal, Ahsan, primary, Luccarini, Craig, primary, Tessier, Daniel, primary, Vincent, Daniel, primary, Bacot, François, primary, Van Den Berg, David J., primary, Nelson, Stefanie, primary, Demetriades, Stephen, primary, Goldgar, David E., primary, Couch, Fergus J., primary, Forman, Judith L., primary, Giles, Graham G., primary, Conti, David V., primary, Bickeböller, Heike, primary, Risch, Angela, primary, Waldenberger, Melanie, primary, Brüske-Hohlfeld, Irene, primary, Hicks, Belynda D., primary, Ling, Hua, primary, McGuffog, Lesley, primary, Lee, Andrew, primary, Kuchenbaecker, Karoline, primary, Soucy, Penny, primary, Manz, Judith, primary, Cunningham, Julie M., primary, Butterbach, Katja, primary, Kote-Jarai, Zsofia, primary, Kraft, Peter, primary, FitzGerald, Liesel, primary, Lindström, Sara, primary, Adams, Marcia, primary, McKay, James D., primary, Phelan, Catherine M., primary, Benlloch, Sara, primary, Kelemen, Linda E., primary, Brennan, Paul, primary, Riggan, Marjorie, primary, O'Mara, Tracy A., primary, Shen, Hongbing, primary, Shi, Yongyong, primary, Thompson, Deborah J., primary, Goodman, Marc T., primary, Nielsen, Sune F., primary, Berchuck, Andrew, primary, Laboissiere, Sylvie, primary, Schmit, Stephanie L., primary, Shelford, Tameka, primary, Edlund, Christopher K., primary, Taylor, Jack A., primary, Field, John K., primary, Park, Sue K., primary, Offit, Kenneth, primary, Thomassen, Mads, primary, Schmutzler, Rita, primary, Ottini, Laura, primary, Hung, Rayjean J., primary, Marchini, Jonathan, primary, Amin Al Olama, Ali, primary, Peters, Ulrike, primary, Eeles, Rosalind A., primary, Seldin, Michael F., primary, Gillanders, Elizabeth, primary, Seminara, Daniela, primary, Antoniou, Antonis C., primary, Pharoah, Paul D.P., primary, Chenevix-Trench, Georgia, primary, Chanock, Stephen J., primary, Simard, Jacques, primary, and Easton, Douglas F., primary

Published
2023
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20. Supplementary Table 5 from Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

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

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

Author

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

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

Author

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

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

Author

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

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

Author

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

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

Author

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

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

Author

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

Published
2023
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28. Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion

Author

Biener-Ramanujan, Eva, primary, Rosier, Florian, additional, Coetzee, Simon G., additional, McGovern, Dermot D. P., additional, Hazelett, Dennis, additional, Targan, Stephan R., additional, and Gonsky, Rivkah, additional

