A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk

Abstract

We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.

APOBEC3B: Pathological consequences of an innate immune DNA mutator

“…Unlike the Japanese study that collected data on the deletion allele frequency from normal healthy patients recruited into their study, these groups relied on data from the 1000 genomes project to determine the frequency of the deletion allele within their cohorts. [54][55][56][57] These findings argue that APOBEC3B is somehow a protective factor, reducing the incidence of breast cancer in the populations studied. These observations are intriguing and may reflect compromised innate immune defenses, with increased levels of viral infection and endogenous retrotransposition expected in the absence of this enzyme.…”

“…[53][54][55][56] These analyses have identified an APOBEC3B deletion polymorphism circulating in the human population with an allelic frequency ranging from approximately 1 to 93%, dependent upon the biogeographical ancestry of the population examined [ Figure 4]. [53,57] One group used a small Japanese cohort (<50 patients) to assess breast cancer incidence and the APOBEC3B deletion polymorphism and found a statistically insignificant trend toward an inverse correlation between APOBEC3B and breast cancer.…”

“…[54] Two other groups used much larger cohorts to assess the relationship between the deletion allele and breast cancer incidence. [55,56] These larger studies determined that there was a significant increase in the APO-BEC3B deletion allele among women with breast cancer. Unlike the Japanese study that collected data on the deletion allele frequency from normal healthy patients recruited into their study, these groups relied on data from the 1000 genomes project to determine the frequency of the deletion allele within their cohorts.…”

“…These observations are intriguing and may reflect compromised innate immune defenses, with increased levels of viral infection and endogenous retrotransposition expected in the absence of this enzyme. [29,[54][55][56][57] The APOBEC3B deletion allele may be protective with Figure 3: Potential mutagenic outcomes of uracil lesions. Canonical base excision repair is the most prevalent pathway and often results in error-free repair of uracil lesions (blue), but at least three intermediates in this process can lead to mutagenic outcomes.…”

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…At first glance though, this is difficult to reconcile with genetic evidence that the A3A_B deletion polymorphism, where the entire A3B protein coding sequence is missing, carries an increased risk of breast cancer [39,40]. Furthermore, a recent reanalysis of public breast cancer mutation data reported higher levels of A3 mutation signatures in patients harboring a copy of A3A_B, and more still in homozygotes (albeit there were very few of the latter), consistent with the A3A_B form (essentially A3A fused to the A3B 3' untranslated region (UTR)) being more mutagenic [41].…”