Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis

Abstract

Background: People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. Methods: We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers. Results: We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship. Conclusions: These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.

Competing Interest Statement

Robert C Grant is an Advisory or Honoraria for Astrazeneca, Eisai and Knight Therapeutics and is in receipt of a Graduate Scholarship from Pfizer. No other conflicts of interest declared.

Funding Statement

This work was supported by the Wellcome Trust [grant number 225541/Z/22/Z (GW4 Clinical Academic Training Programme for Health Professionals) to NC] and Cancer Research UK [grant number C18281/A29019 to RL and PH]. JM was supported by the US National Cancer Institute [grant number 5U01CA257679-02]. D-A.T was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence (IdEX) Full funding acknowledgements for all contributing GWAS can be found in the source publications. For the colorectal cancer GWAS: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) was funded by: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (R01 CA059045, U01 CA164930, R01 201407, R01 CA244588) and in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685. Colon CFR was funded by NCI/NIH award U01 CA167551. For acknowledgements and funding of specific contributing studies please see full funding and acknowledgements. The breast cancer genome-wide association analyses for BCAC and CIMBA were supported by Cancer Research UK (PPRPGM-Nov20\100002, C1287/A10118, C1287/A16563, C1287/A10710, C12292/A20861, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565) and the Gray Foundation, The National Institutes of Health (CA128978, X01HG007492- the DRIVE consortium), the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec and the PSRSIIRI-701 grant, the Quebec Breast Cancer Foundation, the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), the European Union's Horizon 2020 Research and Innovation Programme (634935 and 633784), the Post-Cancer GWAS initiative (U19 CA148537, CA148065 and CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. All studies and funders are listed in Zhang H et al (Nat Genet, 2020). The International Lung Cancer Consortium (ILCCO) was supported by grant U19 CA203654 Funding for the kidney cancer GWAS was provided by the US National Institutes of Health (NIH), National Cancer Institute (U01CA155309) for those studies coordinated by IARC and by the intramural research program of the National Cancer Institute, US NIH, for those studies coordinated by the NCI. For the melanoma GWAS: The MelaNostrum Consortium was funded by the intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics and by the participating institutes in Italy, Spain, and Greece. The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project Grant (C8216/A6129) and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by the intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, and by grants from the National Health and Medical Research Council (NHMRC) of Australia. For acknowledgements and funding of specific contributing studies please see the source publication <Landi 2020>

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 analysis used GWAS summary data only based on analyses of results from previous studies (no individual level data). Approval was obtained by the original GWAS studies by their appropriate ethics review boards: see details in the source GWAS publications (cited in the main text).

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

Data Availability

R scripts used for the analysis are available via GitHub [https://github.com/NaomiC-0/Mendelian-randomisation-analysis-of-VTE-and-Cancer]. Harmonised summary data for all SNPs included in this analysis are available in the Supplementary File. Full summary statistics are publicly available via: the Open GWAS database [https://gwas.mrcieu.ac.uk] for ovarian cancer (accession number: ieu-a-1120) and prostate cancer (accession number: ieu-b-85); the European Bioinformatics Institute GWAS Catalogue [https://www.ebi.ac.uk/gwas] for endometrial cancer (accession number: GCST006464), lung cancer (accession number: GCST004748) and oesophageal cancer (accession number: GCST003739); and the Breast Cancer Association Consortium [bcac.ccge.medschl.cam.ac.uk] for breast cancer. PanScan and PanC4 GWAS data are available through dbGAP (accession numbers phs000206.v5.p3 and phs000648.v1.p1, respectively). Application to the relevant GWAS consortium is required for full summary statistics for the remaining phenotypes.

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