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2. Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression

Author

Diossy, Miklos, Tisza, Viktoria, Li, Hua, Sahgal, Pranshu, Zhou, Jia, Sztupinszki, Zsofia, Young, Denise, Nousome, Darryl, Kuo, Claire, Jiang, Jiji, Chen, Yongmei, Ebner, Reinhard, Sesterhenn, Isabell A., Moncur, Joel T., Chesnut, Gregory T., Petrovics, Gyorgy, Klus, Gregory T., Valcz, Gabor, Nuzzo, Pier Vitale, Ribli, Dezso, Börcsök, Judit, Prosz, Aurel, Krzystanek, Marcin, Ried, Thomas, Szuts, David, Rizwan, Kinza, Kaochar, Salma, Pathania, Shailja, D’Andrea, Alan D., Csabai, Istvan, Srivastava, Shiv, Freedman, Matthew L., Dobi, Albert, Spisak, Sandor, and Szallasi, Zoltan

Published
2024
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4. Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions

Author

Purdue, Mark P., Dutta, Diptavo, Machiela, Mitchell J., Gorman, Bryan R., Winter, Timothy, Okuhara, Dayne, Cleland, Sara, Ferreiro-Iglesias, Aida, Scheet, Paul, Liu, Aoxing, Wu, Chao, Antwi, Samuel O., Larkin, James, Zequi, Stênio C., Sun, Maxine, Hikino, Keiko, Hajiran, Ali, Lawson, Keith A., Cárcano, Flavio, Blanchet, Odile, Shuch, Brian, Nepple, Kenneth G., Margue, Gaëlle, Sundi, Debasish, Diver, W. Ryan, Folgueira, Maria A. A. K., van Bokhoven, Adrie, Neffa, Florencia, Brown, Kevin M., Hofmann, Jonathan N., Rhee, Jongeun, Yeager, Meredith, Cole, Nathan R., Hicks, Belynda D., Manning, Michelle R., Hutchinson, Amy A., Rothman, Nathaniel, Huang, Wen-Yi, Linehan, W. Marston, Lori, Adriana, Ferragu, Matthieu, Zidane-Marinnes, Merzouka, Serrano, Sérgio V., Magnabosco, Wesley J., Vilas, Ana, Decia, Ricardo, Carusso, Florencia, Graham, Laura S., Anderson, Kyra, Bilen, Mehmet A., Arciero, Cletus, Pellegrin, Isabelle, Ricard, Solène, Scelo, Ghislaine, Banks, Rosamonde E., Vasudev, Naveen S., Soomro, Naeem, Stewart, Grant D., Adeyoju, Adebanji, Bromage, Stephen, Hrouda, David, Gibbons, Norma, Patel, Poulam, Sullivan, Mark, Protheroe, Andrew, Nugent, Francesca I., Fournier, Michelle J., Zhang, Xiaoyu, Martin, Lisa J., Komisarenko, Maria, Eisen, Timothy, Cunningham, Sonia A., Connolly, Denise C., Uzzo, Robert G., Zaridze, David, Mukeria, Anush, Holcatova, Ivana, Hornakova, Anna, Foretova, Lenka, Janout, Vladimir, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Gaborieau, Valérie, Abedi-Ardekani, Behnoush, McKay, James, Johansson, Mattias, Phouthavongsy, Larry, Hayman, Lindsay, Li, Jason, Lungu, Ilinca, Bezerra, Stephania M., Souza, Aline G., Sares, Claudia T. G., Reis, Rodolfo B., Gallucci, Fabio P., Cordeiro, Mauricio D., Pomerantz, Mark, Lee, Gwo-Shu M., Freedman, Matthew L., Jeong, Anhyo, Greenberg, Samantha E., Sanchez, Alejandro, Thompson, R. Houston, Sharma, Vidit, Thiel, David D., Ball, Colleen T., Abreu, Diego, Lam, Elaine T., Nahas, William C., Master, Viraj A., Patel, Alpa V., Bernhard, Jean-Christophe, Freedman, Neal D., Bigot, Pierre, Reis, Rui M., Colli, Leandro M., Finelli, Antonio, Manley, Brandon J., Terao, Chikashi, Choueiri, Toni K., Carraro, Dirce M., Houlston, Richard, Eckel-Passow, Jeanette E., Abbosh, Philip H., Ganna, Andrea, Brennan, Paul, Gu, Jian, and Chanock, Stephen J.

