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

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

来源：Nature Genetics, 2016, 48(11): 1330-1338.

DOI：10.1038/ng.3670

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.

• 出版日期2016-11
• 单位河北医科大学