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; PanScan Consortium; TRICL Consortium; GenoMEL Consortium; Rachael S. Stolzenberg-Solomon; Peter Kraft; Brian M. Wolpin; Pascal W. T. C. Jansen; Sara H. 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

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, PanScan ConsortiumTRICL Consortium, GenoMEL Consortium, Rachael S. Stolzenberg-Solomon, Peter Kraft, Brian M. Wolpin, Pascal W. T. C. Jansen, Sara H. 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

^*Corresponding author for this work

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

37 Citations (Scopus)

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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
Article number	15034
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15034
Publication status	Published - 27 Apr 2017

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Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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10.1038/ncomms15034

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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., ... Amundadottir, L. T. (2017). Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nature Communications, 8, 1-15. Article 15034. https://doi.org/10.1038/ncomms15034

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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.",

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note = "Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2017",

month = apr,

day = "27",

doi = "10.1038/ncomms15034",

language = "English",

volume = "8",

pages = "1--15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer, Springer Nature",

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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, PanScan Consortium, TRICL Consortium, GenoMEL Consortium, Stolzenberg-Solomon, RS, Kraft, P, Wolpin, BM, Jansen, PWTC, Olson, SH, 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 2017, 'Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148', Nature Communications, vol. 8, 15034, pp. 1-15. https://doi.org/10.1038/ncomms15034

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 - PanScan Consortium

AU - TRICL Consortium

AU - GenoMEL Consortium

AU - Stolzenberg-Solomon, Rachael S.

AU - Kraft, Peter

AU - Wolpin, Brian M.

AU - Jansen, Pascal W. T. C.

AU - Olson, Sara H.

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

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AU - Hayward, Nicholas K.

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AU - Duffy, David L.

AU - Whiteman, David C.

AU - MacGregor, Stuart

AU - Calista, Donato

AU - Landi, Giorgio

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AU - Arcangeli, Fabio

AU - Bertazzi, Pier Alberto

AU - Ghiorzo, Paola

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AU - Pastorino, Lorenze

AU - Bruno, William

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AU - MacKie, Rona

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AU - Van Nieuwpoort, Frans A.

AU - Out, Coby

AU - Bergman, Wilma

AU - Kukutsch, Nicole

AU - Bavinck, Jan Nico Bouwes

AU - Bakker, Bert

AU - Van Der Stoep, Nienke

AU - Ter Huurne, Jeanet

AU - Van Der Rhee, Han

AU - Bekkenk, Marcel

AU - Snels, Dyon

AU - Van Praag, Marinus

AU - Brochez, Lieve

AU - Gerritsen, Rianne

AU - Crijns, Marianne

AU - Vasen, Hans

AU - Janssen, Bart

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

AU - Helsing, Per

AU - Andresen, Per Arne

AU - Rootwelt, Helge

AU - Akslen, Lars A.

AU - Paillerets, Brigitte Bressac De

AU - Demenais, Florence

AU - Avril, Marie Francoise

AU - Chaudru, Valerie

AU - Jeannin, Patricia

AU - Lesueur, Fabienne

AU - Maubec, Eve

AU - Mohamdi, Hamida

AU - Bossard, Myriam

AU - Vaysse, Amaury

AU - Boitier, Francoise

AU - Caron, Olivier

AU - Caux, Frederic

AU - Dalle, Stephane

AU - Dereure, Olivier

AU - Leroux, Dominique

AU - Martin, Ludovic

AU - Mateus, Christine

AU - Robert, Caroline

AU - Stoppa-Lyonnet, Dominique

AU - Thomas, Luc

AU - Wierzbicka, Eva

AU - Elder, David E.

AU - Ming, Michael

AU - Mitra, Nandita

AU - Debniak, Tadeusz

AU - Lubinski, Jan

AU - Hocevar, Marko

AU - Novakovic, Srdjan

AU - Peric, Barbara

AU - Skerl, Petra

AU - Hansson, Johan

AU - Höiom, Veronica

AU - Friedman, Eitan

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

AU - Tucker, Margaret A.

AU - Goldstein, Alisa M.

AU - Yang, Xiaohong R.

N1 - Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2017/4/27

Y1 - 2017/4/27

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

U2 - 10.1038/ncomms15034

DO - 10.1038/ncomms15034

M3 - Article

C2 - 28447668

AN - SCOPUS:85038930539

SN - 2041-1723

VL - 8

SP - 1

EP - 15

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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