Published
2024
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5. Optimized high-throughput screening of non-coding variants identified from genome-wide association studies

Author

Morova, Tunc, Ding, Yi, Huang, Chia-Chi F, Sar, Funda, Schwarz, Tommer, Giambartolomei, Claudia, Baca, Sylvan C, Grishin, Dennis, Hach, Faraz, Gusev, Alexander, Freedman, Matthew L, Pasaniuc, Bogdan, and Lack, Nathan A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Urologic Diseases, Cancer, Prevention, Human Genome, Prostate Cancer, Aging, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Humans, Male, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Transcription Factors, Environmental Sciences, Information and Computing Sciences, Developmental Biology, Biological sciences, Chemical sciences, Environmental sciences
Abstract

The vast majority of disease-associated single nucleotide polymorphisms (SNP) identified from genome-wide association studies (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and the number of variants tested per loci. Using this strategy, we interrogated known prostate cancer (PCa) risk-associated loci and demonstrated that 35% of them harbor SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.

Published
2023

6. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Author

Kneppers, Jeroen, Severson, Tesa, Siefert, Joseph, Schol, Pieter, Joosten, Stacey, Yu, Ivan, Huang, Chia-Chi, Morova, Tunç, Altıntaş, Umut, Giambartolomei, Claudia, Seo, Ji-Heui, Baca, Sylvan, Carneiro, Isa, Emberly, Eldon, Pasaniuc, Bogdan, Jerónimo, Carmen, Henrique, Rui, Freedman, Matthew, Wessels, Lodewyk, Lack, Nathan, Bergman, Andries, and Zwart, Wilbert

Subjects
Male, Humans, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Prostatic Neoplasms, Prostate, Chromatin
Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Published
2022

7. Liquid biopsy epigenomic profiling for cancer subtyping

Author

Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.

Published
2023
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8. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Author

Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M, Severson, Tesa M, Sanders, Joyce, Huang, Chia-Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C, Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C, de Jong, Jeroen, Kluin, Roelof JC, de Rink, Iris, Giambartolomei, Claudia, Seo, Ji-Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H, Feng, Felix Y, Zoubeidi, Amina, Freedman, Matthew L, Wessels, Lodewyk FA, Butler, Lisa M, Lack, Nathan A, van der Poel, Henk, Bergman, Andries M, and Zwart, Wilbert

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Aging, Urologic Diseases, Biotechnology, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Aetiology, ARNTL Transcription Factors, Androgens, Cell Line, Tumor, Circadian Rhythm, Drug Resistance, Neoplasm, Epigenomics, Humans, Male, Nitriles, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

Published
2022

9. Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Author

Baca, Sylvan C, Singler, Cassandra, Zacharia, Soumya, Seo, Ji-Heui, Morova, Tunc, Hach, Faraz, Ding, Yi, Schwarz, Tommer, Huang, Chia-Chi Flora, Anderson, Jacob, Fay, André P, Kalita, Cynthia, Groha, Stefan, Pomerantz, Mark M, Wang, Victoria, Linder, Simon, Sweeney, Christopher J, Zwart, Wilbert, Lack, Nathan A, Pasaniuc, Bogdan, Takeda, David Y, Gusev, Alexander, and Freedman, Matthew L

Subjects
Biological Sciences, Genetics, Urologic Diseases, Cancer, Human Genome, Prevention, Aging, Cancer Genomics, Biotechnology, Prostate Cancer, 2.1 Biological and endogenous factors, Chromatin, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

