Association of APOBEC3A/B deletion variant with endometrial cancer risk in Norwegian population: A case-control study (242)

Abstract

<b>Objectives:</b> APOBEC3 family of proteins play important roles in intrinsic responses to viral infection by introducing mutations into the viral nucleic acids. APOBEC3 activity targeting the host cell's DNA may lead to mutations contributing to tumorigenesis. Uterine cancers are found to be linked with three APOBEC associated signatures; single-base substitution signatures 2 and -13 and double-base substitution signature 11. A germline deletion of 30Kb in chromosome 22 affecting the APOBEC3A and -B genes leads to the formation of a hybrid transcript, APOBEC3A/B, found to be more stable than the wild-type APOBEC3A and causes more DNA damage through higher protein levels. To the best of our knowledge, the potential association between the APOBEC3A/B deletion variant and the risk of endometrial cancer has not yet been assessed. This study aimed to evaluate the APOBEC3A/B deletion as a potential risk modulating factor for endometrial cancer. <b>Methods:</b> DNA extracted from blood samples of Norwegian (Caucasian) women diagnosed with primary uterine adenocarcinoma (<i>n</i>=1,470), and healthy controls (<i>n</i>=1,918) were screened for germline APOBEC3A/B deletion variant using quantitative polymerase chain reaction high-resolution melting (qPCR-HMR) curves. For technical validation, 35.4% of cases were genotyped for SNP rs12628403 (Chr 22:38962032), an SNP in proximity to the APOBEC3A/B-deletion start point that is found in strong linkage disequilibrium with the deletion allele. The potential difference in results from APOBEC3A/B deletion and rs12628403-analyses were considered negligible due to a very low recombination rate of 5.8x10-3. <b>Results:</b> Cases and controls were in Hardy-Weinberg equilibrium for genotype distribution (p=0.78 and p>0.4, with a MAF of 0.072 and 0.094, respectively). Our study cohort showed a reduced risk of endometrial cancer in dominant and allele models (OR: 0.75, 95 % CI: 0.62-0.91, p=0.003 and OR: 0.75, 95 % CI: 0.63-0.90, p=0.0002, respectively). In a subgroup analysis by histology, endometrioid endometrial cancer showed similar patterns (dominant model: OR: 0.64, 95% CI: 0.51-0.79, p=0.1x10-3 and allele model: OR: 0.64, 95% CI: 0.52-0.79, p=0.1x10-3). No clear risk association was observed in non-endometrioid endometrial cancer subtype. Among age subgroups generated with a 10-year cut-off, dominant and allele models yielded a significantly reduced cancer risk in individuals in the age range 50-59 (OR: 0.51, 95% CI: 0.33-0.78, p=0.002 and OR: 0.54, 95% CI: 0.35-0.81, p=0.002, respectively) and 60-69 (OR = 0.62, 95% CI=0.43-0.88, p=0.8x10-3 and OR=0.62, CI=0.44-0.88, p=0.005, respectively). <b>Conclusions:</b> APOBEC3A/B deletion variant is associated with reduced endometrial cancer risk in Norwegian women.