Abstract
A germline 29.5-kb deletion variant removes the 3’ end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61–0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50–0.95; p = 0.018 and OR = 0.77; CI = 0.62–0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59–1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69–1.00).
Highlights
Epithelial ovarian cancer (OC) is the third most common gynaecologic cancer and accounts for an estimated 300,000 new cases and roughly 185,000 deaths each year w orldwide[1]
For the sample of 1918 healthy female controls, we have previously reported the genotype distribution of the deletion to be in Hardy–Weinberg equilibrium (p values > 0.4), and a minor allele frequency (MAF) of 0.09427
Applying the dominant model for the minor allele (APOBEC3A/B genotypes del/del + ins/del versus ins/ins), we observed a significant association between APOBEC3A/B status and a reduced risk for OC (OR = 0.75; confidence intervals (CIs) = 0.61–0.91; p = 0.003; Table 1, Fig. 1a)
Summary
Epithelial ovarian cancer (OC) is the third most common gynaecologic cancer and accounts for an estimated 300,000 new cases and roughly 185,000 deaths each year w orldwide[1]. As a result of this, a growing number of studies have started to link the apolipoprotein B mRNA editing enzyme catalytic-polypeptide-like (APOBEC) family of cytidine deaminases to specific innate enzymatic mutational processes in human cancers[7,10,11,12,13]. A common germline deletion of 29.5-kb in the APOBEC3 genes removes the 3′ end of the APOBEC3A gene and a large part of APOBEC3B. This deletion creates a hybrid gene transcribing an mRNA containing the. The APOBEC3A/B deletion variant has been linked to hypermutator phenotypes and the presence of ABOPEC-related mutational signatures in breast c ancer[11,22]. The APOBEC3A/B deletion variant is more common among individuals of Asian ancestry compared to European ancestry, with a minor allele frequency of 37% and 6% r espectively[20]
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