Published
2022

10. The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

Author

Berchuck, Jacob, Adib, Elio, Abou Alaiwi, Sarah, Dash, Amit, Shin, Jin, Lowder, Dallin, McColl, Collin, Castro, Patricia, Carelli, Ryan, Benedetti, Elisa, Deng, Jenny, Robertson, Matthew, Baca, Sylvan, Bell, Connor, McClure, Heather, El Zarif, Talal, Davidsohn, Matthew, Lakshminarayanan, Gitanjali, Rizwan, Kinza, Skapura, Darlene, Grimm, Sandra, Davis, Christel, Ehli, Erik, Kelleher, Kaitlin, Seo, Ji-Heui, Mitsiades, Nicholas, Coarfa, Cristian, Pomerantz, Mark, Loda, Massimo, Ittmann, Michael, Freedman, Matthew, and Kaochar, Salma

Subjects
Black or African American, Humans, Immunity, Lipid Metabolism, Male, Prostatic Neoplasms, Receptors, Androgen, Up-Regulation
Abstract

UNLABELLED: African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men. SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

Published
2022

11. Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma

Author

Purdue, Mark P., Dutta, Diptavo, Machiela, Mitchell J., Gorman, Bryan R., Winter, Timothy, Okuhara, Dayne, Cleland, Sara, Ferreiro-Iglesias, Aida, Scheet, Paul, Liu, Aoxing, Wu, Chao, Antwi, Samuel O., Larkin, James, Zequi, Stênio C., Sun, Maxine, Hikino, Keiko, Hajiran, Ali, Lawson, Keith A., Cárcano, Flavio, Blanchet, Odile, Shuch, Brian, Nepple, Kenneth G., Margue, Gaëlle, Sundi, Debasish, Diver, W. Ryan, Folgueira, Maria A.A.K., van Bokhoven, Adrie, Neffa, Florencia, Brown, Kevin M., Hofmann, Jonathan N., Rhee, Jongeun, Yeager, Meredith, Cole, Nathan R., Hicks, Belynda D., Manning, Michelle R., Hutchinson, Amy A., Rothman, Nathaniel, Huang, Wen-Yi, Linehan, W. Marston, Lori, Adriana, Ferragu, Matthieu, Zidane-Marinnes, Merzouka, Serrano, Sérgio, Magnabosco, Wesley J., BioBank Japan Project Consortium, Vilas, Ana, Decia, Ricardo, Carusso, Florencia, Graham, Laura S., Anderson, Kyra, Bilen, Mehmet A., Arciero, Cletus, Pellegrin, Isabelle, Ricard, Solène, FinnGen, Scelo, Ghislaine, Banks, Rosamonde E., Vasudev, Naveen S., Soomro, Naeem, Stewart, Grant D., Adeyoju, Adebanji, Bromage, Stephen, Hrouda, David, Gibbons, Norma, Patel, Poulam, Sullivan, Mark, Protheroe, Andrew, Nugent, Francesca I., Fournier, Michelle J., Zhang, Xiaoyu, Martin, Lisa J., Komisarenko, Maria, Eisen, Timothy, Cunningham, Sonia A., Connolly, Denise C., Uzzo, Robert G., Zaridze, David, Mukeria, Anush, Holcatova, Ivana, Hornakova, Anna, Foretova, Lenka, Janout, Vladimir, Mates, Dana, Jinga, Viorel, Rascu, Stefan, Mijuskovic, Mirjana, Savic, Slavisa, Milosavljevic, Sasa, Gaborieau, Valérie, Abedi-Ardekani, Behnoush, McKay, James, Johansson, Mattias, Phouthavongsy, Larry, Hayman, Lindsay, Li, Jason, Lungu, Ilinca, Bezerra, Stephania M., de Souza, Aline G., Sares, Claudia T.G., Reis, Rodolfo B., Gallucci, Fabio P., Cordeiro, Mauricio D., Pomerantz, Mark, Lee, Gwo-Shu M., Freedman, Matthew L., Jeong, Anhyo, Greenberg, Samantha E., Sanchez, Alejandro, Thompson, R. Houston, Sharma, Vidit, Thiel, David D., Ball, Colleen T., Abreu, Diego, Lam, Elaine T., Nahas, William C., Master, Viraj A., Patel, Alpa V., Bernhard, Jean-Christophe, Freedman, Neal D., Bigot, Pierre, Reis, Rui M., Colli, Leandro M., Finelli, Antonio, Manley, Brandon J., Terao, Chikashi, Choueiri, Toni K., Carraro, Dirce M., Houlston, Richard, Eckel-Passow, Jeanette E., Abbosh, Philip H., Ganna, Andrea, Brennan, Paul, Gu, Jian, Chanock, Stephen J., Guo, Xinyu, Winter, Timothy D., Jahagirdar, Om, Ha, Eunji, and Susztak, Katalin

