Abstract
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 < 5.0 × 10−8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value (“q-value”) <0.05 was used as a threshold to define “strong evidence” to support associations and 0.05 ≤ q-value < 0.20 to define “suggestive evidence”. A colocalisation posterior probability (PPH4) >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).
| Original language | English (US) |
|---|---|
| Article number | 104991 |
| Journal | EBioMedicine |
| Volume | 100 |
| DOIs | |
| State | Published - Feb 2024 |
Funding
MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation . Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184 , P30 CA076292 ), Florida Department of Health Bankhead-Coley Grant 09BN-13 , and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish Research Council ; K2015-55X-22674-01-4 , K2008-55X-20157-03-3 , K2006-72X-20157-01-2 and the Stockholm County Council (ALF project). ASTERISK: A Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire , the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). SMS and REACH: This work was supported by the National Cancer Institute (grant P01 CA074184 to J.D.P. and P.A.N., grants R01 CA097325 , R03 CA153323 , and K05 CA152715 to P.A.N., and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to A.N.B.-H.) NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research ( CRT 43821 ); the National Institutes of Health , U.S. Department of Health and Human Services ( U01 CA074783 ); and National Cancer Institute of Canada grants ( 18223 and 18226 ). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute , NIH , DHHS . Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200 , NIH U01 HG004446 , and NIH GEI U01 HG 004438 . Japan Public Health Center-based Prospective Study was supported by the National Cancer Center Research and Development Fund (23-A-31[toku], 26-A-2, 29-A-4, 2020-J-4) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). NSHDS investigators thank the Västerbotten Intervention Programme, the Northern Sweden MONICA study, the Biobank Research Unit at Umeå University and Biobanken Norr at Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council. IWHS: This study was supported by NIH grants CA107333 (R01 grant awarded to P.J. Limburg) and HHSN261201000032C (N01 contract awarded to the University of Iowa). CORSA: The CORSA study was funded by Austrian Research Funding Agency (FFG) BRIDGE (grant 829675 , to Andrea Gsur), the “ Herzfelder'sche Familienstiftung ” (grant to Andrea Gsur) and was supported by COST Action BM1206. HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1 ). MECC: This work was supported by the National Institutes of Health , U.S. Department of Health and Human Services ( R01 CA081488 , R01 CA197350 , U19 CA148107 , R01 CA242218 , and a generous gift from Daniel and Maryann Fong. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184 (Li/Ulrich), U01 CA206110 (Ulrich/Li/Siegel/Figueiredo/Colditz), 2P30CA015704-40 (Gilliland), R01 CA207371 (Ulrich/Li)), the Matthias Lackas-Foundation , the German Consortium for Translational Cancer Research , and the EU TRANSCAN initiative . MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria . The MCCS was further supported by Australian NHMRC grants 509348 , 209057 , 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. BMLynch was supported by MCRF18005 from the Victorian Cancer Agency . EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria / FEDER ( PI08/0024 , PI08/1276 , PS09/02368 , P111/00219 , PI11/00681 , PI14/00173 , PI14/00230 , PI17/00509 , 17/00878 , PI20/00113 , PI20/00226 , Acción Transversal de Cáncer), Xunta de Galicia ( PGIDIT07PXIB9101209PR ), Ministerio de Economia y Competitividad ( SAF07-64873 , SAF 2010-19273 , SAF2014-54453R ), Fundación Científica de la Asociación Española contra el Cáncer ( GCB13131592CAST ), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología) , Fundación Privada Olga Torres , FP7 CHIBCHA Consortium , Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135 , 2014SGR255 , 2017SGR21 , 2017SGR653 ), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya ), PERIS (SLT002/16/00398, Generalitat de Catalunya ), CERCA Programme ( Generalitat de Catalunya ) and COST Action BM1206 and CA17118 . CIBERehd is funded by the Instituto de Salud Carlos III . CLUE II: We thank the participants of Clue II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the Clue II Cohort Study. Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute , National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107 , R01 CA081488 , P30 CA014089 , R01 CA197350 ; P01 CA196569 ; R01 CA201407 ; R01 CA242218 ), National Institutes of Environmental Health Sciences , National Institutes of Health (grant number T32 ES013678 ) and a generous gift from Daniel and Maryann Fong. NCCCS I & II: We acknowledge funding support for this project from the National Institutes of Health , R01 CA066635 and P30 DK034987 . WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute , National Institutes of Health , U.S. Department of Health and Human Services through contracts HHSN268201100046C , HHSN268201100001C , HHSN268201100002C , HHSN268201100003C , HHSN268201100004C , and HHSN271201100004C . Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation ( CI-8 ); NCI R01CA136726 . Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation , and the Karolinska Institute 's Distinguished Professor Award to Alicja Wolk. EDRN: This work is funded and supported by the NCI , EDRN Grant ( U01-CA152753 ). COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds , including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and The Dutch Cancer Society ( UM 2012–5653 , UW 2013-5927 , UW2015-7946 ), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant ( 98-10030 ); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057 ; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award ( C588/A19167 ). CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III , co-funded by FEDER funds–a way to build Europe–(grants PI14-613 and PI09-1286 ), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723 ), Junta de Castilla y León (grant LE22A10-2 ), the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE and the Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), action Genrisk. Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology . We thank CERCA Programme, Generalitat de Catalunya for institutional support. Funding: JY is supported by a Cancer Research UK Population Research Postdoctoral Fellowship ( C68933/A28534 ). SJL, KKT and RMM are supported by Cancer Research UK ( C18281/A29019 ) programme grant (the Integrative Cancer Epidemiology Programme) ( https://www.cancerresearchuk.org/ ). KKT is also supported by Cancer Research UK ( PPRCPJT∖100005 ) and World Cancer Research Fund ( IIG_FULL_2020_022 ) grants. RMM is a National Institute for Health Research Senior Investigator ( NIHR202411 ). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR ( BRC-1215-20011 ) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. JWR, KB, and GDS are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council ( MC_UU_00011/1 , MC_UU_00011/3 , MC_UU_00011/6 , and MC_UU_00011/4 ) and the University of Bristol ( https://mrc.ukri.org/ ; https://www.bristol.ac.uk/ ). VK is funded by Academy of Finland Project 326291 and the European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause). NM is supported by The French National Cancer Institute (INCa SHSESP20, grant No. 2020-076 ). SSZ is supported by a National Institute for Health Research Clinical Lectureship and works in centres supported by Versus Arthritis (grant no. 21173 , 21754 and 21755 ). INTEGRAL-ILCCO is supported by a National Institutes of Health grant ( U19 CA203654 ) ( https://www.nih.gov/ ). The International Lung Cancer Consortium is supported by a National Cancer Institute grant ( U19CA203654 ) ( https://www.cancer.gov/ ). ESTHER/VERDI. This work was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid . Harvard cohorts: HPFS is supported by the National Institutes of Health ( P01 CA055075 , UM1 CA167552 , U01 CA167552 , R01 CA137178 , R01 CA151993 , and R35 CA197735 ), NHS by the National Institutes of Health ( P01 CA087969 , UM1 CA186107 , R01 CA137178 , R01 CA151993 , and R35 CA197735 ), and PHS by the National Institutes of Health ( R01 CA042182 ). SELECT: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10 CA037429 (CD Blanke), and UM1 CA182883 (CM Tangen/IM Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Czech Republic CCS: This work was supported by the Czech Science Foundation ( 21-04607X , 21-27902S ), by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV NU21-07-00247 and AZV NU21-03-00145 ), and Charles University Research Fund (Cooperation 43-Surgical disciplines). EPIC: The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer , Institut Gustave Roussy , Mutuelle Générale de l’Education Nationale , Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid , German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam- Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy , Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds , Dutch Prevention Funds , Dutch ZON (Zorg Onderzoek Nederland) , World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands) ; Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra , and the Catalan Institute of Oncology - ICO (Spain) ; Swedish Cancer Society , Swedish Research Council and Region Skåne and Region Västerbotten (Sweden) ; Cancer Research UK ( 14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council ( 1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford). (United Kingdom). The ATBC Study is supported by the Intramural Research Program of the U.S. National Cancer Institute , National Institutes of Health , Department of Health and Human Services . NSHDS: The research was supported by Biobank Sweden through funding from the Swedish Research Council ( VR 2017-00650 , VR 2017-01737 ), the Swedish Cancer Society ( CAN 2017/581 ), Region Västerbotten ( VLL-841671 , VLL-833291 ), Knut and Alice Wallenberg Foundation ( VLL-765961 ), and the Lion's Cancer Research Foundation (several grants) and Insamlingsstiftelsen , both at Umeå University . GECCO funding: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute , National Institutes of Health , U.S. Department of Health and Human Services ( R01 CA059045 , U01 CA164930 , R01 CA244588 , R01 CA201407 ). This research was funded in part through the NIH / NCI Cancer Center Support Grant P30 CA015704 . Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685 . DACHS: This work was supported by the German Research Council ( BR 1704/6-1 , BR 1704/6-3 , BR 1704/6-4 , CH 117/1-1 , HO 5117/2-1 , HE 5998/2-1 , KL 2354/3-1 , RO 2270/8-1 and BR 1704/17-1 ), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany , and the German Federal Ministry of Education and Research ( 01KH0404 , 01ER0814 , 01ER0815 , 01ER1505A and 01ER1505B ). CLUE II funding was from the National Cancer Institute ( U01 CA086308 , Early Detection Research Network; P30 CA006973 ), National Institute on Aging ( U01 AG018033 ), and the American Institute for Cancer Research . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Maryland Cancer Registry (MCR) Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund . The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333 , funded by the Centers for Disease Control and Prevention . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. CPS-II: The authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries and cancer registries supported by the National Cancer Institute's Surveillance Epidemiology and End Results Program. The authors assume full responsibility for all analyses and interpretation of results. The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society – Cancer Action Network. The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551 ). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The CCFR Set-1 (Illumina 1M/1M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143237 (to GC). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to SBG). The CCFR Set-4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG), and through generous support from the Ontario Ministry of Research and Innovation . The SFCCR Illumina HumanCytoSNP array was supported in part through NCI / NIH awards U01/U24 CA074794 and R01 CA076366 (to PAN). The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR.
Keywords
- Cancer
- Genetic epidemiology
- Inflammation
- Mendelian randomization
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
