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 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; P Peeters

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-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, , P Peeters

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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
Journal	Nature Communications [E]
Volume	8
DOIs	https://doi.org/10.1038/ncomms15034
Publication status	Published - 27 Apr 2017

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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., ... Peeters, P. (2017). Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nature Communications [E], 8, Article 15034. https://doi.org/10.1038/ncomms15034

@article{4d500b751ed346d1a66e8d64d656f983,

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 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 Bishop, \{D. Timothy\} 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 P Peeters",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = apr,

day = "27",

doi = "10.1038/ncomms15034",

language = "English",

volume = "8",

journal = "Nature Communications [E]",

issn = "2041-1723",

publisher = "Nature Research",

}

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, SH, McGlynn, KA, Kanetsky, PA, Chatterjee, N, Barrett, JH, Dunning, AM, Taylor, JC, Newton-Bishop, JA, Bishop, DT, Andresson, T, Petersen, GM, Amos, CI, Iles, MM, Nathanson, KL, Landi, MT, Vermeulen, M, Brown, KM, Amundadottir, LT & Peeters, P 2017, 'Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148', Nature Communications [E], vol. 8, 15034. 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 - 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 - Bishop, D. Timothy

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 - Peeters, P

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.

U2 - 10.1038/ncomms15034

DO - 10.1038/ncomms15034

M3 - Article

C2 - 28447668

SN - 2041-1723

VL - 8

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 15034

ER -

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

Abstract

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