Published
2024
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12. Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Author

El Zarif, Talal, Semaan, Karl, Eid, Marc, Seo, Ji-Heui, Garinet, Simon, Davidsohn, Matthew P., Sahgal, Pranshu, Fortunato, Brad, Canniff, John, Nassar, Amin H., Abou Alaiwi, Sarah, Bakouny, Ziad, Lakshminarayanan, Gitanjali, Savignano, Hunter, Lyons, Kevin, Matar, Sayed, Ali, Atef, Saad, Eddy, Saliby, Renee Maria, Cordeiro, Paulo, Zhang, Ziwei, El Ahmar, Nourhan, Laimon, Yasmin Nabil, Labaki, Chris, Shah, Valisha, Freeman, Dory, O’Toole, Jillian, Lee, Gwo-Shu Mary, Hwang, Justin, Pomerantz, Mark, Signoretti, Sabina, Van Allen, Eliezer M., Xie, Wanling, Berchuck, Jacob E., Viswanathan, Srinivas R., Braun, David A., Choueiri, Toni K., Freedman, Matthew L., and Baca, Sylvan C.

Published
2024
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13. 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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14. A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Author

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

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

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

Published
2022

15. H3K27ac HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility

Author

Giambartolomei, Claudia, Seo, Ji-Heui, Schwarz, Tommer, Freund, Malika Kumar, Johnson, Ruth Dolly, Spisak, Sandor, Baca, Sylvan C, Gusev, Alexander, Mancuso, Nicholas, Pasaniuc, Bogdan, and Freedman, Matthew L

Subjects
Genetics, Prostate Cancer, Human Genome, Prevention, Urologic Diseases, Aging, Cancer, Aetiology, 2.1 Biological and endogenous factors, Cell Line, Tumor, Chromatin Immunoprecipitation Sequencing, Chromosomes, Human, Clustered Regularly Interspaced Short Palindromic Repeats, Genetic Predisposition to Disease, Genetic Techniques, Genome-Wide Association Study, Histone Code, Humans, Male, Prostatic Neoplasms, Quantitative Trait Loci, CRISPRi, GWAS, HiChIP, PrCa risk loci, eQTL, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies (GWASs) have identified more than 200 prostate cancer (PrCa) risk regions, which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues, thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirm previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g., MLPH). Interestingly, HiChIP identifies links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g., AR) that are not detected by eQTL-based methods. HiChIP predicted enhancer elements at the AR and NKX3-1 prostate cancer risk loci, and both were experimentally confirmed to regulate expression of the corresponding genes through CRISPR interference (CRISPRi) perturbation in LNCaP cells. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.

Published
2021

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

Author

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

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Orphan Drug, Women's Health, Rare Diseases, Genetics, Cancer Genomics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors
Abstract

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

Published
2021

17. Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer

Author

Bakht, Martin K., Yamada, Yasutaka, Ku, Sheng-Yu, Venkadakrishnan, Varadha Balaji, Korsen, Joshua A., Kalidindi, Teja M., Mizuno, Kei, Ahn, Shin Hye, Seo, Ji-Heui, Garcia, Maria Mica, Khani, Francesca, Elemento, Olivier, Long, Henry W., Chaglassian, Alain, Pillarsetty, Nagavarakishore, Lewis, Jason S., Freedman, Matthew, Belanger, Anthony P., Nguyen, Quang-De, and Beltran, Himisha

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

Author

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

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

Author

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

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

Author

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

Published
2023
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22. Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer.

Author

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

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

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

Published
2021

23. Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping

Author

Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.

