Inflammatory Cytokine Genotypic Markers and Ovarian Cancer Risk

Ovarian cancer is the most lethal gynecological malignancy worldwide, largely due to late diagnosis and lack of effective population-level screening tools. Inflammatory cytokines regulate proliferation, apoptosis, angiogenesis, and immune surveillance, making inherited variation in cytokine pathways biologically plausible determinants of ovarian cancer susceptibility and progression. Since the early 2000s, numerous candidate-gene studies have evaluated polymorphisms of genes such as the interleukin (IL) families, tumor necrosis factor alpha (TNFA), transforming growth factor beta 1 (TGFB1), and components of the nuclear factor kappa B (NFKB) signaling pathway and adhesion pathways, across diverse populations. In this review, we summarize these potential markers to give readers an overview showing accumulated evidence supports a coherent model in which genetically modulated inflammation is an integral driver of epithelial ovarian carcinogenesis. Collectively, studies reveal recurrent patterns of risk-increasing and risk-protective variants. Risky genotypes predicted to enhance pro-inflammatory, pro-angiogenic, or immunosuppressive signaling include IL1B rs16944 CC, IL6 rs1800795, IL8 rs2227306 TT, IL8 rs1126647 TT, IL16 rs11556218 GT/GG, IL16 rs4778889 CT/CC, IL23R rs10889677 AC/CC, IL31 rs4758680 CA/AA, IL32 rs28372698 TT, TNFA rs1800629 GA/AA, and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 CG genotypes. Conversely, protective variants tend to dampen inflammatory tone or rebalance cytokine networks, including IL1A rs17561 GT/TT, IL1A rs4848300 CT/CC, IL1A rs3783553 insertion/insertion, IL1B rs7596684 CT/CC, IL6 rs1880242 GT/TT, IL31 rs7977932 CG/GG, TGFB1 rs1800469 CT/TT, selectin E (SELE) rs5361 AC, intercellular adhesion molecule 1 (ICAM1) rs5498 AG genotypes and specific IL6 haplotypes. Beyond risk per se, several polymorphisms appear predictive of clinical features, including tumor stage, cytoreductive resectability and recurrence, highlighting potential prognostic relevance. Notably, associations are often population-specific, reflecting differences in allelic frequencies and linkage disequilibrium across ethnic groups, underscoring the need for cross-ethnic replication. Further investigations may ultimately enable further improved the prevention, early detection, and personalized management of ovarian cancer.