The incidence of numerous multifactorial diseases, including skin cancer and inflammatory bowel diseases, has steadily increased worldwide over the past several decades (1-3). Previous studies have proposed an increased risk of both melanoma and non-melanoma skin cancers (NMSC) in patients with inflammatory bowel disease (IBD) (4-6). This association was previously considered to be a direct consequence of thiopurine therapy due to the increased generation of reactive oxygen species from 6-thioguanine (4,7). However, Lo et al (8) reported in their meta-analysis that patients with IBD demonstrate an increased risk of NMSC even when controlled for immunosuppressant use [Crohn's disease (CD) incidence rate ratio (IRR)=2.22; 95% confidence interval (CI): 1.41-3.48]; ulcerative colitis (UC) IRR=1.38; 95% CI: 1.12-1.71]. Genome-wide association studies (GWAS) have also identified numerous susceptibility loci associated with IBD, with some loci also implicated in cancer, but not skin cancer specifically (9). Although a clear biological explanation linking IBD with skin cancer has yet to be established, sustained cutaneous inflammation (10), immune suppression (11), and shared germline susceptibility are suspected to play a role (12).

While ultraviolet radiation (UVR)-induced mutagenesis remains to be the most well-established risk factor for skin cancer (13), emerging evidence suggests that neuro-immuno-endocrine mechanisms within the skin may contribute to skin cancer susceptibility (14-17). The neuro-immuno-endocrine functions of the skin involves a complex set of components and interactions spanning different organs, including the brain, gut and adrenal glands (14). Circulating immune cells, such as macrophages, lymphocytes and Langerhans cells, interact with cutaneous nerve fibers to modulate host defense, inflammation and tissue repair (18). Neuropeptides released from nerve terminals may further modulate the function of cutaneous immune cells, while immune-derived mediators can influence neuronal activity, contributing to sensations such as itch and pain (19). UVR-induced modulation of cytokines such as TNFα, IL-1 and IL-6 drive pathways such as the central HPA axis to generate immunosuppressive effects (20).

Vitamin D signaling, particularly through the vitamin D receptor (VDR), plays a significant role in melanoma progression and management (21,22). The VDR is a nuclear receptor activated by 1,25-dihydroxyvitamin D3 (calcitriol), which influences various cellular processes including proliferation, differentiation and immune responses. High VDR expression in melanoma cells is associated with improved outcomes and reduced melanoma-related mortality (22). This is partly due to the inhibition of the Wnt/β-catenin signaling pathway, which is known to promote melanoma progression (23). Despite increasing evidence unraveling the neuro-immuno-endocrine potential of the skin, current mechanisms remain to be poorly understood and are primarily derived from animal models and limited clinical studies.

Mendelian randomization (MR) is a powerful tool used to explore causal relationships between exposure traits and disease outcomes by utilizing genetic variants as proxies for the exposure of interest, thereby minimizing confounding and reverse causation (24). Over the past year, recent MR efforts for IBD and skin cancer have yielded mixed results, with some evidence to support causal effects for UC on NMSC in East Asian and European cohorts (25,26).

Given the growing availability of GWAS data and the need to clarify these associations, it was sought to determine whether there is a causal genetic relationship between IBD subtypes (CD and UC) and skin cancer (both melanoma and non-melanoma) using publicly available GWAS repositories. The present study aims to provide further insights into the potential shared genetic architecture between these conditions and to elucidate whether the observed associations are likely to be causal or a result of confounding factors.

Genetic associations for IBD and three major types of skin cancer [cutaneous melanoma (SKCM), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] were retrieved from FinnGen Release 8 (R8) and subjected to two-sample MR. There were a total of 371 significantly-associated variants for CD and 3,193 variants for UC available for MR. An overview for genetic instrument selection is shown in Fig. 1.

There were 26 significant SNPs associated with UC as an exposure post-harmonization (Fig. 2). Fixed-effect IVW regression showed significant causal effects for SKCM (beta=0.097, se=0.039, P=0.0138) and SCC (beta=0.171, se=0.054, P=0.0014), but not BCC (beta=0.056, se=0.030, P=0.0610) (Table SI). A causal association was also observed using MR-EGGER regression, although MR estimates were found to lack significance. Using Cochran's Q test, the presence of heterogeneity was observed for SKCM (Q=27.043, P=0.302), which was shown to increase for SCC (Q=51.914, P=8.03x10^-4) (Table I). Due to presence of heterogeneity, a random-effect IVW analysis was performed and showed a consistent association for SKCM (beta=0.0862, P=0.0157) and SCC (OR=0.174, P=6.57x10^-4). For SKCM, the MR-EGGER intercept test showed presence of directional pleiotropy (intercept=-0.0058, P<2.2x10^-16) with no outlier correction using MR-PRESSO. For SCC, there was also presence of directional pleiotropy (intercept=-0.068, P<2.2x10^-16) with outlier correction (OR=0.0392, P=0.102) showing no significant association.

