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

Lookup NU author(s): Dr Jérémie Nsengimana

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2017.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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Author(s): 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 M-C, 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 K-T, Krogh V, Kurtz RC, LaCroix A, Le Marchand L, Mannisto S, Patel AV, Peeters PHM, Riboli E, Shu X-O, Sund M, Thornquist M, Tjonneland 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 J-A, 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, Jonsson G, Borg A, Harbst K, Nielsen K, Zander AS, Molven A, Helsing P, Andresen PA, Rootwelt H, Akslen LA, Paillerets BB-D, Demenais F, Avril M-F, 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, Hoiom 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

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2017

Volume: 8

Online publication date: 27/04/2017

Acceptance date: 23/02/2017

Date deposited: 11/06/2020

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms15034

DOI: 10.1038/ncomms15034

PubMed id: 28447668

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