Common genetic variation in the APOE gene and risk of cancer: a systematic review and meta-analysis

BACKGROUND AND AIMS: Already decades ago, apolipoprotein E (apoE) was suggested to be implemented in risk of cancer. The aim was to investigate the current evidence on the association between APOE ε2/ε3/ε4 carrier status and risk of cancer.

METHODS: This systematic review and meta-analysis performed per PRISMA guidelines included a search of PubMed and Embase (PROSPERO CRD42024498793). Studies had to report APOE ε2/ε3/ε4 genotype/allele status, and ε33, non-ε4 or non-ε2 served as reference groups.

RESULTS: Of 3189 screened records, we included 38 studies in the meta-analysis. For all cancer the risk increased from ε2 to ε3 to ε4 (P for trend: p = 0.01). For breast cancer ε4 was the risk allele (p = 0.03). The risk for colorectal cancer increased from ε2 to ε3 to ε4 (p for trend: p = 0.02). The Odds Ratio (OR) (95 % confidence interval (CI)) for colorectal cancer was 1.07 (1.00-1.13) for ε43 vs. ε33. For lung cancer the OR was 1.52 (1.04-2.2) for ε22 vs. ε33, and 2.80 (1.38-5.69) for ε4 vs. non-ε4. For the analyses for larynx and pharynx cancer, the OR was 0.72 (0.54-0.95) for ε2 vs. non-ε2.

CONCLUSIONS: APOE ε2/ε3/ε4 genotype does not constitute a major risk factor for cancer. Effect sizes were overall small, and we did not find a clear pattern appearing throughout all cancer types with none of the comparisons (for individual alleles/genotypes) statistically significant for risk of all cancer. The study cannot exclude small but biologically interesting allele and genotype specific patterns for some cancer types with ε4 posing to be a risk factor and ε2 a protective factor.