Published
2022
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29. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Jr, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja K H, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen B M, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, Dossus, Laure, Duran, Mercedes, Dürst, Matthias, Dworniczak, Bernd, Eccles, Diana, Edwards, Todd, Eeles, Ros, Eilber, Ursula, Ejlertsen, Bent, Ekici, Arif B, Ellis, Steve, Elvira, Mingajeva, Eng, Kevin H, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Ferguson, Sarah, Ferrer, Sandra Fert, Flanagan, James M, Fogarty, Zachary C, Fortner, Renée T, Fostira, Florentia, Foulkes, William D, Fountzilas, George, Fridley, Brooke L, Friebel, Tara M, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, García, María J, Garcia-Barberan, Vanesa, Gehrig, Andrea, Gentry-Maharaj, Aleksandra, Gerdes, Anne-Marie, Giles, Graham G, Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Goranova, Teodora, Gore, Martin, Greene, Mark H, Gronwald, Jacek, Gruber, Stephen, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V O, Harrington, Patricia A, Harris, Holly R, Hauke, Jan, Hein, Alexander, Henderson, Alex, Hildebrandt, Michelle A T, Hillemanns, Peter, Hodgson, Shirley, Høgdall, Claus K, Høgdall, Estrid, Hogervorst, Frans B L, Holland, Helene, Hooning, Maartje J, Hosking, Karen, Huang, Ruea-Yea, Hulick, Peter J, Hung, Jillian, Hunter, David J, Huntsman, David G, Huzarski, Tomasz, Imyanitov, Evgeny N, Isaacs, Claudine, Iversen, Edwin S, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jernetz, Mats, Jensen, Allan, Jensen, Uffe Birk, John, Esther M, Johnatty, Sharon, Jones, Michael E, Kannisto, Päivi, Karlan, Beth Y, Karnezis, Anthony, Kast, Karin, Kennedy, Catherine J, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kiiski, Johanna I, Kim, Sung-Won, Kjaer, Susanne K, Köbel, Martin, Kopperud, Reidun K, Kruse, Torben A, Kupryjanczyk, Jolanta, Kwong, Ava, Laitman, Yael, Lambrechts, Diether, Larrañaga, Nerea, Larson, Melissa C, Lazaro, Conxi, Le, Nhu D, Le Marchand, Loic, Lee, Jong Won, Lele, Shashikant B, Leminen, Arto, Leroux, Dominique, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A, Liang, Dong, Liebrich, Clemens, Lilyquist, Jenna, Lipworth, Loren, Lissowska, Jolanta, Lu, Karen H, Lubinński, Jan, Luccarini, Craig, Lundvall, Lene, Mai, Phuong L, Mendoza-Fandiño, Gustavo, Manoukian, Siranoush, Massuger, Leon F A G, May, Taymaa, Mazoyer, Sylvie, McAlpine, Jessica N, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Meijers-Heijboer, Hanne, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R, Merritt, Melissa A, Milne, Roger L, Mitchell, Gillian, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moffitt, Melissa, Montagna, Marco, Moysich, Kirsten B, Mulligan, Anna Marie, Musinsky, Jacob, Nathanson, Katherine L, Nedergaard, Lotte, Ness, Roberta B, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Odunsi, Kunle, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Olswold, Curtis, O'Malley, David M, Ong, Kai-ren, Onland-Moret, N Charlotte, Orr, Nicholas, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Papi, Laura, Park-Simon, Tjoung-Won, Paul, James, Pearce, Celeste L, Pedersen, Inge Søkilde, Peeters, Petra H M, Peissel, Bernard, Peixoto, Ana, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jennifer B, Peterlongo, Paolo, Pezzani, Lidia, Pfeiler, Georg, Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C, Piskorz, Anna M, Poblete, Samantha R, Pocza, Timea, Poole, Elizabeth M, Poppe, Bruce, Porteous, Mary E, Prieur, Fabienne, Prokofyeva, Darya, Pugh, Elizabeth, Pujana, Miquel Angel, Pujol, Pascal, Radice, Paolo, Rantala, Johanna, Rappaport-Fuerhauser, Christine, Rennert, Gad, Rhiem, Kerstin, Rice, Patricia, Richardson, Andrea, Robson, Mark, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, Romm, Jane, Rookus, Matti A, Rossing, Mary Anne, Rothstein, Joseph H, Rudolph, Anja, Runnebaum, Ingo B, Salvesen, Helga B, Sandler, Dale P, Schoemaker, Minouk J, Senter, Leigha, Setiawan, V Wendy, Severi, Gianluca, Sharma, Priyanka, Shelford, Tameka, Siddiqui, Nadeem, Side, Lucy E, Sieh, Weiva, Singer, Christian F, Sobol, Hagay, Song, Honglin, Southey, Melissa C, Spurdle, Amanda B, Stadler, Zsofia, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Sucheston-Campbell, Lara E, Sukiennicki, Grzegorz, Sutphen, Rebecca, Sutter, Christian, Swerdlow, Anthony J, Szabo, Csilla I, Szafron, Lukasz, Tan, Yen Y, Taylor, Jack A, Tea, Muy-Kheng, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Kathryn L, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L, Tihomirova, Laima, Tinker, Anna V, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Tone, Alicia, Trabert, Britton, Travis, Ruth C, Trichopoulou, Antonia, Tung, Nadine, Tworoger, Shelley S, van Altena, Anne M, Van Den Berg, David, van der Hout, Annemarie H, van der Luijt, Rob B, Van Heetvelde, Mattias, Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J, Vanderstichele, Adriaan, Varon-Mateeva, Raymonda, Vega, Ana, Edwards, Digna Velez, Vergote, Ignace, Vierkant, Robert A, Vijai, Joseph, Vratimos, Athanassios, Walker, Lisa, Walsh, Christine, Wand, Dorothea, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Webb, Penelope M, Weinberg, Clarice R, Weitzel, Jeffrey N, Wentzensen, Nicolas, Whittemore, Alice S, Wijnen, Juul T, Wilkens, Lynne R, Wolk, Alicja, Woo, Michelle, Wu, Xifeng, Wu, Anna H, Yang, Hannah, Yannoukakos, Drakoulis, Ziogas, Argyrios, Zorn, Kristin K, Narod, Steven A, Easton, Douglas F, Amos, Christopher I, Schildkraut, Joellen M, Ramus, Susan J, Ottini, Laura, Goodman, Marc T, Park, Sue K, Kelemen, Linda E, Risch, Harvey A, Thomassen, Mads, Offit, Kenneth, Simard, Jacques, Schmutzler, Rita Katharina, Hazelett, Dennis, Monteiro, Alvaro N, Couch, Fergus J, Berchuck, Andrew, Chenevix-Trench, Georgia, Goode, Ellen L, Sellers, Thomas A, Gayther, Simon A, Antoniou, Antonis C, and Pharoah, Paul D P

