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

Jun Fang; Jinping Jia; Matthew Makowski; Mai Xu; Zhaoming Wang; Tongwu Zhang; Jason W. Hoskins; Jiyeon Choi; Younghun Han; Mingfeng Zhang; Janelle Thomas; Michael Kovacs; Irene Collins; Marta Dzyadyk; Abbey Thompson; Maura O'Neill; Sudipto Das; Qi Lan; Roelof Koster; Rachael S. Stolzenberg-Solomon; Peter Kraft; Brian M. Wolpin; Pascal W.T.C. Jansen; Sara Olson; Katherine A. McGlynn; Peter A. Kanetsky; Nilanjan Chatterjee; Jennifer H. Barrett; Alison M. Dunning; John C. Taylor; Julia A. Newton-Bishop; D. Timothy Bishop; Thorkell Andresson; Gloria M. Petersen; Christopher I. Amos; Mark M. Iles; Katherine L. Nathanson; Maria Teresa Landi; Michiel Vermeulen; Kevin M. Brown; Laufey T. Amundadottir; Federico Canzian; Charles Kooperberg; Alan A. Arslan; Paige M. Bracci; Julie Buring; Eric J. Duell; Steven Gallinger; Eric J. Jacobs; Aruna Kamineni; Stephen Van Den Eeden; Alison P. Klein; Laurence N. Kolonel; Donghui Li; Sara H. Olson; Harvey A. Risch; Howard D. Sesso; Kala Visvanathan; Wei Zheng; Demetrius Albanes; Melissa A. Austin; Marie Christine Boutron-Ruault; H. Bas Bueno-De-Mesquita; Michelle Cotterchio; J. Michael Gaziano; Edward L. Giovannucci; Michael Goggins; Myron Gross; Manal Hassan; Kathy J. Helzlsouer; Elizabeth A. Holly; David J. Hunter; Mazda Jenab; Rudolf Kaaks; Timothy J. Key; Kay Tee Khaw; Vittorio Krogh; Robert C. Kurtz; Andrea LaCroix; Loic Le Marchand; Satu Mannisto; Alpa V. Patel; Petra H.M. Peeters; Elio Riboli; Xiao Ou Shu; Malin Sund; Mark Thornquist; Anne Tjønneland; 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; Demetrios Albanes; Neil E. Caporaso; Paul Brennan; James McKay; Xifeng Wu; Rayjean J. Hung; John R. McLaughlin; Heike Bickeboller; Angela Risch; Erich Wichmann; Richard S. Houlston; Graham Mann; John Hopper; Joanne Aitken; Bruce Armstrong; Graham Giles; Elizabeth Holland; Richard Kefford; Anne Cust; Mark Jenkins; Helen Schmid; Susana Puig; Paula Aguilera; Celia Badenas; Alicia Barreiro; Cristina Carrera; Daniel Gabriel; Pol Gimenez Xavier; Pablo Iglesias-Garcia; Josep Malvehy; Montse Mila; Ramon Pigem; Miriam Potrony; Joan Anton Puig Butille; Gemma Tell-Marti; Nicholas K. Hayward; Nicholas G. Martin; Grant Montgomery; David L. Duffy; David C. Whiteman; Stuart MacGregor; Donato Calista; Giorgio Landi; Paola Minghetti; Fabio Arcangeli; Pier Alberto Bertazzi; Paola Ghiorzo; Giovanna Bianchi-Scarra; Lorenze Pastorino; William Bruno; Virginia Andreotti; Paola Queirolo; Francesco Spagnolo; Rona MacKie; Julie Lang; Nelleke Gruis; Frans A. Van Nieuwpoort; Coby Out; Wilma Bergman; Nicole Kukutsch; Jan Nico Bouwes Bavinck; Bert Bakker; Nienke Van Der Stoep; Jeanet Ter Huurne; Han Van Der Rhee; Marcel Bekkenk; Dyon Snels; Marinus Van Praag; Lieve Brochez; Rianne Gerritsen; Marianne Crijns; Hans Vasen; Bart Janssen; Christian Ingvar; Håkan Olsson; Göran Jönsson; Åke Borg; Katja Harbst; Kari Nielsen; Anita Schmidt Zander; Anders Molven; Per Helsing; Per Arne Andresen; Helge Rootwelt; Lars A. Akslen; Brigitte Bressac De Paillerets; Florence Demenais; Marie Francoise Avril; Valerie Chaudru; Patricia Jeannin; Fabienne Lesueur; Eve Maubec; Hamida Mohamdi; Myriam Bossard; Amaury Vaysse; Francoise Boitier; Olivier Caron; Frederic Caux; Stephane Dalle; Olivier Dereure; Dominique Leroux; Ludovic Martin; Christine Mateus; Caroline Robert; Dominique Stoppa-Lyonnet; 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; Veronica Höiom; Eitan Friedman; Esther Azizi; Orna Baron-Epel; Alon Scope; 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

