Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors
Open accessAbstract
High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors. In contrast, a 30-kb deletion that eliminates APOBEC3B and creates an APOBEC3A-APOBEC3B chimera was not important in bladder cancer, whereas it was associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast tumors. In vitro, APOBEC3B expression was predominantly induced by treatment with a DNA-damaging drug in bladder cancer cell lines, and APOBEC3A expression was induced as part of the antiviral interferon-stimulated response in breast cancer cell lines. These findings suggest a tissue-specific role of environmental oncogenic triggers, particularly in individuals with germline APOBEC3 risk variants.
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Case FBC070169 had a strong APOBEC substitution signature accounting for 94% of somatic mutations, but no APOBEC3A or APOBEC3B germline variants previously linked to this signature were found.
“Case FBC070169 had a strong APOBEC substitution signature accounting for 94% of the somatic mutations, yet there was no evidence of the APOBEC3A or APOBEC3B germline variants previously associated with this signature [15, 16].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [16]
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References 57 · Cited by 185
- Authors
- Middlebrooks, C. D., Banday, A. R., Matsuda, K., Udquim, K.-I., Onabajo, O. O., Paquin, A., Figueroa, J. D., Zhu, B., Koutros, S., Kubo, M., Shuin, T., Freedman, N. D., Kogevinas, M., Malats, N., Chanock, S. J., Garcia-Closas, M., Silverman, D. T., Rothman, N., & Prokunina-Olsson, L.
- Affiliations
- National Institutes of Health (US)
- Institute of Medical Science, The University of Tokyo (JP)
- University of Edinburgh (GB)
- RIKEN (JP)
- University of Kochi (JP)
- Centro de Investigación Biomédica en Red (ES)
- ORCID
- Venue
- Nature Genetics
- Published
- 2016-09-19
- Volume
- 48
- Issue
- 11
- Pages
- 1330-1338
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6583788
- OpenAlex
- W2523216993
- Cited by
- 185
- References
- 57
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 28 · 2022: 23 · 2021: 18 · 2020: 21 · 2019: 25 · 2018: 15 · 2017: 23 · 2016: 2
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health (HHSN261200800001C, Z99 CA999999)
- National Human Genome Research Institute (U01HG004438, HHSN268200782096C)
- National Cancer Institute (N02 CP011015, HHSN261200800001E), R01CA089715, R01CA034627)
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- APOBEC3, germline mutations, cancer risk, bladder cancer, breast cancer, APOBEC3B, APOBEC3A, DNA mutagenesis, environmental exposure, DNA-damaging agents, tissue-specific mutagenesis
- MeSH terms
- Urinary Bladder Neoplasms, Breast Neoplasms, Chromosome Mapping, Cytidine Deaminase, DNA, Neoplasm, DNA, Single-Stranded, Environment, Female, Humans, Male, Mutation, Proteins, Minor Histocompatibility Antigens, Survival Analysis, Mutagenesis, Germ-Line Mutation, Risk Assessment, Genetic Predisposition to Disease, Protein Isoforms, Polymorphism, Single Nucleotide, Cell Line, Tumor
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