Published
2017
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32. Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS.

Author

Vogelaar, Ingrid P., Greer, Stephanie, Wang, Fan, Shin, GiWon, Lau, Billy, Hu, Yajing, Haraldsdottir, Sigurdis, Alvarez, Rocio, Hazelett, Dennis, Nguyen, Peter, Aguirre, Francesca P., Guindi, Maha, Hendifar, Andrew, Balcom, Jessica, Leininger, Anna, Fairbank, Beth, Ji, Hanlee, and Hitchins, Megan P.

Subjects
DIAGNOSIS of hereditary nonpolyposis colorectal cancer, GENETIC mutation, DNA, ONCOGENES, HEREDITARY nonpolyposis colorectal cancer, RNA, GENETIC testing, EARLY detection of cancer, GENETIC variation, GENETIC carriers, RESEARCH funding, DESCRIPTIVE statistics, DISEASE susceptibility, GENETIC techniques, GENETIC counseling, GENEALOGY, DISEASE risk factors
Abstract

Simple Summary: Lynch syndrome is a hereditary cancer condition caused by a pathogenic variant (mutation) within one of the mismatch repair (MMR) genes. Risks for cancer vary by which MMR gene is mutated and sex, although colorectal and uterine cancers are most common. A major challenge in genetic testing is that this frequently reveals a variant of uncertain significance (VUS), which hinders clinical decision-making. We describe a large, four-generation, 13-branched, cancer-affected family with a mutation in MSH2 (c.2006G>T) in which one branch also carries a VUS in MSH6 (c.3936_4001+8dup). Functional studies in samples from family members show this MSH6 VUS is likely to be pathogenic. In addition, other cancer-relevant mutations were identified in branches without either MMR gene mutation so genetic counseling was highly individualized. Our study suggests multi-cancer gene panel testing should be offered to all members of cancer-effected families rather than targeted testing for specific mutations for accurate genetic diagnosis. Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives. [ABSTRACT FROM AUTHOR]

Published
2023
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35. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Author

Amin Al Olama, Ali, Dadaev, Tokhir, Hazelett, Dennis J., Li, Qiuyan, Leongamornlert, Daniel, Saunders, Edward J., Stephens, Sarah, Cieza-Borrella, Clara, Whitmore, Ian, Benlloch Garcia, Sara, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schumacher, Fredrick, Haiman, Christopher A., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L., Nordestgaard, Børge G., Key, Tim J., Travis, Ruth C., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L., Thibodeau, Stephen N., Mcdonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokołorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Park, Jong Y., Sellers, Thomas, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A., Spurdle, Amanda, Teixeira, Manuel R., Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Govindasami, Koveela, Guy, Michelle, Lophatonanon, Artitaya, Muir, Kenneth, Viñuela, Ana, Brown, Andrew A., Freedman, Mathew, Conti, David V., Easton, Douglas, Coetzee, Gerhard A., Eeles, Rosalind A., Kote-Jarai, Zsofia, Easton, Douglas F., Pharoah, Paul, Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Berchuck, Andrew, Eeles, Rosalind A., Easton, Douglas F., Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Chenevix-Trench, Georgia, Antoniou, Antonis, McGuffog, Lesley, Couch, Fergus, Offit, Ken, Dennis, Joe, Dunning, Alison M., Lee, Andrew, Dicks, Ed, Luccarini, Craig, Benitez, Javier, Gonzalez-Neira, Anna, Simard, Jacques, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Bojesen, Stig E., Nielsen, Sune F., Nordestgaard, Borge G., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., and Meyer, Jeffrey

