Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

van Nieuwpoort, Frans A.; van der Stoep, Nienke; ter Huurne, Jeanet; van der Rhee, Han; van Praag, Marinus; Fang, Jun; Jia, Jinping; Makowski, Matthew; O’Neill, Maura; Xu, Mai; Hoskins, Jason W.; Wang, Zhaoming; Zhang, Tongwu; O'Neill, Maura; Das, Sudipto; Choi, Jiyeon; Lan, Qi; Han, Younghun; Koster, Roelof; Timothy Bishop, D.; Zhang, Mingfeng; Canzian, Federico; Thomas, Janelle; Kooperberg, Charles; Arslan, Alan A.; Bracci, Paige M.; Kovacs, Michael; Buring, Julie; Duell, Eric J.; Gallinger, Steven; Collins, Irene; Stolzenberg-Solomon, Rachael S.; Jacobs, Eric J.; Bueno-De-Mesquita, H. Bas; Kamineni, Aruna; Gaziano, J. Michael; Kraft, Peter; Van Den Eeden, Stephen; Klein, Alison P.; Wolpin, Brian M.; Zheng, Wei; Kolonel, Laurence N.; Jansen, Pascal W. T. C.; Dzyadyk, Marta; Li, Donghui; Olson, Sara H.; Risch, Harvey A.; Sesso, Howard D.; McGlynn, Katherine A.; Visvanathan, Kala; Thompson, Abbey; Kanetsky, Peter A.; Austin, Melissa A.; Boutron-Ruault, Marie-Christine; Chatterjee, Nilanjan; Cotterchio, Michelle; Barrett, Jennifer H.; Giovannucci, Edward L.; Goggins, Michael; Dunning, Alison M.; Gross, Myron; Hassan, Manal; Taylor, John C.; Helzlsouer, Kathy J.; Holly, Elizabeth A.; Newton-Bishop, Julia A.; Le Marchand, Loic; Hunter, David J.; Jenab, Mazda; Kaaks, Rudolf; Andresson, Thorkell; Key, Timothy J.; Landi, Maria Teresa; Bas Bueno De Mesquita, H.; Khaw, Kay-Tee; Petersen, Gloria M.; Krogh, Vittorio; Michael Gaziano, J.; Kurtz, Robert C.; Albanes, Demetrius; Amos, Christopher I.; LaCroix, Andrea; Iles, Mark M.; Mannisto, Satu; Nathanson, Katherine L.; Patel, Alpa V.; Peeters, Petra H. M.; Albanes, Demetrios; Riboli, Elio; Shu, Xiao-Ou; Vermeulen, Michiel; Sund, Malin; Thornquist, Mark; Brown, Kevin M.; Tjønneland, Anne; Marchand, Loic Le; Amundadottir, Laufey T.; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Wactawski-Wende, Jean; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Hartge, Patricia; Fuchs, Charles; Chanock, Stephen J.; Stevens, Victoria; Caporaso, Neil E.; Brennan, Paul; Jw, Hoskins; McKay, James; Wu, Xifeng; Hung, Rayjean J.; McLaughlin, John R.; Bickeboller, Heike; Risch, Angela; Batille, Joan-Antonpuig; Wichmann, Erich; Houlston, Richard S.; Mann, Graham; Hopper, John; Marti, Gemma Tell; Aitken, Joanne; Armstrong, Bruce; Giles, Graham; Holland, Elizabeth; Kefford, Richard; Cust, Anne; Jenkins, Mark; Schmid, Helen; Puig, Susana; Aguilera, Paula; Consortium, PanScan; Gregor, Stuart Mac; Badenas, Celia; Barreiro, Alicia; Tricl, Consortium; Carrera, Cristina; Gabriel, Daniel; Xavier, Pol Gimenez; Consortium, GenoMEL; Iglesias-Garcia, Pablo; Malvehy, Josep; Scarra, Giovanna Bianchi; Mila, Montse; Pigem, Ramon; Hayward, Nick K.; Potrony, Miriam; Butille, Joan Anton Puig; Martin, Nicholas G.; Puig Butille, J.-A.; Montgomery, Grant; Tell-Marti, Gemma; Duffy, David L.; Whiteman, David C.; Landi, Giorgi; Calista, Donato; MacGregor, Stuart; Minghetti, Paola; Arcangeli, Fabio; Bertazzi, Pier Alberto; Ghiorzo, Paola; Pastorino, Lorenze; Bruno, William; Bianchi-Scarra, Giovanna; Andreotti, Virginia; Queirolo, Paola; Spagnolo, Francesco; Mackie, Rona; Lang, Julie; Gruis, Nelleke; Out, Coby; Bergman, Wilma; Kukutsch, Nicole; Bavinck, Jan Nico Bouwes; Molvern, Anders; Bakker, Bert; Bekkenk, Marcel; Snels, Dyon; Brochez, Lieve; Borg, Ake; Bressac-De Paillerets, Brigitte; Gerritsen, Rianne; Crijns, Marianne; Vasen, Hans; Janssen, Bart; Ingvar, Christian; Olsson, Hakan; Jonsson, Goran; Harbst, Katja; Borg, Å.; Nielsen, Kari; Zander, Anita Schmidt; Helsing, Per; Andresen, Per Arne; Molven, Anders; Rootwelt, Helge; Akslen, Lars A.; Demenais, Florence; Avril, Marie-Francoise; De Paillerets, Brigitte Bressac; Chaudru, Valerie; Jeannin, Patricia; Paillerets, B. B.-D.; Lesueur, Fabienne; Maubec, Eve; Mohamdi, Hamida; Bossard, Myriam; Vaysse, Amaury; Caron, Oliver; Boitier, Francoise; Dereure, Oliviier; Caux, Frederic; Dalle, Stephane; Bishop, D. Timothy; Leroux, Dominique; Martin, Ludovic; Mateus, Christine; Robert, Caroline; Hoiom, Veronica; Stoppa-Lyonnet, Dominique; Freidman, Eitan; Thomas, Luc; Wierzbicka, Eva; Elder, David E.; Ming, Michael; Mitra, Nandita; Debniak, Tadeusz; Lubinski, Jan; Hocevar, Marko; Novakovic, Srdjan; Peric, Barbara; Skerl, Petra; Hansson, Johan; Azizi, Esther; Baron-Epel, Orna; Höiom, Veronica; Scope, Alon; Friedman, Eitan; Pavlotsky, Felix; Cohen-Manheim, Irit; Laitman, Yael; Harland, Mark; Randerson-Moor, Juliette; Laye, Jon; Davies, John; Nsengimana, Jeremie; O'Shea, Sally; Chan, May; Gascoyne, Jo; Tucker, Margaret A.; Goldstein, Alisa M.; Yang, Xiaohong R.; Lt, Amundadottir