doi:10.1038/ncomms15034

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

Jun Fang, Jinping Jia, Matthew Makowski, Mai Xu, Zhaoming Wang, Tongwu Zhang, Jason W. Hoskins, Jiyeon Choi, Younghun Han, Mingfeng Zhang, Janelle Thomas, Michael Kovacs, Irene Collins, Marta Dzyadyk, Abbey Thompson, Maura O'Neill, Sudipto Das, Qi Lan, Roelof Koster, Rachael S. Stolzenberg-SolomonPeter Kraft, Brian M. Wolpin, Pascal W.T.C. Jansen, Sara Olson, Katherine A. McGlynn, Peter A. Kanetsky, Nilanjan Chatterjee, Jennifer H. Barrett, Alison M. Dunning, John C. Taylor, Julia A. Newton-Bishop, D. Timothy Bishop, Thorkell Andresson, Gloria M. Petersen, Christopher I. Amos, Mark M. Iles, Katherine L. Nathanson, Maria Teresa Landi, Michiel Vermeulen, Kevin M. Brown, Laufey T. Amundadottir, Federico Canzian, Charles Kooperberg, Alan A. Arslan, Paige M. Bracci, Julie Buring, Eric J. Duell, Steven Gallinger, Eric J. Jacobs, Aruna Kamineni, Stephen Van Den Eeden, Alison P. Klein, Laurence N. Kolonel, Donghui Li, Sara H. Olson, Harvey A. Risch, Howard D. Sesso, Kala Visvanathan, Wei Zheng, Demetrius Albanes, Melissa A. Austin, Marie Christine Boutron-Ruault, H. Bas Bueno-De-Mesquita, Michelle Cotterchio, J. Michael Gaziano, Edward L. Giovannucci, Michael Goggins, Myron Gross, Manal Hassan, Kathy J. Helzlsouer, Elizabeth A. Holly, David J. Hunter, Mazda Jenab, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Vittorio Krogh, Robert C. Kurtz, Andrea LaCroix, Loic Le Marchand, Satu Mannisto, Alpa V. Patel, Petra H.M. Peeters, Elio Riboli, Xiao Ou Shu, Malin Sund, Mark Thornquist, Anne Tjønneland, 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, Demetrios Albanes, Neil E. Caporaso, Paul Brennan, James McKay, Xifeng Wu, Rayjean J. Hung, John R. McLaughlin, Heike Bickeboller, Angela Risch, Erich Wichmann, Richard S. Houlston, Graham Mann, John Hopper, Joanne Aitken, Bruce Armstrong, Graham Giles, Elizabeth Holland, Richard Kefford, Anne Cust, Mark Jenkins, Helen Schmid, Susana Puig, Paula Aguilera, Celia Badenas, Alicia Barreiro, Cristina Carrera, Daniel Gabriel, Pol Gimenez Xavier, Pablo Iglesias-Garcia, Josep Malvehy, Montse Mila, Ramon Pigem, Miriam Potrony, Joan Anton Puig Butille, Gemma Tell-Marti, Nicholas K. Hayward, Nicholas G. Martin, Grant Montgomery, David L. Duffy, David C. Whiteman, Stuart MacGregor, Donato Calista, Giorgio Landi, Paola Minghetti, Fabio Arcangeli, Pier Alberto Bertazzi, Paola Ghiorzo, Giovanna Bianchi-Scarra, Lorenze Pastorino, William Bruno, Virginia Andreotti, Paola Queirolo, Francesco Spagnolo, Rona MacKie, Julie Lang, Nelleke Gruis, Frans A. Van Nieuwpoort, Coby Out, Wilma Bergman, Nicole Kukutsch, Jan Nico Bouwes Bavinck, Bert Bakker, Nienke Van Der Stoep, Jeanet Ter Huurne, Han Van Der Rhee, Marcel Bekkenk, Dyon Snels, Marinus Van Praag, Lieve Brochez, Rianne Gerritsen, Marianne Crijns, Hans Vasen, Bart Janssen, Christian Ingvar, Håkan Olsson, Göran Jönsson, Åke Borg, Katja Harbst, Kari Nielsen, Anita Schmidt Zander, Anders Molven, Per Helsing, Per Arne Andresen, Helge Rootwelt, Lars A. Akslen, Brigitte Bressac De Paillerets, Florence Demenais, Marie Francoise Avril, Valerie Chaudru, Patricia Jeannin, Fabienne Lesueur, Eve Maubec, Hamida Mohamdi, Myriam Bossard, Amaury Vaysse, Francoise Boitier, Olivier Caron, Frederic Caux, Stephane Dalle, Olivier Dereure, Dominique Leroux, Ludovic Martin, Christine Mateus, Caroline Robert, Dominique Stoppa-Lyonnet, 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, Veronica Höiom, Eitan Friedman, Esther Azizi, Orna Baron-Epel, Alon Scope, 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

