TY - JOUR
T1 - Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors
AU - Middlebrooks, Candace D.
AU - Banday, A. Rouf
AU - Matsuda, Konichi
AU - Udquim, Krizia Ivana
AU - Onabajo, Olusegun O.
AU - Paquin, Ashley
AU - Figueroa, Jonine D.
AU - Zhu, Bin
AU - Koutros, Stella
AU - Kubo, Michiaki
AU - Shuin, Taro
AU - Freedman, Neal D.
AU - Kogevinas, Manolis
AU - Malats, Nuria
AU - Chanock, Stephen J.
AU - Garcia-Closas, Montserrat
AU - Silverman, Debra T.
AU - Rothman, Nathaniel
AU - Prokunina-Olsson, Ludmila
N1 - Funding Information:
We thank the Breast Cancer Association Consortium (BCAC) for access to summary results for the association between rs1014971 and breast cancer risk. The results presented here are in part based upon data generated by the TCGA Research Network. The study was supported by federal funds from the Intramural Research Program (IRP), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was funded with National Institutes of Health Genes, Environment, and Health Initiative (GEI) grants HG-06-033-NCI-01 and RO1HL091172-01, U01HG004438, and NIH HHSN268200782096C. The Spanish Bladder Cancer Study (SBCS) was funded with intramural contract NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, and G03/174, Fundació Marató TV3, Red Temática Investigación Cooperativa en Cáncer (RTICC), Consolíder ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. The Biobank Japan Project was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government. The funders did not have a role in study design, data collection and analysis, writing, or submission of the manuscript.
Publisher Copyright:
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84988431028&partnerID=8YFLogxK
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U2 - 10.1038/ng.3670
DO - 10.1038/ng.3670
M3 - Article
AN - SCOPUS:84988431028
SN - 1061-4036
VL - 48
SP - 1330
EP - 1338
JO - Nature genetics
JF - Nature genetics
IS - 11
ER -