Published
2024
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24. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

Author

Watt, April C, Cejas, Paloma, DeCristo, Molly J, Metzger-Filho, Otto, Lam, Enid YN, Qiu, Xintao, BrinJones, Haley, Kesten, Nikolas, Coulson, Rhiannon, Font-Tello, Alba, Lim, Klothilda, Vadhi, Raga, Daniels, Veerle W, Montero, Joan, Taing, Len, Meyer, Clifford A, Gilan, Omer, Bell, Charles C, Korthauer, Keegan D, Giambartolomei, Claudia, Pasaniuc, Bogdan, Seo, Ji-Heui, Freedman, Matthew L, Ma, Cynthia, Ellis, Matthew J, Krop, Ian, Winer, Eric, Letai, Anthony, Brown, Myles, Dawson, Mark A, Long, Henry W, Zhao, Jean J, and Goel, Shom

Subjects
Genetics, Breast Cancer, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Breast Neoplasms, Cell Cycle Checkpoints, Cyclin-Dependent Kinase 4, Female, Genes, cdc, Humans, Mice, Transcription Factor AP-1
Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

Published
2021

26. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

Author

Giri, Veda N, Knudsen, Karen E, Kelly, William K, Cheng, Heather H, Cooney, Kathleen A, Cookson, Michael S, Dahut, William, Weissman, Scott, Soule, Howard R, Petrylak, Daniel P, Dicker, Adam P, AlDubayan, Saud H, Toland, Amanda E, Pritchard, Colin C, Pettaway, Curtis A, Daly, Mary B, Mohler, James L, Parsons, J Kellogg, Carroll, Peter R, Pilarski, Robert, Blanco, Amie, Woodson, Ashley, Rahm, Alanna, Taplin, Mary-Ellen, Polascik, Thomas J, Helfand, Brian T, Hyatt, Colette, Morgans, Alicia K, Feng, Felix, Mullane, Michael, Powers, Jacqueline, Concepcion, Raoul, Lin, Daniel W, Wender, Richard, Mark, James Ryan, Costello, Anthony, Burnett, Arthur L, Sartor, Oliver, Isaacs, William B, Xu, Jianfeng, Weitzel, Jeffrey, Andriole, Gerald L, Beltran, Himisha, Briganti, Alberto, Byrne, Lindsey, Calvaresi, Anne, Chandrasekar, Thenappan, Chen, David YT, Den, Robert B, Dobi, Albert, Crawford, E David, Eastham, James, Eggener, Scott, Freedman, Matthew L, Garnick, Marc, Gomella, Patrick T, Handley, Nathan, Hurwitz, Mark D, Izes, Joseph, Karnes, R Jeffrey, Lallas, Costas, Languino, Lucia, Loeb, Stacy, Lopez, Ana Maria, Loughlin, Kevin R, Lu-Yao, Grace, Malkowicz, S Bruce, Mann, Mark, Mille, Patrick, Miner, Martin M, Morgan, Todd, Moreno, Jose, Mucci, Lorelei, Myers, Ronald E, Nielsen, Sarah M, O'Neil, Brock, Pinover, Wayne, Pinto, Peter, Poage, Wendy, Raj, Ganesh V, Rebbeck, Timothy R, Ryan, Charles, Sandler, Howard, Schiewer, Matthew, Scott, E Michael D, Szymaniak, Brittany, Tester, William, Trabulsi, Edouard J, Vapiwala, Neha, Yu, Evan Y, Zeigler-Johnson, Charnita, and Gomella, Leonard G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Genetic Testing, Cancer, Health Services, Urologic Diseases, Prostate Cancer, Aging, Genetics, Good Health and Well Being, Germ-Line Mutation, History, 20th Century, Humans, Male, Prostatic Neoplasms, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Published
2020

27. Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Author

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

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

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

Published
2020

28. 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

29. IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma

Author

Taylor, Chelsea A., Watson, Robert A., Tong, Orion, Ye, Weiyu, Nassiri, Isar, Gilchrist, James J., de los Aires, Alba Verge, Sharma, Piyush Kumar, Koturan, Surya, Cooper, Rosalin A., Woodcock, Victoria K., Jungkurth, Elsita, Shine, Brian, Coupe, Nicholas, Payne, Miranda J., Church, David N., Naranbhai, Vivek, Groha, Stefan, Emery, Paul, Mankia, Kulveer, Freedman, Matthew L., Choueiri, Toni K., Middleton, Mark R., Gusev, Alexander, and Fairfax, Benjamin P.

