The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population

Abstract

APOBEC3B, in addition to other members of the APOBEC3 gene family, has recently been intensively studied due to its identification as a gene whose activation in cancer is responsible for a specific pattern of massively occurring somatic mutations. It was recently shown that a common large deletion in the APOBEC3 cluster (the APOBEC3B deletion) may increase the risk of breast cancer. However, conflicting evidence regarding this association was also reported. In the first step of our study, using different approaches, including an in-house designed multiplex ligation-dependent probe amplification assay, we analyzed the structure of the deletion and showed that although the breakpoints are located in highly homologous regions, which may generate recurrent occurrence of similar but not identical deletions, there is no sign of deletion heterogeneity. This knowledge allowed us to distinguish transcripts of all affected genes, including the highly homologous canonical APOBEC3A and APOBEC3B, and the hybrid APOBEC3A/APOBEC3B gene. We unambiguously confirmed the presence of the hybrid transcript and showed that the APOBEC3B deletion negatively correlates with APOBEC3A and APOBEC3B expression and positively correlates with APOBEC3A/APOBEC3B expression, whose mRNA level is >10-fold and >1500-fold lower than the level of APOBEC3A and APOBEC3B, respectively. In the next step, we performed a large-scale association study in three different cohorts (2972 cases and 3682 controls) and showed no association of the deletion with breast cancer, familial breast cancer or ovarian cancer. Further, we conducted a meta-analysis that confirmed the lack of the association of the deletion with breast cancer in non-Asian populations.

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

“…This locus was shown to be significantly associated with breast cancer risk in different populations including those of Chinese, Iranian, and European ancestries [ 18 , 47 , 48 ]. It was demonstrated also that deletion in the APOBEC3 loci disrupting APOBEC3A and APOBEC3B genes lead to the decreased expression of the corresponding genes [ 66 , 67 ]. Moreover, the association between GSTT1 gene deletion and breast cancer risk has been widely studied and it was demonstrated that GSTT1 null genotype is associated with increased breast cancer risk [ 68 ] and also with significant downregulation of GSTT1 gene resulting in loss of protein expression [ 69 – 71 ].…”

The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: a long road ahead

“…A genome-wide association study in the Chinese population demonstrated the A3B deletion is associated with BRCA (odds ratio (OR) 1.3 one-copy, 1.8 two-copy deletion, p = 2.0 × 10 −24 ) [ 155 ], which was replicated in a European population (OR 1.2 one-copy, 2.3 two-copy deletion, p = 0.005) [ 156 ]. However, including familial BRCA for the first time, a later study showed a lack of association of the A3B deletion with BRCA risk, which was independently validated in three European cohorts (in total: 2972 cases and 3682 controls) [ 157 ]. This study provided direct evidence for the generation of the transcriptionally active hybrid gene A3A/A3B from the allele with the A3B deletion and confirmed the suggested structure of A3A/A3B transcript, which enabled A3A, A3B and A3A/A3B expression levels to be distinguished.…”

Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

“…A3H Hap I was identified to induce genomic mutations specifically in lung cancer 13 . Interestingly, the activity of A3H Hap I was found because researchers wanted to investigate how genomic mutations with a cytidine deaminase signature were still occurring in people with an A3B-/-deletion [51][52][53][54] , which occurs in the world population at 22.5%, although it primarily occurs in Oceanic populations 44 . Although A3A is also involved in cancer mutagenesis, it appears to be strongly associated with breast cancer 31,55 .…”