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Genetic and Environmental Factors Influence APOBEC Mutagenesis in Tumors


High rates of APOBEC-signature mutations (generated by APOBEC3 enzymes) are found in many tumors, but factors affecting this mutation pattern are not well understood.


Ludmila Prokunina-Olsson, Ph.D., and collaborators found that two common germline variants in the APOBEC3 region on chromosome 22, previously associated with risk for bladder and breast cancer, were also associated with increased expression of mRNA transcripts that encode the APOBEC3B and APOBEC3A enzymes in bladder and breast tumors in The Cancer Genome Atlas (TCGA). Furthermore, the same germline variants and mRNA transcripts were significantly associated with increased number of APOBEC-signature mutations in these tumors. When the investigators exposed cancer cell lines to a viral infection or a DNA-damaging drug, they observed a strongly induced expression of APOBEC3A and APOBEC3B.


These findings suggest a tissue-specific role of environmental triggers for APOBEC mutagenesis that may lead to cancer, particularly in individuals with germline APOBEC3 risk variants.

Middlebrooks CD, Banday AR, Matsuda K, et al. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nature Genetics 2016