K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, 5021, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Sci Rep. 2021 Dec 6;11(1):23463. doi: 10.1038/s41598-021-02820-z.
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).
种系 29.5kb 缺失变体去除 APOBEC3A 基因的 3'末端和 APOBEC3B 的大部分，形成一种杂合基因，与人类癌症中 APOBEC3 活性和 DNA 损伤增加有关。我们对 1398 名挪威上皮性卵巢癌患者的基于医院的样本进行了 APOBEC3A/B 缺失的基因分型，这些患者没有检测到 BRCA1/2 种系突变，并与 1918 名健康女性对照进行了比较，以评估该缺失与癌症风险之间的潜在关联。我们发现，APOBEC3A/B 状态与卵巢癌风险降低之间存在关联（OR=0.75；95%CI=0.61-0.91；p=0.003，采用显性模型）。在其他模型中也发现了类似的结果。这种关联在非浆液性和浆液性病例中都有观察到（显性模型：OR=0.69；95%CI=0.50-0.95；p=0.018 和 OR=0.77；95%CI=0.62-0.96；p=0.019），以及高级别浆液性病例中（显性模型：OR=0.79；95%CI=0.59-1.05）。为了验证目的，我们挖掘了一个可用的大型多国基于 GWAS 的数据集，该数据集包含了超过 18000 例病例和超过 26000 例对照，用于 SNP rs12628403 的分析，该 SNP 已知与 APOBEC3A/B 缺失呈连锁不平衡。我们发现，SNP rs12628403 与卵巢癌总体风险降低呈非显著趋势，所有亚型均呈类似趋势。对于透明细胞癌，风险降低达到显著水平（OR=0.85；95%CI=0.69-1.00）。