Published
2022
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30. Germline variants associated with toxicity to immune checkpoint blockade

Author

Groha, Stefan, Alaiwi, Sarah Abou, Xu, Wenxin, Naranbhai, Vivek, Nassar, Amin H., Bakouny, Ziad, El Zarif, Talal, Saliby, Renee Maria, Wan, Guihong, Rajeh, Ahmad, Adib, Elio, Nuzzo, Pier V., Schmidt, Andrew L., Labaki, Chris, Ricciuti, Biagio, Alessi, Joao Victor, Braun, David A., Shukla, Sachet A., Keenan, Tanya E., Van Allen, Eliezer, Awad, Mark M., Manos, Michael, Rahma, Osama, Zubiri, Leyre, Villani, Alexandra-Chloe, Fairfax, Benjamin, Hammer, Christian, Khan, Zia, Reynolds, Kerry, Semenov, Yevgeniy, Schrag, Deborah, Kehl, Kenneth L., Freedman, Matthew L., Choueiri, Toni K., and Gusev, Alexander

Published
2022
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34. Geared Rotationally Identical and Invariant Convolutional Neural Network Systems

Author

Lo, ShihChung B., D., Ph., Freedman, Matthew T., D., M., Mun, Seong K., Chan, Heang-Ping, and D, Ph.

Subjects
Computer Science - Neural and Evolutionary Computing, Computer Science - Machine Learning, Computer Science - Social and Information Networks, Statistics - Machine Learning
Abstract

Theorems and techniques to form different types of transformationally invariant processing and to produce the same output quantitatively based on either transformationally invariant operators or symmetric operations have recently been introduced by the authors. In this study, we further propose to compose a geared rotationally identical CNN system (GRI-CNN) with a small step angle by connecting networks of participated processes at the first flatten layer. Using an ordinary CNN structure as a base, requirements for constructing a GRI-CNN include the use of either symmetric input vector or kernels with an angle increment that can form a complete cycle as a "gearwheel". Four basic GRI-CNN structures were studied. Each of them can produce quantitatively identical output results when a rotation angle of the input vector is evenly divisible by the step angle of the gear. Our study showed when an input vector rotated with an angle does not match to a step angle, the GRI-CNN can also produce a highly consistent result. With a design of using an ultra-fine gear-tooth step angle (e.g., 1 degree or 0.1 degree), all four GRI-CNN systems can be constructed virtually isotropically., Comment: 14 pages, 6 figures, 8 tables

Published
2018

35. Transformationally Identical and Invariant Convolutional Neural Networks by Combining Symmetric Operations or Input Vectors

Author

Lo, ShihChung B., Freedman, Matthew T., and Mun, Seong K.

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Transformationally invariant processors constructed by transformed input vectors or operators have been suggested and applied to many applications. In this study, transformationally identical processing based on combining results of all sub-processes with corresponding transformations at one of the processing steps or at the beginning step were found to be equivalent for a given condition. This property can be applied to most convolutional neural network (CNN) systems. Specifically, a transformationally identical CNN can be constructed by arranging internally symmetric operations in parallel with the same transformation family that includes a flatten layer with weights sharing among their corresponding transformation elements. Other transformationally identical CNNs can be constructed by averaging transformed input vectors of the family at the input layer followed by an ordinary CNN process or by a set of symmetric operations. Interestingly, we found that both types of transformationally identical CNN systems are mathematically equivalent by either applying an averaging operation to corresponding elements of all sub-channels before the activation function or without using a non-linear activation function., Comment: 9 pages, 3 figures