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Genome 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.

Original language	English (US)
Article number	15034
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15034
State	Published - 2017

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1038/ncomms15034

Cite this

Fang, J., Jia, J., Makowski, M., Xu, M., Wang, Z., Zhang, T., Hoskins, J. W., Choi, J., Han, Y., Zhang, M., Thomas, J., Kovacs, M., Collins, I., Dzyadyk, M., Thompson, A., O'Neill, M., Das, S., Lan, Q., Koster, R., ... Yang, X. R. (2017). Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nature communications, 8, Article 15034. https://doi.org/10.1038/ncomms15034

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, JW, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Stolzenberg-Solomon, RS, Kraft, P, Wolpin, BM, Jansen, PWTC, Olson, S, McGlynn, KA, Kanetsky, PA, Chatterjee, N, Barrett, JH, Dunning, AM, Taylor, JC, Newton-Bishop, JA, Timothy Bishop, D, Andresson, T, Petersen, GM, Amos, CI, Iles, MM, Nathanson, KL, Landi, MT, Vermeulen, M, Brown, KM, Amundadottir, LT, Canzian, F, Kooperberg, C, Arslan, AA, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Jacobs, EJ, Kamineni, A, Van Den Eeden, S, Klein, AP, Kolonel, LN, Li, D, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, Zheng, W, Albanes, D, Austin, MA, Boutron-Ruault, MC, Bueno-De-Mesquita, HB, Cotterchio, M, Gaziano, JM, Giovannucci, EL, Goggins, M, Gross, M, Hassan, M, Helzlsouer, KJ, Holly, EA, Hunter, DJ, Jenab, M, Kaaks, R, Key, TJ, Khaw, KT, Krogh, V, Kurtz, RC, LaCroix, A, Le Marchand, L, Mannisto, S, Patel, AV, Peeters, PHM, Riboli, E, Shu, XO, Sund, M, Thornquist, M, Tjønneland, A, Tobias, GS, Trichopoulos, D, Wactawski-Wende, J, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stevens, V, Albanes, D, Caporaso, NE, Brennan, P, McKay, J, Wu, X, Hung, RJ, McLaughlin, JR, Bickeboller, H, Risch, A, Wichmann, E, Houlston, RS, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, PG, Iglesias-Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Puig Butille, JA, Tell-Marti, G, Hayward, NK, Martin, NG, Montgomery, G, Duffy, DL, Whiteman, DC, MacGregor, S, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, PA, Ghiorzo, P, Bianchi-Scarra, G, Pastorino, L, Bruno, W, Andreotti, V, Queirolo, P, Spagnolo, F, MacKie, R, Lang, J, Gruis, N, Van Nieuwpoort, FA, Out, C, Bergman, W, Kukutsch, N, Bavinck, JNB, Bakker, B, Van Der Stoep, N, Ter Huurne, J, Van Der Rhee, H, Bekkenk, M, Snels, D, Van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jönsson, G, Borg, Å, Harbst, K, Nielsen, K, Zander, AS, Molven, A, Helsing, P, Andresen, PA, Rootwelt, H, Akslen, LA, Paillerets, BBD, Demenais, F, Avril, MF, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa-Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, DE, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Höiom, V, Friedman, E, Azizi, E, Baron-Epel, O, Scope, A, Pavlotsky, F, Cohen-Manheim, I, Laitman, Y, Harland, M, Randerson-Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, MA, Goldstein, AM & Yang, XR 2017, 'Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148', Nature communications, vol. 8, 15034. https://doi.org/10.1038/ncomms15034

