Search

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Abstract Introduction Prostate cancer (PCa) is by far the most common type of cancer among men in western countries. However, relatively little is known about its etiology despite the high morbidity and mortality. It has been suggested that chronic inflammation may be involved in prostate carcinogenesis. We investigated the role of sexually and non‐sexually transmitted infections in prostate cancer risk with a specific interest in the aggressive types. Methods We used data from epidemiological study of prostate cancer (EPICAP), a population‐based case–control study. A total of 819 incident cases and 879 controls were interviewed face‐to‐face using a standardized questionnaire gathering information on known or suspected risk factors of prostate cancer and personal history of specific sexually and non‐sexually transmitted infections: gonorrhea, syphilis, trichomonas, herpes, mononucleosis, Epstein–Barr virus, varicella‐zoster, and dengue. Odds ratios (OR) and their 95% confidence interval were estimated using multivariate unconditional logistic regression. Results There was no significant association between gonorrhea (OR: 0.90, 95% CI: 0.61–1.33), trichomonas (OR: 0.74, 95% CI: 0.27–2.07), genital herpes (OR: 0.69, 95% CI: 0.38–1.27), and the risk of prostate cancer. No association emerged for overall sexually transmitted bacterial and viral infections (OR 1.05, 95% CI: 0.86–1.29) and overall non‐sexually transmitted viral infections (OR 1.11, 95% CI: 0.90–1.35) and the risk of prostate cancer. Conclusion Our results showed that sexually or non‐sexually transmitted infections, either bacterial or viral, were not associated to prostate cancer. Therefore, further investigation is needed to help advance our understanding of the role of chronic inflammation in the etiology of prostate cancer, with a particular focus on its most aggressive types.