Published
2018

36. Transformationally Identical and Invariant Convolutional Neural Networks through Symmetric Element Operators

Author

Lo, Shih Chung B., Freedman, Matthew T., Mun, Seong K., and Gu, Shuo

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Mathematically speaking, a transformationally invariant operator, such as a transformationally identical (TI) matrix kernel (i.e., K= T{K}), commutes with the transformation (T{.}) itself when they operate on the first operand matrix. We found that by consistently applying the same type of TI kernels in a convolutional neural networks (CNN) system, the commutative property holds throughout all layers of convolution processes with and without involving an activation function and/or a 1D convolution across channels within a layer. We further found that any CNN possessing the same TI kernel property for all convolution layers followed by a flatten layer with weight sharing among their transformation corresponding elements would output the same result for all transformation versions of the original input vector. In short, CNN[ Vi ] = CNN[ T{Vi} ] providing every K = T{K} in CNN, where Vi denotes input vector and CNN[.] represents the whole CNN process as a function of input vector that produces an output vector. With such a transformationally identical CNN (TI-CNN) system, each transformation, that is not associated with a predefined TI used in data augmentation, would inherently include all of its corresponding transformation versions of the input vector for the training. Hence the use of same TI property for every kernel in the CNN would serve as an orientation or a translation independent training guide in conjunction with the error-backpropagation during the training. This TI kernel property is desirable for applications requiring a highly consistent output result from corresponding transformation versions of an input. Several C programming routines are provided to facilitate interested parties of using the TI-CNN technique which is expected to produce a better generalization performance than its ordinary CNN counterpart., Comment: 20 pages, 2 figures

Published
2018

37. 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, Cancer, Ovarian Cancer, Women's Health, Rare Diseases, Genetics, 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

38. Genome-wide germline correlates of the epigenetic landscape of prostate cancer

Author

Houlahan, Kathleen E, Shiah, Yu-Jia, Gusev, Alexander, Yuan, Jiapei, Ahmed, Musaddeque, Shetty, Anamay, Ramanand, Susmita G, Yao, Cindy Q, Bell, Connor, O’Connor, Edward, Huang, Vincent, Fraser, Michael, Heisler, Lawrence E, Livingstone, Julie, Yamaguchi, Takafumi N, Rouette, Alexandre, Foucal, Adrien, Espiritu, Shadrielle Melijah G, Sinha, Ankit, Sam, Michelle, Timms, Lee, Johns, Jeremy, Wong, Ada, Murison, Alex, Orain, Michèle, Picard, Valérie, Hovington, Hélène, Bergeron, Alain, Lacombe, Louis, Lupien, Mathieu, Fradet, Yves, Têtu, Bernard, McPherson, John D, Pasaniuc, Bogdan, Kislinger, Thomas, Chua, Melvin LK, Pomerantz, Mark M, van der Kwast, Theodorus, Freedman, Matthew L, Mani, Ram S, He, Housheng H, Bristow, Robert G, and Boutros, Paul C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Cancer Genomics, Prostate Cancer, Human Genome, Urologic Diseases, Genetics, 2.1 Biological and endogenous factors, DNA Methylation, Epigenome, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Humans, Male, Neoplasm Recurrence, Local, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Quantitative Trait Loci, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

Published
2019

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

Author

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

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

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

Published
2019

40. Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants

Author

Wu, Lang, Wang, Jifeng, Cai, Qiuyin, Cavazos, Taylor B, Emami, Nima C, Long, Jirong, Shu, Xiao-Ou, Lu, Yingchang, Guo, Xingyi, Bauer, Joshua A, Pasaniuc, Bogdan, Penney, Kathryn L, Freedman, Matthew L, Kote-Jarai, Zsofia, Witte, John S, Haiman, Christopher A, Eeles, Rosalind A, and Zheng, Wei

Subjects
Cancer, Urologic Diseases, Human Genome, Genetics, Prevention, Aging, Biotechnology, Prostate Cancer, Aetiology, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Risk, Transcriptome, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS Consortia, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.

Published
2019

41. 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, Prevention, Human Genome, Genetics, Rare Diseases, Ovarian Cancer, Cancer, Cancer Genomics, Women's Health, Clinical Research, 2.1 Biological and endogenous factors, 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

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

Author

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

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

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

Published
2019

45. A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

Author

Tang, Stephen, Sethunath, Vidyalakshmi, Metaferia, Nebiyou Y., Nogueira, Marina F., Gallant, Daniel S., Garner, Emma R., Lairson, Lauren A., Penney, Christopher M., Li, Jiao, Gelbard, Maya K., Alaiwi, Sarah Abou, Seo, Ji-Heui, Hwang, Justin H., Strathdee, Craig A., Baca, Sylvan C., AbuHammad, Shatha, Zhang, Xiaoyang, Doench, John G., Hahn, William C., Takeda, David Y., Freedman, Matthew L., Choi, Peter S., and Viswanathan, Srinivas R.