@article{4bbac5ba4d314fe58c1740b2677ca861,

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

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

note = "Funding Information: We acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR, NCI), as well as Mr Timothy Myers and Lea Jessop (LTG, DCEG, NCI) for their invaluable help throughout the project. We are grateful to Dr Francisco X. Real, The Spanish National Cancer Institute (CNIO) in Madrid, Spain for providing reagents. We are grateful to Dr Dom Esposito, Frederick National Laboratory for Cancer Research, Frederick, MD, USA, for cloning for lentiviral production. We thank Paul D.P. Pharoah, Department of Oncology, University of Cambridge, Cambridge, UK and Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK for providing GWAS data. Furthermore, we thank Dr Stephen Chanock for his advice, encouragement and critical reading of the manuscript. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, by contract number HHSN261200800001E, by Cancer Research UK for SEARCH (C490/A10124). Funding for M.V. was provided by the Netherlands Organization for Scientific Research (NWO Gravitation Program Cancer Genomics Netherlands). Funding for M.M. was provided by a grant from the Marie Curie Initial Training Network (ITN) DevCom (FP7, grant number 607142). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

doi = "10.1038/ncomms15034",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

AU - Fang, Jun

AU - Jia, Jinping

AU - Makowski, Matthew

AU - Xu, Mai

AU - Wang, Zhaoming

AU - Zhang, Tongwu

AU - Hoskins, Jason W.

AU - Choi, Jiyeon

AU - Han, Younghun

AU - Zhang, Mingfeng

AU - Thomas, Janelle

AU - Kovacs, Michael

AU - Collins, Irene

AU - Dzyadyk, Marta

AU - Thompson, Abbey

AU - O'Neill, Maura

AU - Das, Sudipto

AU - Lan, Qi

AU - Koster, Roelof

AU - Stolzenberg-Solomon, Rachael S.

AU - Kraft, Peter

AU - Wolpin, Brian M.

AU - Jansen, Pascal W.T.C.

AU - Olson, Sara

AU - McGlynn, Katherine A.

AU - Kanetsky, Peter A.

AU - Chatterjee, Nilanjan

AU - Barrett, Jennifer H.

AU - Dunning, Alison M.

AU - Taylor, John C.

AU - Newton-Bishop, Julia A.

AU - Timothy Bishop, D.

AU - Andresson, Thorkell

AU - Petersen, Gloria M.

AU - Amos, Christopher I.

AU - Iles, Mark M.

AU - Nathanson, Katherine L.

AU - Landi, Maria Teresa

AU - Vermeulen, Michiel

AU - Brown, Kevin M.

AU - Amundadottir, Laufey T.

AU - Canzian, Federico

AU - Kooperberg, Charles

AU - Arslan, Alan A.

AU - Bracci, Paige M.

AU - Buring, Julie

AU - Duell, Eric J.

AU - Gallinger, Steven

AU - Jacobs, Eric J.

AU - Kamineni, Aruna

AU - Van Den Eeden, Stephen

AU - Klein, Alison P.

AU - Kolonel, Laurence N.

AU - Li, Donghui

AU - Olson, Sara H.

AU - Risch, Harvey A.

AU - Sesso, Howard D.

AU - Visvanathan, Kala

AU - Zheng, Wei

AU - Albanes, Demetrius

AU - Austin, Melissa A.

AU - Boutron-Ruault, Marie Christine

AU - Bueno-De-Mesquita, H. Bas

AU - Cotterchio, Michelle

AU - Gaziano, J. Michael

AU - Giovannucci, Edward L.

AU - Goggins, Michael

AU - Gross, Myron

AU - Hassan, Manal

AU - Helzlsouer, Kathy J.

AU - Holly, Elizabeth A.

AU - Hunter, David J.

AU - Jenab, Mazda

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Khaw, Kay Tee

AU - Krogh, Vittorio

AU - Kurtz, Robert C.

AU - LaCroix, Andrea

AU - Le Marchand, Loic

AU - Mannisto, Satu

AU - Patel, Alpa V.

AU - Peeters, Petra H.M.

AU - Riboli, Elio

AU - Shu, Xiao Ou

AU - Sund, Malin

AU - Thornquist, Mark

AU - Tjønneland, Anne

AU - Tobias, Geoffrey S.

AU - Trichopoulos, Dimitrios

AU - Wactawski-Wende, Jean

AU - Yu, Herbert

AU - Yu, Kai

AU - Zeleniuch-Jacquotte, Anne

AU - Hoover, Robert

AU - Hartge, Patricia

AU - Fuchs, Charles

AU - Chanock, Stephen J.

AU - Stevens, Victoria

AU - Albanes, Demetrios

AU - Caporaso, Neil E.

