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Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer

  • Authors:
    • Sarem Rashid
    • Dmitrii Usoltsev
    • Sameer Gupta
    • Mykyta Artomov
    • Hensin Tsao
  • View Affiliations / Copyright

    Affiliations: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, 02114 MA, USA, Broad Institute, Cambridge, 02142 MA, USA, Massachusetts Eye and Ear, Boston, 02114 MA, USA
    Copyright: © Rashid et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 83
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    Published online on: July 10, 2025
       https://doi.org/10.3892/mco.2025.2878
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Abstract

Limited and conflicting data have been available regarding the association between inflammatory bowel disease and skin cancer. It was hypothesized that inflammatory bowel diseases [Crohn's disease (CD) and ulcerative colitis (UC)] harbor a genetically increased risk of skin cancer [skin cutaneous melanoma (SKCM), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and performed two‑sample mendelian randomization (MR) analysis using genome‑wide association (GWAS) studies of European ancestry retrieved from FinnGen R8. The inverse variance weighted method was used to approximate MR effects. Sensitivity analyses including weighted median, MR‑Egger and MR‑pleiotropy residual sum and outlier were performed to estimate pleiotropy and heterogeneity a priori. MR results suggest a significant causal association between UC and SKCM, (beta=0.097, P=0.0138) and UC and SCC (beta=0.171, P=0.0014). These findings were then validated using summary‑level GWAS from the UK Biobank and an independent meta‑analysis which demonstrated a suggestive or causal genetic association between UC and SCC (beta=0.065, P=0.036), UC and BCC (beta=0.056, P=0.002), but not UC and SKCM (beta=0.02, P=0.432). Due to limited sample size for CD instruments, only 5 significant single nucleotide polymorphisms were found with no significant causal effects on skin cancer. These results provide evidence for a causal genetic association between UC and skin cancer through shared polymorphisms involving the IL‑23/Th17 axis, which may inform preventative counseling and precision medicine in the future.
View Figures

Figure 1

Flowchart of data collection,
processing and analysis for the present study. The primary study
was conducted using IVs selected from FinnGen R8, whereas the
secondary study was conducted using IVs sourced from a 2015
meta-analysis (9) and UKBB for
exposure and outcome IVs, respectively. IVs, instrumental
variables; SKCM, skin cutaneous melanoma; BCC, basal cell
carcinoma; SCC, squamous cell carcinoma; GWAS, genome-wide
association studies; MR, mendelian randomization; IVW, inverse
variance weighted.

Figure 2

Forest plot of two-sample MR analysis
for inflammatory bowel disease (CD and UC) and skin cancer (SKCM,
BCC and SCC) using fixed-effect IVW regression. Primary study (1°)
instrument variables are derived from FinnGen R8. Secondary study
(2°) instrument variables are sourced from Liu et al
(9) and the UK Biobank for
exposure and outcome, respectively. Black squares represent the
effect size (β) estimates for each association and error bars
indicate standard error. MD, mendelian randomization; CD, Crohn's
disease; UC, ulcerative colitis; SKCM, skin cutaneous melanoma;
BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

Figure 3

IL-23 promotes the differentiation of
naïve CD4+ T cells into IL-17-producing Th17 cells
through the TYK2-JAK2 signaling pathway, influenced by genetic
variants rs9888642 and rs78696968. Th17 cells secrete IL-17,
contributing to inflammatory responses. Similarly, IL-12 drives Th1
differentiation, leading to TNF-α and IFN-γ production, with
rs4263839 in TNFSF15/TL1A associated with Th1 regulation. IL-4
induces Th2 differentiation, promoting IL-10 secretion, with
rs3024403 linked to this pathway. Figure created using BioRender
(https://www.biorender.com/).
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Spandidos Publications style
Rashid S, Usoltsev D, Gupta S, Artomov M and Tsao H: Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer. Mol Clin Oncol 23: 83, 2025.
APA
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., & Tsao, H. (2025). Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer. Molecular and Clinical Oncology, 23, 83. https://doi.org/10.3892/mco.2025.2878
MLA
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., Tsao, H."Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer". Molecular and Clinical Oncology 23.3 (2025): 83.
Chicago
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., Tsao, H."Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer". Molecular and Clinical Oncology 23, no. 3 (2025): 83. https://doi.org/10.3892/mco.2025.2878
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Spandidos Publications style
Rashid S, Usoltsev D, Gupta S, Artomov M and Tsao H: Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer. Mol Clin Oncol 23: 83, 2025.
APA
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., & Tsao, H. (2025). Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer. Molecular and Clinical Oncology, 23, 83. https://doi.org/10.3892/mco.2025.2878
MLA
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., Tsao, H."Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer". Molecular and Clinical Oncology 23.3 (2025): 83.
Chicago
Rashid, S., Usoltsev, D., Gupta, S., Artomov, M., Tsao, H."Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin cancer". Molecular and Clinical Oncology 23, no. 3 (2025): 83. https://doi.org/10.3892/mco.2025.2878
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