Published
2015
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37. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

Buckley, Melissa A, Woods, Nicholas T, Tyrer, Jonathan P, Mendoza-Fandiño, Gustavo, Lawrenson, Kate, Hazelett, Dennis J, Najafabadi, Hamed S, Gjyshi, Anxhela, Carvalho, Renato S, Lyra, Paulo C, Coetzee, Simon G, Shen, Howard C, Yang, Ally W, Earp, Madalene A, Yoder, Sean J, Risch, Harvey, Chenevix-Trench, Georgia, Ramus, Susan J, Phelan, Catherine M, Coetzee, Gerhard A, Noushmehr, Houtan, Hughes, Timothy R, Sellers, Thomas A, Goode, Ellen L, Pharoah, Paul D, Gayther, Simon A, Monteiro, Alvaro NA, Ovarian Cancer Association Consortium, Lawrenson, Kate [0000-0002-6469-2515], Hazelett, Dennis J [0000-0003-0749-9935], Najafabadi, Hamed S [0000-0003-2735-4231], Coetzee, Simon G [0000-0003-4267-5930], Yoder, Sean J [0000-0003-0005-7798], Coetzee, Gerhard A [0000-0003-4267-5930], Noushmehr, Houtan [0000-0003-4051-8114], and Apollo - University of Cambridge Repository

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

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

Published
2018
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38. A mosaic genetic screen reveals distinct roles for trithorax and Polycomb group genes in Drosophila eye development

Author

Janody, Florence, Lee, Jeffrey D., Jahren, Neal, Hazelett, Dennis J., Benlali, Aude, Miura, Grant I., Draskovic, Irena, and Treisman, Jessica E.

Subjects
Biological sciences
Abstract

The wave of differentiation that traverses the Drosophila eye disc requires rapid transitions in gene expression that are controlled by a number of signaling molecules also required in other developmental processes. We have used a mosaic genetic screen to systematically identify autosomal genes required for the normal pattern of photoreceptor differentiation, independent of their requirements for viability. In addition to genes known to be important for eye development and to known and novel components of the Hedgehog, Decapentaplegic, Wingless, Epidermal growth factor receptor, and Notch signaling pathways, we identified several members of the Polycomb and trithorax classes of genes encoding general transcriptional regulators. Mutations in these genes disrupt the transitions between zones along the anterior-posterior axis of the eye disc that express different combinations of transcription factors. Different trithorax group genes have very different mutant phenotypes, indicating that target genes differ in their requirements for chromatin remodeling, histone modification, and coactivation factors.

Published
2004

39. Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites

Author

Jones, Michelle R., primary, Peng, Pei-Chen, additional, Coetzee, Simon G., additional, Tyrer, Jonathan, additional, Reyes, Alberto Luiz P., additional, Corona, Rosario I., additional, Davis, Brian, additional, Chen, Stephanie, additional, Dezem, Felipe, additional, Seo, Ji-Heui, additional, Kar, Siddartha, additional, Dareng, Eileen, additional, Berman, Benjamin P., additional, Freedman, Matthew L., additional, Plummer, Jasmine T., additional, Lawrenson, Kate, additional, Pharoah, Paul, additional, Hazelett, Dennis J., additional, and Gayther, Simon A., additional

Published
2020
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42. Abstract AP11: IDENTIFYING FUNCTIONAL NONCODING SOMATIC MUTATIONS IN OVARIAN CANCER

Author

Corona, Rosario I., primary, Seo, Ji-Heui, additional, Hazelett, Dennis J., additional, Lin, Xianzhi, additional, Mhawech-Fauceglia, Paulette Y., additional, Lester, Jenny, additional, Shah, Sohrab P., additional, Huntsman, David G., additional, Karlan, Beth Y., additional, Gusev, Alexander, additional, Berman, Benjamin P., additional, Freedman, Matthew L., additional, Gayther, Simon A., additional, and Lawrenson, Kate, additional

Published
2019
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46. Additional file 1: of CRISPR-mediated deletion of prostate cancer risk-associated CTCF loop anchors identifies repressive chromatin loops

Author

Guo, Yu, Perez, Andrew, Hazelett, Dennis, Coetzee, Gerhard, Suhn Rhie, and Farnham, Peggy

