Prospective Mendelian Randomization Study of Ancestry-Specific Blood-Cell Genetics in Predicting Pan-Cancer Risk Across 28 Malignant Neoplasms

Background: Research on the link between hematological characteristics and cancer risk has gained significant attention. Traditional epidemiological and cell biology studies, have identified correlations between blood traits and cancer risks. These findings are important as they suggest potential risk factors and biological mechanisms. However, these studies often can't confirm causality, pointing to the need for further investigation to understand these relationships better. Methods: Mendelian randomization (MR), utilizing single-nucleotide polymorphisms as instrumental variables, was employed to investigate hematological trait causal effects on cancer risk. Thirty-six hematological traits were analyzed, and their impact on 28 major cancer outcomes was assessed using data from the FinnGen cohort, with eight major cancer outcomes and 97 cancer subsets. Furthermore, 1,008 MR analyses were conducted, incorporating sensitivity analyses (weighted median, MR-Egger, and MR-PRESSO) to address potential pleiotropy and heterogeneity. Findings: The analysis (data from 173,480 individuals primarily of European descent) revealed significant results. A decrease in eosinophil count was associated with a reduced risk of colorectal malignancies (OR 0.7702, 95% CI 0.6852, 0.8658; p = 1.22E-05). Similarly, an increase in total eosinophil and basophil count was linked to a decreased risk of colorectal malignancies (OR 0.7798, 95% CI 0.6904, 0.8808;p = 6.30E-05). Elevated hematocrit (HCT) levels were associated with a reduced risk of ovarian cancer (OR 0.5857, 95% CI 0.4443, 0.7721;p =1.47E-04). No significant heterogeneity or horizontal pleiotropy was observed. Interpretation: Specific hematological traits may serve as valuable indicators and biomarkers for cancer monitoring. Funding: None. ### 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: The hematological features are sourced from the GWAS database (https://www.ebi.ac.uk/gwas/). Cancer data is sourced from FinnGen, available at https://www.finngen.fi/en. Colorectal cancer data is from GECCO, CORECT, CCFR, and UK Biobank. Details can be found at https://www.ebi.ac.uk/gwas/studies/GCST90255675. Renal cell cancer data is provided by IARC, NCI, UT MD Anderson Cancer, and ICR, UK. Details are available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study\_id=phs001736.v2.p1. Ovarian cancer data is from the Ovarian Cancer Association Consortium. Details can be found at https://www.ebi.ac.uk/gwas/studies/GCST004415. Prostate cancer data is provided by PRACTICAL. Details are available at http://practical.icr.ac.uk/blog/?page\_id=8164. Gastric cancer data is from Biobank Japan. Details can be found at https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90018849/. Oral cavity cancer data is provided by INHANCE, EPIC, and HN5000. Details are available at https://www.ebi.ac.uk/gwas/studies/GCST012237. Oropharynx cancer data is also provided by INHANCE, EPIC, and HN5000. Details can be found at https://www.ebi.ac.uk/gwas/studies/GCST012241. 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 All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript All data produced are available online at