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

PanScan Consortium; TRICL Consortia; GenoMEL Consortium

doi:10.1038/ncomms15034

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

PanScan Consortium, TRICL Consortia, GenoMEL Consortium

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

39 Citations (Web of Science)

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
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15034
Publication status	Published - 2017
Externally published	Yes

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10.1038/ncomms15034Licence: CC BY

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@article{14f92d5331f840c783c9428bbb3f6c35,

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 = "{PanScan Consortium} and {TRICL Consortia} and {GenoMEL Consortium} and 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 Olson, {Sara H.} 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.}",

year = "2017",

doi = "10.1038/ncomms15034",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

}

TY - JOUR

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

AU - PanScan Consortium

AU - TRICL Consortia

AU - GenoMEL Consortium

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 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

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

AU - Hayward, Nicholas K.

AU - Martin, Nicholas G.

AU - Montgomery, Grant

AU - Duffy, David L.

AU - Whiteman, David C.

AU - MacGregor, Stuart

AU - Calista, Donato

AU - Landi, Giorgio

AU - Minghetti, Paola

AU - Arcangeli, Fabio

AU - Bertazzi, Pier Alberto

AU - Ghiorzo, Paola

AU - Bianchi-Scarra, Giovanna

AU - Pastorino, Lorenze

AU - Bruno, William

AU - Andreotti, Virginia

AU - Queirolo, Paola

AU - Spagnolo, Francesco

AU - MacKie, Rona

AU - Lang, Julie

AU - Gruis, Nelleke

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.

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

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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