Abstract

Figure S1. High confidence ChIP-seq peaks. Figure S2. Genome-wide RNA-seq analysis of cells deleted for PCa risk-associated CTCF sites. Figure S3. Deletion of PCa risk-associated CTCF site 1 in different cell lines. Figure S4. Deletion of PCa risk-associated CTCF site 4 in different cell lines. (PDF 2538 kb)

Published
2018
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48. Non-coding Somatic Mutations Converge on the PAX8 Pathway in Epithelial Ovarian Cancer

Author

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

Published
2019
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49. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Author

Amin Al Olama, Ali, Dadaev, Tokhir, Hazelett, Dennis J., Li, Qiuyan, Leongamornlert, Daniel, Saunders, Edward J., Stephens, Sarah, Cieza-Borrella, Clara, Whitmore, Ian, Benlloch Garcia, Sara, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schumacher, Fredrick, Haiman, Christopher A., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L., Nordestgaard, Børge G., Key, Tim J., Travis, Ruth C., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L., Thibodeau, Stephen N., Mcdonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokołorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Park, Jong Y., Sellers, Thomas, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A., Spurdle, Amanda, Teixeira, Manuel R., Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Govindasami, Koveela, Guy, Michelle, Lophatonanon, Artitaya, Muir, Kenneth, Viñuela, Ana, Brown, Andrew A., Freedman, Mathew, Conti, David V., Easton, Douglas, Coetzee, Gerhard A., Eeles, Rosalind A., Kote-Jarai, Zsofia, Easton, Douglas F., Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Berchuck, Andrew, Al Olama, Ali Amin, Benlloch, Sara, Chenevix-Trench, Georgia, Antoniou, Antonis, McGuffog, Lesley, Couch, Fergus, Offit, Ken, Dennis, Joe, Dunning, Alison M., Lee, Andrew, Dicks, Ed, Luccarini, Craig, Benitez, Javier, Gonzalez-Neira, Anna, Simard, Jacques, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Bojesen, Stig E., Nielsen, Sune F., Nordestgaard, Borge G., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., and Meyer, Jeffrey

