Person:
Pomerantz, Mark

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Pomerantz

First Name

Mark

Name

Pomerantz, Mark
Author's Publications: search.filters.isAuthorOfPublication.4a8ff6b6-f2d4-46f5-95a6-27d466efc5dc

Search Results

Now showing 1 - 7 of 7
  • No Thumbnail Available
    Publication
    The 8q24 Cancer Risk Variant Rs6983267 Shows Long-Range Interaction With MYC in Colorectal Cancer
    (Springer Science and Business Media LLC, 2009-06-28) Pomerantz, Mark; Ahmadiyeh, Nasim; Jia, Li; Herman, Paula; Verzi, Michael; Doddapaneni, Harshavardhan; Beckwith, Christine A.; Chan, Jennifer A.; Hills, Adam; Davis, Matt; Yao, Keluo; Kehoe, Sarah M.; Lenz, Heinz-Josef; Haiman, Christopher A.; Yan, Chunli; Henderson, Brian E.; Frenkel, Baruch; Barretina, Jordi; Bass, Adam; Tabernero, Josep; Baselga, Jose; Regan, Meredith; Manak, J. Robert; Shivdasani, Ramesh; Coetzee, Gerhard A.; Freedman, Matthew
    An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that this region is a transcriptional enhancer, that the risk region physically interacts with the MYC proto-oncogene, and that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2). These data provide strong support for a biological mechanism underlying this non-protein coding risk variant.
  • Thumbnail Image
    Publication
    The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis
    (2015) Pomerantz, Mark; Li, Fugen; Takeda, David; Lenci, Romina; Chonkar, Apurva; Chabot, Matthew; Cejas, Paloma; Vazquez, Francisca; Cook, Jennifer; Shivdasani, Ramesh; Bowden, Michaela; Lis, Rosina; Hahn, William; Kantoff, Philip; Brown, Myles; Loda, Massimo; Long, Henry; Freedman, Matthew
    Master transcription factors interact with DNA to establish cell-type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13, co-localized with the reprogrammed AR sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium towards transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.
  • Thumbnail Image
    Publication
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
    (Nature Publishing Group, 2016) Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; 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 J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; 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; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, John; Giovannucci, Edward; Hoover, Robert; Hunter, David; Johansson, Mattias; Kraft, Phillip; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes; Freedman, Matthew; Haiman, Christopher A.; Pasaniuc, Bogdan
    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
  • Thumbnail Image
    Publication
    Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis
    (Public Library of Science, 2010) Chanock, Stephen J.; Schafer, Eric J.; Tabernero, Josep; Baselga, José; Oh, William K.; Pomerantz, Mark; Shrestha, Yashaswi; Flavin, Richard John; Regan, Meredith; Penney, Kathryn; Mucci, Lorelei; Stampfer, Meir; Hunter, David; Chan, Jennifer; Richardson, Andrea; Loda, Massimo; Kantoff, Philip; Hahn, William; Freedman, Matthew
    Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
  • Thumbnail Image
    Publication
    Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus
    (Public Library of Science, 2009) Landan, Gilad; Jaschek, Rami; Herman, Paula; Yan, Chunli; Khalid, Omar; Oh, William; Manak, J. Robert; Henderson, Brian E.; Frenkel, Baruch; Haiman, Christopher A.; Tanay, Amos; Coetzee, Gerhard A.; Jia, Li; Pomerantz, Mark; Reich, David; Kantoff, Philip; Berman, Benjamin P; Freedman, Matthew
    Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.
  • No Thumbnail Available
    Publication
    Genetic Determinants of Chromatin Reveal Prostate Cancer Risk Mediated by Context-Dependent Gene Regulation
    (Cold Spring Harbor Laboratory, 2022-09-07) Baca, Sylvan; Singler, Cassandra; Zacharia, Soumya; Seo, Ji-Heui; Morova, Tunc; Hach, Faraz; Ding, Yi; Schwarz, Tommer; Huang, Chia-Chi Flora; Anderson, Jacob; Fay, Andre; Kalita, Cynthia; Groha, Stefan; Pomerantz, Mark; Wang, Victoria; Linder, Simon; Sweeney, Christopher; Zwart, Wilbert; Lack, Nathan A.; Pasaniuc, Bogdan; Takeda, David; Gusev, Alexander; Freedman, Matthew
    AbstractMethods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.
  • No Thumbnail Available
    Publication
    Genome-wide germline correlates of the epigenetic landscape of prostate cancer
    (Springer Science and Business Media LLC, 2019-10) Houlahan, Kathleen E.; Shiah, Yu-Jia; Gusev, Alexander; Yuan, Jiapei; Ahmed, Musaddeque; 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 L. K.; Pomerantz, Mark; van der Kwast, Theodorus; Freedman, Matthew; Mani, Ram S.; He, Housheng H.; Bristow, Robert G.; Boutros, Paul C.; Shetty, Anamay
    Cancer initiation and progression are driven by germline, environmental and stochastic factors. How these interact to produce the molecular phenotypes of primary human tumours remains unknown. To better understand the role germline variation plays, we quantified the influence of germline single nucleotide polymorphisms (SNPs) on the somatic methylome of 589 primary localized prostate tumours with genome-wide DNA and methylation sequencing. We show that known risk loci influence a tumour’s epigenetic landscape, uncovering a mechanism for cancer susceptibility. We then identify and validate 1,178 loci associated with altered methylation levels in tumour tissue but not in non-malignant tissue. These tumour methylation quantitative trait loci (tumour meQTLs) influence chromatin structure, RNA abundance and protein abundance and recapitulate previously reported risk loci. One prominent tumour meQTL is associated with tumour-specific methylation and expression of TCERG1L, a transcription elongation factor predictive of rapid biochemical relapse following definitive local management. Another tumour meQTL is associated with expression of the oncogene AKT1 and is predictive of relapse in both our discovery cohort and an independent 101-patient validation cohort. Taken together, these data reveal a strong interplay between the germline mutational profile and the epigenomic features of primary tumours which can be exploited to understand the role of germline genetics in the heritability of aggressive prostate cancer.