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Roelof Koster
van Nieuwpoort et al., 2017

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Nature Research, Nature Communications, 1(8), 2017

DOI: 10.1038/ncomms15034

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@article{van Nieuwpoort2017,
  abstract = {AbstractGenome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.},
  author = {van Nieuwpoort, Frans A. and van der Stoep, Nienke and ter Huurne, Jeanet and van der Rhee, Han and van Praag, Marinus and Fang, Jun and Jia, Jinping and Makowski, Matthew and O’Neill, Maura and Xu, Mai and Hoskins, Jason W. and Wang, Zhaoming and Zhang, Tongwu and O'Neill, Maura and Das, Sudipto and Choi, Jiyeon and Lan, Qi and Han, Younghun and Koster, Roelof and Timothy Bishop, D. and Zhang, Mingfeng and Canzian, Federico and Thomas, Janelle and Kooperberg, Charles and Arslan, Alan A. and Bracci, Paige M. and Kovacs, Michael and Buring, Julie and Duell, Eric J. and Gallinger, Steven and Collins, Irene and Stolzenberg-Solomon, Rachael S. and Jacobs, Eric J. and Bueno-De-Mesquita, H. Bas and Kamineni, Aruna and Gaziano, J. Michael and Kraft, Peter and Van Den Eeden, Stephen and Klein, Alison P. and Wolpin, Brian M. and Zheng, Wei and Kolonel, Laurence N. and Jansen, Pascal W. T. C. and Dzyadyk, Marta and Li, Donghui and Olson, Sara H. and Risch, Harvey A. and Sesso, Howard D. and McGlynn, Katherine A. and Visvanathan, Kala and Thompson, Abbey and Kanetsky, Peter A. and Austin, Melissa A. and Boutron-Ruault, Marie-Christine and Chatterjee, Nilanjan and Cotterchio, Michelle and Barrett, Jennifer H. and Giovannucci, Edward L. and Goggins, Michael and Dunning, Alison M. and Gross, Myron and Hassan, Manal and Taylor, John C. and Helzlsouer, Kathy J. and Holly, Elizabeth A. and Newton-Bishop, Julia A. and Le Marchand, Loic and Hunter, David J. and Jenab, Mazda and Kaaks, Rudolf and Andresson, Thorkell and Key, Timothy J. and Landi, Maria Teresa and Bas Bueno De Mesquita, H. and Khaw, Kay-Tee and Petersen, Gloria M. and Krogh, Vittorio and Michael Gaziano, J. and Kurtz, Robert C. and Albanes, Demetrius and Amos, Christopher I. and LaCroix, Andrea and Iles, Mark M. and Mannisto, Satu and Nathanson, Katherine L. and Patel, Alpa V. and Peeters, Petra H. M. and Albanes, Demetrios and Riboli, Elio and Shu, Xiao-Ou and Vermeulen, Michiel and Sund, Malin and Thornquist, Mark and Brown, Kevin M. and Tjønneland, Anne and Marchand, Loic Le and Amundadottir, Laufey T. and Tobias, Geoffrey S. and Trichopoulos, Dimitrios and Wactawski-Wende, Jean and Yu, Herbert and Yu, Kai and Zeleniuch-Jacquotte, Anne and Hoover, Robert and Hartge, Patricia and Fuchs, Charles and Chanock, Stephen J. and Stevens, Victoria and Caporaso, Neil E. and Brennan, Paul and Jw, Hoskins and McKay, James and Wu, Xifeng and Hung, Rayjean J. and McLaughlin, John R. and Bickeboller, Heike and Risch, Angela and Batille, Joan-Antonpuig and Wichmann, Erich and Houlston, Richard S. and Mann, Graham and Hopper, John