Posted on September 19, 2016
Investigators in the Laboratory of Translational Genomics (LTG), part of the Division of Cancer Epidemiology and Genetics, and their collaborators, have described a relationship between common, inherited genetic variants associated with cancer risk, found in the APOBEC3 region of the genome, environmental exposures, and the pattern of somatic mutations that are caused by the APOBEC3 enzymes. These enzymes fight infections at the cellular level by mutating genetic material in viruses. However, they can sometimes misfire and end up mutating the host DNA as well, causing damage that could contribute to the development of cancer.
APOBEC3 enzymes generate DNA mutations of a specific type, known as the APOBEC signature mutation pattern, which has been observed in over half of the tumor types evaluated by The Cancer Genome Atlas (TCGA). However, until now the factors contributing to APOBEC mutagenesis were unknown. This study, published online in Nature Genetics on September 19, 2016, is the first to link APOBEC mutagenesis in tumors with functional germline variants associated with cancer risk, and environmental exposures.
In particular, the investigators showed 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, respectively. Furthermore, the same germline variants and mRNA transcripts were significantly associated with increased number of APOBEC signature mutations in 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. Co-first author Rouf Banday, Ph.D., from LTG, commented, “our finding suggests that even transient environmental exposures that induce APOBEC3s could be a cause of DNA mutagenesis, and eventually, tumor initiation and progression. Individuals with germline variants affecting APOBEC3 expression may more easily acquire APOBEC signature mutations.”
The investigators also reported that in bladder tumors, increased APOBEC signature mutation load and homozygosity for the risk allele of the bladder cancer-associated SNP, were associated with improved survival for patients with aggressive, muscle-invasive bladder cancer. This genotype group includes more than half of all bladder cancer patients. “We were surprised by this finding,” said senior author Ludmila Prokunina-Olsson, Ph.D., also from LTG. “One explanation is that higher mutation load may improve the effectiveness of treatments that cause DNA damage, since the tumor cells will be less likely to recover. Tumor cells with more mutations are also more vulnerable to synthetic lethality due to mutation combinations, and they express more cell-surface neoantigens that can trigger the patient’s immune response, leading to elimination of the tumor cells. Thus, APOBEC mutagenesis could help eliminate tumors cells through several mechanisms. On the other hand, APOBEC mutagenesis contributes to tumor evolution and resistance to treatment.”
Since most bladder tumors and many other tumor types show evidence of APOBEC mutagenesis, these findings may contribute to our understanding of important, clinically significant biological mechanisms and open new avenues for research.
Reference: Candace D Middlebrooks, A Rouf Banday, Konichi Matsuda, et al. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nature Genetics 2016.