Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
(2017) In Nature Communications 8.- 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... (More)
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.
(Less)
- author
- Fang, Jun and Amundadottir, Laufey T.
- contributor
- Ingvar, Christian
LU
; Olsson, Håkan
LU
; Jönsson, Göran
LU
; Borg, Åke
LU
; Harbst, Katja
LU
; Nielsen, Kari
LU
and Zander, Anita Schmidt
LU
- author collaboration
- organization
-
- Lund Melanoma Study Group (research group)
- Surgery (Lund)
- Tumor microenvironment
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- EpiHealth: Epidemiology for Health
- Medical oncology
- Melanoma Genomics (research group)
- Breastcancer-genetics
- Familial Breast Cancer (research group)
- Dermatology and Venereology (Lund)
- Clinical Sciences, Helsingborg
- publishing date
- 2017-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 8
- article number
- 15034
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:28447668
- scopus:85038930539
- ISSN
- 2041-1723
- DOI
- 10.1038/ncomms15034
- language
- English
- LU publication?
- yes
- id
- fd63e035-620a-4ae4-af20-2275a95a0376
- date added to LUP
- 2019-05-23 09:03:16
- date last changed
- 2024-05-14 11:09:22
@article{fd63e035-620a-4ae4-af20-2275a95a0376,
abstract = {{<p>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.</p>}},
author = {{Fang, Jun and Amundadottir, Laufey T.}},
issn = {{2041-1723}},
language = {{eng}},
month = {{01}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148}},
url = {{http://dx.doi.org/10.1038/ncomms15034}},
doi = {{10.1038/ncomms15034}},
volume = {{8}},
year = {{2017}},
}