and Marti, Gemma Tell and Aitken, Joanne and Armstrong, Bruce and Giles, Graham and Holland, Elizabeth and Kefford, Richard and Cust, Anne and Jenkins, Mark and Schmid, Helen and Puig, Susana and Aguilera, Paula and Consortium, PanScan and Gregor, Stuart Mac and Badenas, Celia and Barreiro, Alicia and Tricl, Consortium and Carrera, Cristina and Gabriel, Daniel and Xavier, Pol Gimenez and Consortium, GenoMEL and Iglesias-Garcia, Pablo and Malvehy, Josep and Scarra, Giovanna Bianchi and Mila, Montse and Pigem, Ramon and Hayward, Nick K. and Potrony, Miriam and Butille, Joan Anton Puig and Martin, Nicholas G. and Puig Butille, J.-A. and Montgomery, Grant and Tell-Marti, Gemma and Duffy, David L. and Whiteman, David C. and Landi, Giorgi and Calista, Donato and MacGregor, Stuart and Minghetti, Paola and Arcangeli, Fabio and Bertazzi, Pier Alberto and Ghiorzo, Paola and Pastorino, Lorenze and Bruno, William and Bianchi-Scarra, Giovanna and Andreotti, Virginia and Queirolo, Paola and Spagnolo, Francesco and Mackie, Rona and Lang, Julie and Gruis, Nelleke and Out, Coby and Bergman, Wilma and Kukutsch, Nicole and Bavinck, Jan Nico Bouwes and Molvern, Anders and Bakker, Bert and Bekkenk, Marcel and Snels, Dyon and Brochez, Lieve and Borg, Ake and Bressac-De Paillerets, Brigitte and Gerritsen, Rianne and Crijns, Marianne and Vasen, Hans and Janssen, Bart and Ingvar, Christian and Olsson, Hakan and Jonsson, Goran and Harbst, Katja and Borg, Å. and Nielsen, Kari and Zander, Anita Schmidt and Helsing, Per and Andresen, Per Arne and Molven, Anders and Rootwelt, Helge and Akslen, Lars A. and Demenais, Florence and Avril, Marie-Francoise and De Paillerets, Brigitte Bressac and Chaudru, Valerie and Jeannin, Patricia and Paillerets, B. B.-D. and Lesueur, Fabienne and Maubec, Eve and Mohamdi, Hamida and Bossard, Myriam and Vaysse, Amaury and Caron, Oliver and Boitier, Francoise and Dereure, Oliviier and Caux, Frederic and Dalle, Stephane and Bishop, D. Timothy and Leroux, Dominique and Martin, Ludovic and Mateus, Christine and Robert, Caroline and Hoiom, Veronica and Stoppa-Lyonnet, Dominique and Freidman, Eitan and Thomas, Luc and Wierzbicka, Eva and Elder, David E. and Ming, Michael and Mitra, Nandita and Debniak, Tadeusz and Lubinski, Jan and Hocevar, Marko and Novakovic, Srdjan and Peric, Barbara and Skerl, Petra and Hansson, Johan and Azizi, Esther and Baron-Epel, Orna and Höiom, Veronica and Scope, Alon and Friedman, Eitan and Pavlotsky, Felix and Cohen-Manheim, Irit and Laitman, Yael and Harland, Mark and Randerson-Moor, Juliette and Laye, Jon and Davies, John and Nsengimana, Jeremie and O'Shea, Sally and Chan, May and Gascoyne, Jo and Tucker, Margaret A. and Goldstein, Alisa M. and Yang, Xiaohong R. and Lt, Amundadottir},
  doi = {10.1038/ncomms15034},
  journal = {Nature Communications},
  month = {may},
  title = {Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148},
  url = {https://www.nature.com/articles/ncomms15034.pdf},
  volume = {8},
  year = {2017}
}