AU - Brennan, Paul

AU - McKay, James

AU - Wu, Xifeng

AU - Hung, Rayjean J.

AU - McLaughlin, John R.

AU - Bickeboller, Heike

AU - Risch, Angela

AU - Wichmann, Erich

AU - Houlston, Richard S.

AU - Mann, Graham

AU - Hopper, John

AU - Aitken, Joanne

AU - Armstrong, Bruce

AU - Giles, Graham

AU - Holland, Elizabeth

AU - Kefford, Richard

AU - Cust, Anne

AU - Jenkins, Mark

AU - Schmid, Helen

AU - Puig, Susana

AU - Aguilera, Paula

AU - Badenas, Celia

AU - Barreiro, Alicia

AU - Carrera, Cristina

AU - Gabriel, Daniel

AU - Xavier, Pol Gimenez

AU - Iglesias-Garcia, Pablo

AU - Malvehy, Josep

AU - Mila, Montse

AU - Pigem, Ramon

AU - Potrony, Miriam

AU - Puig Butille, Joan Anton

AU - Tell-Marti, Gemma

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AU - Landi, Giorgio

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AU - Bianchi-Scarra, Giovanna

AU - Pastorino, Lorenze

AU - Bruno, William

AU - Andreotti, Virginia

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AU - Spagnolo, Francesco

AU - MacKie, Rona

AU - Lang, Julie

AU - Gruis, Nelleke

AU - Van Nieuwpoort, Frans A.

AU - Out, Coby

AU - Bergman, Wilma

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AU - Bekkenk, Marcel

AU - Snels, Dyon

AU - Van Praag, Marinus

AU - Brochez, Lieve

AU - Gerritsen, Rianne

AU - Crijns, Marianne

AU - Vasen, Hans

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AU - Ingvar, Christian

AU - Olsson, Håkan

AU - Jönsson, Göran

AU - Borg, Åke

AU - Harbst, Katja

AU - Nielsen, Kari

AU - Zander, Anita Schmidt

AU - Molven, Anders

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AU - Rootwelt, Helge

AU - Akslen, Lars A.

AU - Paillerets, Brigitte Bressac De

AU - Demenais, Florence

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AU - Chaudru, Valerie

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AU - Lesueur, Fabienne

AU - Maubec, Eve

AU - Mohamdi, Hamida

AU - Bossard, Myriam

AU - Vaysse, Amaury

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AU - Mitra, Nandita

AU - Debniak, Tadeusz

AU - Lubinski, Jan

AU - Hocevar, Marko

AU - Novakovic, Srdjan

AU - Peric, Barbara

AU - Skerl, Petra

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AU - Azizi, Esther

AU - Baron-Epel, Orna

AU - Scope, Alon

AU - Pavlotsky, Felix

AU - Cohen-Manheim, Irit

AU - Laitman, Yael

AU - Harland, Mark

AU - Randerson-Moor, Juliette

AU - Laye, Jon

AU - Davies, John

AU - Nsengimana, Jeremie

AU - O'Shea, Sally

AU - Chan, May

AU - Gascoyne, Jo

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N1 - Funding Information: We acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR, NCI), as well as Mr Timothy Myers and Lea Jessop (LTG, DCEG, NCI) for their invaluable help throughout the project. We are grateful to Dr Francisco X. Real, The Spanish National Cancer Institute (CNIO) in Madrid, Spain for providing reagents. We are grateful to Dr Dom Esposito, Frederick National Laboratory for Cancer Research, Frederick, MD, USA, for cloning for lentiviral production. We thank Paul D.P. Pharoah, Department of Oncology, University of Cambridge, Cambridge, UK and Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK for providing GWAS data. Furthermore, we thank Dr Stephen Chanock for his advice, encouragement and critical reading of the manuscript. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, by contract number HHSN261200800001E, by Cancer Research UK for SEARCH (C490/A10124). Funding for M.V. was provided by the Netherlands Organization for Scientific Research (NWO Gravitation Program Cancer Genomics Netherlands). Funding for M.M. was provided by a grant from the Marie Curie Initial Training Network (ITN) DevCom (FP7, grant number 607142). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Publisher Copyright: © The Author(s) 2017.

PY - 2017

Y1 - 2017

N2 - Genome 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.

AB - Genome 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.

UR - http://www.scopus.com/inward/record.url?scp=85038930539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038930539&partnerID=8YFLogxK

U2 - 10.1038/ncomms15034

DO - 10.1038/ncomms15034

M3 - Article

C2 - 28447668

AN - SCOPUS:85038930539

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 15034

ER -

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

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