Published
2022
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46. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Author

Giri, Veda N, Knudsen, Karen E, Kelly, William K, Abida, Wassim, Andriole, Gerald L, Bangma, Chris H, Bekelman, Justin E, Benson, Mitchell C, Blanco, Amie, Burnett, Arthur, Catalona, William J, Cooney, Kathleen A, Cooperberg, Matthew, Crawford, David E, Den, Robert B, Dicker, Adam P, Eggener, Scott, Fleshner, Neil, Freedman, Matthew L, Hamdy, Freddie C, Hoffman-Censits, Jean, Hurwitz, Mark D, Hyatt, Colette, Isaacs, William B, Kane, Christopher J, Kantoff, Philip, Karnes, R Jeffrey, Karsh, Lawrence I, Klein, Eric A, Lin, Daniel W, Loughlin, Kevin R, Lu-Yao, Grace, Malkowicz, S Bruce, Mann, Mark J, Mark, James R, McCue, Peter A, Miner, Martin M, Morgan, Todd, Moul, Judd W, Myers, Ronald E, Nielsen, Sarah M, Obeid, Elias, Pavlovich, Christian P, Peiper, Stephen C, Penson, David F, Petrylak, Daniel, Pettaway, Curtis A, Pilarski, Robert, Pinto, Peter A, Poage, Wendy, Raj, Ganesh V, Rebbeck, Timothy R, Robson, Mark E, Rosenberg, Matt T, Sandler, Howard, Sartor, Oliver, Schaeffer, Edward, Schwartz, Gordon F, Shahin, Mark S, Shore, Neal D, Shuch, Brian, Soule, Howard R, Tomlins, Scott A, Trabulsi, Edouard J, Uzzo, Robert, Vander Griend, Donald J, Walsh, Patrick C, Weil, Carol J, Wender, Richard, and Gomella, Leonard G

Subjects
Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Prognosis, Risk Factors, Predictive Value of Tests, Pedigree, Age Factors, Heredity, Phenotype, Adult, Aged, Middle Aged, Male, Genetic Testing, Biomarkers, Tumor, Clinical Decision-Making, Genetics, Aging, Cancer, Prevention, Prostate Cancer, Urologic Diseases, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Published
2018

47. MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Author

Qiu, Xintao, Boufaied, Nadia, Hallal, Tarek, Feit, Avery, de Polo, Anna, Luoma, Adrienne M., Alahmadi, Walaa, Larocque, Janie, Zadra, Giorgia, Xie, Yingtian, Gu, Shengqing, Tang, Qin, Zhang, Yi, Syamala, Sudeepa, Seo, Ji-Heui, Bell, Connor, O’Connor, Edward, Liu, Yang, Schaeffer, Edward M., Jeffrey Karnes, R., Weinmann, Sheila, Davicioni, Elai, Morrissey, Colm, Cejas, Paloma, Ellis, Leigh, Loda, Massimo, Wucherpfennig, Kai W., Pomerantz, Mark M., Spratt, Daniel E., Corey, Eva, Freedman, Matthew L., Shirley Liu, X., Brown, Myles, Long, Henry W., and Labbé, David P.

Published
2022
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50. Novel epigenomic liquid biopsy assay to predict estrogen receptor (ER) status and to infer ER pathway activation in breast cancer.

Author

Morganti, Stefania, primary, Beagan, Jonathan, additional, D'Ippolito, Anthony, additional, Smith, Kalie, additional, Hughes, Melissa E., additional, Chmielecki, Juliann, additional, Gorthi, Aparna, additional, Painter, Corrie, additional, Barrett, J. Carl, additional, Eaton, Matthew L, additional, Freedman, Matthew, additional, Tolaney, Sara M., additional, Lin, Nancy U., additional, and Parsons, Heather Anne, additional

Published
2024
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