Identification of Causal Risk Factors for Pan-Cancers: a Mendelian Randomization Study

Abstract Background: Evidence from observational studies and clinical trials suggests an association between plasma protein and metabolite levels and cancers. However, the causal relationship between them is still unclear. Methods: We collected genome–wide association study (GWAS) summary statistics of plasma protein levels from the UK Biobank Pharma Proteomics Project (UKB–PPP, 9,216 to 34,090 participants) and plasma metabolites from the GWAS Catalog (3,441 to 8,299 participants), paired with summary statistics of 99 types of cancers from FinnGen database (131,348 to 412,181 participants). We conducted univariable and multivariable Mendelian randomization (MR) analyses to explore the causal association between plasma protein and metabolites and cancers. Results: We identified 175 plasma proteins and 28 metabolites causally associated with cancers (p < 1 × 10 − 5). Notably, BTN2A1 is causally associated with an increased risk of bone and articular cartilage cancer (OR = 1.776, 95% CI = 1.429 – 2.207), colorectal cancer (OR = 1.200, 95% CI = 1.129 – 1.275), eye and adnexa cancer (OR = 2.686, 95% CI = 1.943 – 3.714), lip cancer (OR = 3.004, 95% CI = 2.193 – 4.114), oral cancer (OR = 1.905, 95% CI = 1.577 – 2.302), ovary cancer (OR = 1.265, 95% CI = 1.143 – 1.400), and rectum cancer (OR = 1.393, 95% CI = 1.263 – 1.536). N6–carbamoylthreonyladenosine level is causally associated with various cancers including colorectal cancer (OR = 1.800, 95% CI = 1.444 – 2.243), head and neck cancer (OR = 2.423, 95% CI = 1.665 – 3.525), hepatocellular carcinoma (OR = 6.476, 95% CI = 2.841 – 14.762), oral cancer and skin cancer (OR = 1.271, 95% CI = 1.161 – 1.392). Additionally, all results are available at the online database: www.causal–risk.net. Conclusions: Our MR analysis reveals causal risk factors for cancers. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is performed using published studies and publicly available summary statistics. All original studies have been approved by the corresponding ethical review board. The participants have provided informed consent. Therefore, no new ethical review board approval was required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The plasma protein GWAS summary statistics were downloaded from the UKB-PPP website (https://www.synapse.org/#!Synapse:syn51365301). The plasma metabolite GWAS summary statistics were downloaded from the GWAS Catalog website (https://www.ebi.ac.uk/gwas/). The GWAS summary statistics from FinnGen were downloaded following the instruction on its website (https://www.finngen.fi/en/access_results).