Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors

Candace D. Middlebrooks, A. Rouf Banday, Konichi Matsuda, Krizia Ivana Udquim, Olusegun O. Onabajo, Ashley Paquin, Jonine D. Figueroa, Bin Zhu, Stella Koutros, Michiaki Kubo, Taro Shuin, Neal D. Freedman, Manolis Kogevinas, Nuria Malats, Stephen J. Chanock, Montserrat Garcia-Closas, Debra T. Silverman, Nathaniel Rothman, Ludmila Prokunina-Olsson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1330-1338
Number of pages9
JournalNature genetics
Volume48
Issue number11
DOIs
StatePublished - Nov 1 2016

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

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. (2016). Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nature genetics, 48(11), 1330-1338. https://doi.org/10.1038/ng.3670