Abstract

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region

Published
2017

50. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, Catherine M. Kuchenbaecker, Karoline B. Tyrer, Jonathan P. Kar, Siddhartha P. Lawrenson, Kate Winham, Stacey J. and Dennis, Joe Pirie, Ailith Riggan, Marjorie J. Chornokur, Ganna Earp, Madalene A. Lyra, Jr., Paulo C. Lee, Janet M. and Coetzee, Simon Beesley, Jonathan McGuffog, Lesley Soucy, Penny Dicks, Ed Lee, Andrew Barrowdale, Daniel and Lecarpentier, Julie Leslie, Goska Aalfs, Cora M. Aben, Katja K. H. Adams, Marcia Adlard, Julian Andrulis, Irene L. and Anton-Culver, Hoda Antonenkova, Natalia Aravantinos, Gerasimos and Arnold, Norbert Arun, Banu K. Arver, Brita Azzollini, Jacopo Balmana, Judith Banerjee, Susana N. Barjhoux, Laure and Barkardottir, Rosa B. Bean, Yukie Beckmann, Matthias W. and Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina and Bernardini, Marcus Q. Birrer, Michael J. Bjorge, Line Black, Amanda Blankstein, Kenneth Blok, Marinus J. Bodelon, Clara and Bogdanova, Natalia Bojesen, Anders Bonanni, Bernardo and Borg, Ake Bradbury, Angela R. Brenton, James D. Brewer, Carole Brinton, Louise Broberg, Per Brooks-Wilson, Angela and Bruinsma, Fiona Brunet, Joan Buecher, Bruno Butzow, Ralf and Buys, Saundra S. Caldes, Trinidad Caligo, Maria A. and Campbell, Ian Cannioto, Rikki Carney, Michael E. Cescon, Terence Chan, Salina B. Chang-Claude, Jenny Chanock, Stephen and Chen, Xiao Qing Chiew, Yoke-Eng Chiquette, Jocelyne and Chung, Wendy K. Claes, Kathleen B. M. Conner, Thomas Cook, Linda S. Cook, Jackie Cramer, Daniel W. Cunningham, Julie M. and D'Aloisio, Aimee A. Daly, Mary B. Damiola, Francesca and Damirovna, Sakaeva Dina Dansonka-Mieszkowska, Agnieszka Dao, Fanny Davidson, Rosemarie DeFazio, Anna Delnatte, Capucine and Doheny, Kimberly F. Diez, Orland Ding, Yuan Chun and Doherty, Jennifer Anne Domchek, Susan M. Dorfling, Cecilia M. and Dork, Thilo Dossus, Laure Duran, Mercedes Durst, Matthias Dworniczak, Bernd Eccles, Diana Edwards, Todd and Eeles, Ros Eilber, Ursula Ejlertsen, Bent Ekici, Arif B. and Ellis, Steve Elvira, Mingajeva Eng, Kevin H. Engel, Christoph Evans, D. Gareth Fasching, Peter A. Ferguson, Sarah Ferrer, Sandra Fert Flanagan, James M. Fogarty, Zachary C. Fortner, Renee T. Fostira, Florentia Foulkes, William D. Fountzilas, George Fridley, Brooke L. Friebel, Tara M. Friedman, Eitan Frost, Debra Ganz, Patricia A. and Garber, Judy Garcia, Maria J. Garcia-Barberan, Vanesa and Gehrig, Andrea Gentry-Maharaj, Aleksandra Gerdes, Anne-Marie and Giles, Graham G. Glasspool, Rosalind Glendon, Gord Godwin, Andrew K. Goldgar, David E. Goranova, Teodora Gore, Martin and Greene, Mark H. Gronwald, Jacek Gruber, Stephen Hahnen, Eric Haiman, Christopher A. Hakansson, Niclas Hamann, Ute and Hansen, Thomas V. O. Harrington, Patricia A. Harris, Holly R. Hauke, Jan Hein, Alexander Henderson, Alex and Hildebrandt, Michelle A. T. Hillemanns, Peter Hodgson, Shirley and Hogdall, Claus K. Hogdall, Estrid Hogervorst, Frans B. L. and Holland, Helene Hooning, Maartje J. Hosking, Karen and Huang, Ruea-Yea Hulick, Peter J. Hung, Jillian Hunter, David J. Huntsman, David G. Huzarski, Tomasz Imyanitov, Evgeny N. and Isaacs, Claudine Iversen, Edwin S. Izatt, Louise and Izquierdo, Angel Jakubowska, Anna James, Paul Janavicius, Ramunas Jernetz, Mats Jensen, Allan Jensen, Uffe Birk and John, Esther M. Johnatty, Sharon Jones, Michael E. Kannisto, Paivi Karlan, Beth Y. Karnezis, Anthony Kast, Karin and Kennedy, Catherine J. Khusnutdinova, Elza Kiemeney, Lambertus A. and Kiiski, Johanna I. Kim, Sung-Won Kjaer, Susanne K. and Kobel, Martin Kopperud, Reidun K. Kruse, Torben A. and Kupryjanczyk, Jolanta Kwong, Ava Laitman, Yael Lambrechts, Diether Larranaga, Nerea Larson, Melissa C. Lazaro, Conxi and Le, Nhu D. Le Marchand, Loic Lee, Jong Won Lele, Shashikant B. Leminen, Arto Leroux, Dominique Lester, Jenny and Lesueur, Fabienne Levine, Douglas A. Liang, Dong and Liebrich, Clemens Lilyquist, Jenna