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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Journal article published in 2017 by Frans A. van Nieuwpoort, Nienke van der Stoep, Jeanet ter Huurne, Han van der Rhee, Marinus van Praag, Jun Fang, Jinping Jia, Matthew Makowski, Maura O’Neill, Mai Xu, Jason W. Hoskins, Zhaoming Wang, Tongwu Zhang, Maura O'Neill, Sudipto Das and other authors. Frans A. van Nieuwpoort, Nienke van der Stoep, Jeanet ter Huurne, Han van der Rhee, Marinus van Praag, Jun Fang, Jinping Jia, Matthew Makowski, Maura O’Neill, Mai Xu, Jason W. Hoskins, Zhaoming Wang, Tongwu Zhang, Maura O'Neill, Sudipto Das, Jiyeon Choi, Qi Lan, Younghun Han, Roelof Koster

, D. Timothy Bishop, Mingfeng Zhang, Federico Canzian, Janelle Thomas, Charles Kooperberg, Alan A. Arslan, Paige M. Bracci, Michael Kovacs, Julie Buring, Eric J. Duell, Steven Gallinger, Irene Collins, Rachael S. Stolzenberg-Solomon, Eric J. Jacobs, H. Bas Bueno-De-Mesquita, Aruna Kamineni, J. Michael Gaziano, Peter Kraft, Stephen Van Den Eeden, Alison P. Klein, Brian M. Wolpin, Wei Zheng, Laurence N. Kolonel, Pascal W. T. C. Jansen, Marta Dzyadyk, Donghui Li, Sara H. Olson, Harvey A. Risch, Howard D. Sesso, Katherine A. McGlynn, Kala Visvanathan, Abbey Thompson, Peter A. Kanetsky, Melissa A. Austin, Marie-Christine Boutron-Ruault, Nilanjan Chatterjee, Michelle Cotterchio, Jennifer H. Barrett, Edward L. Giovannucci, Michael Goggins, Alison M. Dunning, Myron Gross, Manal Hassan, John C. Taylor, Kathy J. Helzlsouer, Elizabeth A. Holly, Julia A. Newton-Bishop, Loic Le Marchand, David J. Hunter, Mazda Jenab, Rudolf Kaaks, Thorkell Andresson, Timothy J. Key, Maria Teresa Landi, H. Bas Bueno De Mesquita, Kay-Tee Khaw, Gloria M. Petersen, Vittorio Krogh, J. Michael Gaziano, Robert C. Kurtz, Demetrius Albanes, Christopher I. Amos, Andrea LaCroix, Mark M. Iles, Satu Mannisto, Katherine L. Nathanson

