Åke Borg
Principal investigator
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
Author
Other contributions
- Christian Ingvar
- Håkan Olsson
- Göran Jönsson
- Åke Borg
- Katja Harbst
- Kari Nielsen
- Anita Schmidt Zander
Summary, in English
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.
Department/s
- Lund Melanoma Study Group
- Surgery (Lund)
- Tumor microenvironment
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- EpiHealth: Epidemiology for Health
- Medical oncology
- Melanoma Genomics
- Breastcancer-genetics
- Familial Breast Cancer
- Dermatology and Venereology (Lund)
- Clinical Sciences, Helsingborg
Publishing year
2017-01-01
Language
English
Publication/Series
Nature Communications
Volume
8
Document type
Journal article
Publisher
Nature Publishing Group
Topic
- Medical Genetics
Status
Published
Research group
- Lund Melanoma Study Group
- Melanoma Genomics
- Familial Breast Cancer
ISBN/ISSN/Other
- ISSN: 2041-1723