Lipworth, Loren and Lissowska, Jolanta Lu, Karen H. Lubinski, Jan Luccarini, Craig Lundvall, Lene Mai, Phuong L. Mendoza-Fandino, Gustavo and Manoukian, Siranoush Massuger, Leon F. A. G. May, Taymaa and Mazoyer, Sylvie McAlpine, Jessica N. McGuire, Valerie and McLaughlin, John R. McNeish, Iain Meijers-Heijboer, Hanne and Meindl, Alfons Menon, Usha Mensenkamp, Arjen R. Merritt, Melissa A. Milne, Roger L. Mitchell, Gillian Modugno, Francesmary Moes-Sosnowska, Joanna Moffitt, Melissa and Montagna, Marco Moysich, Kirsten B. Mulligan, Anna Marie and Musinsky, Jacob Nathanson, Katherine L. Nedergaard, Lotte and Ness, Roberta B. Neuhausen, Susan L. Nevanlinna, Heli and Niederacher, Dieter Nussbaum, Robert L. Odunsi, Kunle Olah, Edith Olopade, Olufunmilayo I. Olsson, Hakan Olswold, Curtis and O'Malley, David M. Ong, Kai-ren Onland-Moret, N. Charlotte and Orr, Nicholas Orsulic, Sandra Osorio, Ana Palli, Domenico Papi, Laura Park-Simon, Tjoung-Won Paul, James and Pearce, Celeste L. Pedersen, Inge Sokilde Peeters, Petra H. M. and Peissel, Bernard Peixoto, Ana Pejovic, Tanja Pelttari, Liisa M. Permuth, Jennifer B. Peterlongo, Paolo Pezzani, Lidia Pfeiler, Georg Phillips, Kelly-Anne Piedmonte, Marion and Pike, Malcolm C. Piskorz, Anna M. Poblete, Samantha R. and Pocza, Timea Poole, Elizabeth M. Poppe, Bruce Porteous, Mary E. Prieur, Fabienne Prokofyeva, Darya Pugh, Elizabeth and Pujana, Miquel Angel Pujol, Pascal Radice, Paolo Rantala, Johanna Rappaport-Fuerhauser, Christine Rennert, Gad Rhiem, Kerstin Rice, Patricia Richardson, Andrea Robson, Mark and Rodriguez, Gustavo C. Rodriguez-Antona, Cristina Romm, Jane and Rookus, Matti A. Rossing, Mary Anne Rothstein, Joseph H. and Rudolph, Anja Runnebaum, Ingo B. Salvesen, Helga B. Sandler, Dale P. Schoemaker, Minouk J. Senter, Leigha Setiawan, V. Wendy Severi, Gianluca Sharma, Priyanka Shelford, Tameka and Siddiqui, Nadeem Side, Lucy E. Sieh, Weiva Singer, Christian F. Sobol, Hagay Song, Honglin Southey, Melissa C. and Spurdle, Amanda B. Stadler, Zsofia Steinemann, Doris and Stoppa-Lyonnet, Dominique Sucheston-Campbell, Lara E. and Sukiennicki, Grzegorz Sutphen, Rebecca Sutter, Christian and Swerdlow, Anthony J. Szabo, Csilla I. Szafron, Lukasz Tan, Yen Y. Taylor, Jack A. Tea, Muy-Kheng Teixeira, Manuel R. and Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. and Thomsen, Liv Cecilie Vestrheim Thull, Darcy L. Tihomirova, Laima and Tinker, Anna V. Tischkowitz, Marc Tognazzo, Silvia and Toland, Amanda Ewart Tone, Alicia Trabert, Britton Travis, Ruth C. Trichopoulou, Antonia Tung, Nadine Tworoger, Shelley S. Van Altena, Anne M. Van den Berg, David van der Hout, Annemarie H. van der Luijt, Rob B. Van Heetvelde, Mattias and Van Nieuwenhuysen, Els Van Rensburg, Elizabeth J. and Vanderstichele, Adriaan Varon-Mateeva, Raymonda Vega, Ana and Edwards, Digna Velez Vergote, Ignace Vierkant, Robert A. and Vijai, Joseph Vratimos, Athanassios Walker, Lisa Walsh, Christine Wand, Dorothea Wang-Gohrke, Shan Wappenschmidt, Barbara Webb, Penelope M. Weinberg, Clarice R. Weitzel, Jeffrey N. Wentzensen, Nicolas Whittemore, Alice S. Wijnen, Juul T. Wilkens, Lynne R. Wolk, Alicja Woo, Michelle Wu, Xifeng Wu, Anna H. Yang, Hannah Yannoukakos, Drakoulis and Ziogas, Argyrios Zorn, Kristin K. Narod, Steven A. Easton, Douglas F. Amos, Christopher I. Schildkraut, Joellen M. and Ramus, Susan J. Ottini, Laura Goodman, Marc T. Park-, Sue K. and Kelemen, Linda E. Risch, Harvey A. Thomassen, Mads and Offit, Kenneth Simard, Jacques Schmutzler, Rita Katharina and Hazelett, Dennis Monteiro, Alvaro N. Couch, Fergus J. and Berchuck, Andrew Chenevix-Trench, Georgia Goode, Ellen L. and Sellers, Thomas A. Gayther, Simon A. Antoniou, Antonis C. and Pharoah, Paul D. P. AOCS Study Grp EMEMBRACE Study GEMO Study Collaborators HEBON Study KConFab Investigators OPAL Study Grp

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

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

Published
2017

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