, Alpa V. Patel, Petra H. M. Peeters, Demetrios Albanes, Elio Riboli, Xiao-Ou Shu, Michiel Vermeulen, Malin Sund, Mark Thornquist, Kevin M. Brown, Anne Tjønneland, Loic Le Marchand, Laufey T. Amundadottir, Geoffrey S. Tobias, Dimitrios Trichopoulos, Jean Wactawski-Wende, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Robert Hoover, Patricia Hartge, Charles Fuchs, Stephen J. Chanock, Victoria Stevens, Neil E. Caporaso, Paul Brennan, Hoskins Jw, James McKay, Xifeng Wu, Rayjean J. Hung, John R. McLaughlin, Heike Bickeboller, Angela Risch

, Joan-Antonpuig Batille, Erich Wichmann, Richard S. Houlston, Graham Mann, John Hopper, Gemma Tell Marti, Joanne Aitken, Bruce Armstrong, Graham Giles, Elizabeth Holland, Richard Kefford

, Anne Cust, Mark Jenkins, Helen Schmid, Susana Puig, Paula Aguilera

, PanScan Consortium, Stuart Mac Gregor, Celia Badenas, Alicia Barreiro, Consortium Tricl, Cristina Carrera

, Daniel Gabriel, Pol Gimenez Xavier, GenoMEL Consortium, Pablo Iglesias-Garcia, Josep Malvehy, Giovanna Bianchi Scarra, Montse Mila, Ramon Pigem, Nick K. Hayward, Miriam Potrony, Joan Anton Puig Butille, Nicholas G. Martin, J.-A. Puig Butille, Grant Montgomery, Gemma Tell-Marti, David L. Duffy, David C. Whiteman, Giorgi Landi, Donato Calista, Stuart MacGregor, Paola Minghetti, Fabio Arcangeli, Pier Alberto Bertazzi, Paola Ghiorzo, Lorenze Pastorino, William Bruno

, Giovanna Bianchi-Scarra, Virginia Andreotti, Paola Queirolo, Francesco Spagnolo, Rona Mackie, Julie Lang, Nelleke Gruis, Coby Out, Wilma Bergman, Nicole Kukutsch, Jan Nico Bouwes Bavinck, Anders Molvern, Bert Bakker, Marcel Bekkenk, Dyon Snels, Lieve Brochez, Ake Borg, Brigitte Bressac-De Paillerets, Rianne Gerritsen, Marianne Crijns, Hans Vasen, Bart Janssen, Christian Ingvar, Hakan Olsson, Goran Jonsson, Katja Harbst, Å. Borg, Kari Nielsen, Anita Schmidt Zander, Per Helsing, Per Arne Andresen, Anders Molven, Helge Rootwelt, Lars A. Akslen, Florence Demenais, Marie-Francoise Avril, Brigitte Bressac De Paillerets, Valerie Chaudru, Patricia Jeannin, B. B.-D. Paillerets, Fabienne Lesueur, Eve Maubec, Hamida Mohamdi, Myriam Bossard, Amaury Vaysse, Oliver Caron, Francoise Boitier, Oliviier Dereure, Frederic Caux, Stephane Dalle, D. Timothy Bishop

, Dominique Leroux, Ludovic Martin, Christine Mateus, Caroline Robert, Veronica Hoiom, Dominique Stoppa-Lyonnet, Eitan Freidman, Luc Thomas, Eva Wierzbicka, David E. Elder, Michael Ming, Nandita Mitra, Tadeusz Debniak, Jan Lubinski, Marko Hocevar, Srdjan Novakovic, Barbara Peric, Petra Skerl, Johan Hansson, Esther Azizi, Orna Baron-Epel, Veronica Höiom, Alon Scope, Eitan Friedman, Felix Pavlotsky, Irit Cohen-Manheim, Yael Laitman, Mark Harland, Juliette Randerson-Moor, Jon Laye, John Davies, Jeremie Nsengimana

, Sally O'Shea, May Chan, Jo Gascoyne, Margaret A. Tucker, Alisa M. Goldstein, Xiaohong R. Yang, Amundadottir Lt

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Abstract

AbstractGenome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

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Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Abstract