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

Fang, J. et al. (2017) Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nature Communications, 8, 15034. (doi: 10.1038/ncomms15034) (PMID:28447668) (PMCID:PMC5414179)

[img]
Preview
Text
156608.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mackie, Professor Rona
Authors: 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., Canzian, F., Kooperberg, C., Wang, Z., Arslan, A. A., Bracci, P. M., Buring, J., Duell, E. J., Gallinger, S., Jacobs, E. J., Kamineni, A., Van Den Eeden, S., Klein, A. P., Kolonel, L. N., Li, D., Olson, S. H., Risch, H. A., Sesso, H. D., Visvanathan, K., Zheng, W., Albanes, D., Austin, M. A., Boutron-Ruault, M.-C., Bueno-de-Mesquita, H. B., Cotterchio, M., Gaziano, J. M., Giovannucci, E. L., Goggins, M., Gross, M., Hassan, M., Helzlsouer, K. J., Holly, E. A., Hunter, D. J., Jenab, M., Kaaks, R., Key, T. J., Khaw, K.-T., Krogh, V., Kurtz, R. C., LaCroix, A., Le Marchand, L., Mannisto, S., Patel, A. V., Peeters, P. H. M., Riboli, E., Shu, X.-O., Sund, M., Thornquist, M., Tjønneland, A., Tobias, G. S., Trichopoulos, D., Wactawski-Wende, J., Yu, H., Yu, K., Zeleniuch-Jacquotte, A., Hoover, R., Hartge, P., Fuchs, C., Chanock, S. J., Stevens, V., Albanes, D., Caporaso, N. E., Brennan, P., McKay, J., Wu, X., Hung, R. J., McLaughlin, J. R., Bickeboller, H., Risch, A., Wichmann, E., Houlston, R., 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, P. G., Iglesias-Garcia, P., Malvehy, J., Mila, M., Pigem, R., Potrony, M., Batille, J.-A., Marti, G. T., Hayward, N., Martin, N., Montgomery, G., Duffy, D., Whiteman, D., Gregor, S. M., Calista, D., Landi, G., Minghetti, P., Arcangeli, F., Bertazzi, P. A., Ghiorzo, P., Scarra, G. B., Pastorino, L., Bruno, W., Andreotti, V., Queirolo, P., Spagnolo, F., Mackie, R., Lang, J., Gruis, N., van Nieuwpoort, F. A., Out, C., Bergman, W., Kukutsch, N., Bavinck, J. N. B., 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, A. S., Molvern, A., Helsing, P., Andresen, P. A., Rootwelt, H., Akslen, L. A., Bressac-de Paillerets, B., 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, D., Ming, M., Mitra, N., Debniak, T., Lubinski, J., Hocevar, M., Novakovic, S., Peric, B., Skerl, P., Hansson, J., Hoiom, V., Freidman, 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, M. A., Goldstein, A. M., Yang, X. R., Stolzenberg-Solomon, R. S., Kraft, P., Wolpin, B. M., Jansen, P. W. T. C., Olson, S., McGlynn, K. A., Kanetsky, P. A., Chatterjee, N., Barrett, J. H., Dunning, A. M., Taylor, J. C., Newton-Bishop, J. A., Bishop, D. T., Andresson, T., Petersen, G. M., Amos, C. I., Iles, M. M., Nathanson, K. L., Landi, M. T., Vermeulen, M., Brown, K. M., and Amundadottir, L. T.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications8(1):15034
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record