Journal Article

DKFZ-2025-00215

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator.

Lee, M. A. ; Hatcher, C. A. ; Hazelwood, E. ; Goudswaard, L. J. ; Tsilidis, K. K. ; Vincent, E. E. ; Martin, R. M. ; Smith-Byrne, K. ; Brenner, H.DKFZ* ; Cheng, I. ; Kweon, S.-S. ; Le Marchand, L. ; Newcomb, P. A. ; Schoen, R. E. ; Peters, U. ; Gunter, M. J. ; Van Guelpen, B. ; Murphy, N.

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/ije/dyae175

Abstract: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated-suggestive of a potential mediating role-most strongly for the BMI-overall CRC association in women.Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.

Keyword(s): Humans (MeSH) ; Adiposity: genetics (MeSH) ; Colorectal Neoplasms: genetics (MeSH) ; Colorectal Neoplasms: epidemiology (MeSH) ; Body Mass Index (MeSH) ; Female (MeSH) ; Male (MeSH) ; Mendelian Randomization Analysis (MeSH) ; Waist-Hip Ratio (MeSH) ; Risk Factors (MeSH) ; Intercellular Signaling Peptides and Proteins: genetics (MeSH) ; Obesity: genetics (MeSH) ; Proteomics (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Mendelian randomization ; adiposity ; colocalization ; colorectal cancer ; proteome ; GREM1 protein, human ; Intercellular Signaling Peptides and Proteins

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. Primäre Krebsprävention (C120)
3. DKTK HD zentral (HD01)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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