Using CD as an exposure, only 5 significant SNPs were included post-harmonization for MR analysis. MR using IVW regression demonstrated no significant causal effects for SKCM (beta=0.003, se=0.059, P=0.955), BCC (beta=4.82x10^-4, se=2.54x10^-2, P=0.985), or SCC (beta=0.024, se=0.058, P=0.676). No heterogeneity was found using Cochran's Q test. Directional pleiotropy was again detected for SKCM (intercept=0.004, P=8.93x10^-3) and SCC (intercept=-0.054, P=3.62x10^-5), with no outlier correction using MR-PRESSO.

To test the reproducibility of causal effects observed for UC, GWAS summary statistics from Liu et al (9) and the UK Biobank (Fig. 1) were utilized for a secondary study. A total of 83 significant SNPs were found post-harmonization for SKCM, and 81 significant SNPs found for both BCC and SCC. MR analysis demonstrated suggestive or significant causal effects between UC and SCC (beta=0.065, se=0.031, P=0.036) and UC and BCC (beta=0.056, se=0.018, P=0.002), but not UC and SKCM (beta=0.020, se=0.026, P=0.432).

The current analysis indicates causal effects for UC on SCC, which is supported by a recent meta-GWAS East Asian and European ancestries (25). Secondary analysis using datasets from the UK Biobank replicated the significant associations for UC and SCC, providing additional evidence for this relationship using European cohorts. Utilization of the FinnGen R8 dataset in the present study offered a high prevalence of cases relative to total population compared with other publicly available datasets. Moreover, imputation with Finnish-specific panels has also been shown to demonstrate high accuracy for low-frequency variants (30). The influence of confounding bias was controlled for using strict selection of instrumental variables and a priori sensitivity analyses. Sensitivity testing showed moderate heterogeneity with possible pleiotropy for the UC and skin cancer associations. Ultimately, these findings suggest that select genetic variants may influence skin cancer through pathways unrelated to UC, although outlier correction was applied to account for the observed pleiotropy.

There are a few noteworthy observations from the 26 UC-associated SNPs used for MR (Table SII). First, rs3024493, proximal to interleukin 10 (IL-10), has been linked to the development of IBD in genetic studies (31,32). IL-10 is an important immunoregulator of mucosal immunity which acts by inhibiting proinflammatory cytokines (IL-1β, TNF-α and IL-6), Th2 cell-derived cytokines (IL-4 and IL-5), and chemokines (MIP-1α and interleukin-8), while increasing synthesis of several anti-inflammatory proteins (33). In patients with melanoma, rs3024493 has been linked with downregulation of IL-10 secretion in CD4⁺ T cells. Multivariate analyses have demonstrated decreased melanoma overall survival [hazard ratio (HR): 4.73; 95% CI: 1.68-13.29] for minor allele homozygotes (TT) compared with major allele homozygotes (GG), although interestingly show improved overall survival (HR: 0.58, 95% CI: 0.39-0.86) in heterozygotes (GT). Conversely, increased production of IL-10 in keratinocyte carcinomas has been hypothesized as a mechanism for evading local T cell-mediated immune responses (34). This may suggest that the regulatory function of IL-10 extends to skin immunity and cancer progression. Given that UV radiation modulates cytokine expression, including IL-10, it is plausible that chronic UV exposure may may provide a potential link between chronic inflammation and immune escape mechanisms in skin cancer (35).

More broadly, the IL-23/Th-17 axis for inflammation has been implicated in both IBD (36) and skin cancers (37,38). When bound to IL-23R (rs9988642), IL-23 activates JAK2 (rs7869668) to facilitate differentiation of naïve CD4+ T-cells into IL-17-secreting Th17 cells (Fig. 3). This differentiation process establishes a pro-inflammatory microenvironment which favors tumorigenesis. TL1A (rs4263839) interacts with DR3 to synergistically increase the production of IL-17 and other pro-inflammatory cytokine as observed in CD (39,40). IL-17 then acts to promote infiltration of myeloid-derived suppressor cells and activate the STAT3 signaling pathway, which has been canonically associated with increased tumor cell proliferation, survival, and angiogenesis (41-43). Together, these interactions collectively reinforce the IL-23/Th17 axis as a potential driver of inflammation-mediated tumorigenesis.

The skin and gut function as the two largest immune systems in the human body, each employing distinct yet overlapping biological mechanisms (44). Dysbiosis in the gut microbiota drives biological crosstalk in what is known as the skin-gut axis, in which cell trafficking between the skin and gut promotes frequent comorbidity of inflammatory diseases (45). Recent findings suggest that gut-derived metabolites (for example, short-chain fatty acids, bile acids and vitamins) influence skin barrier function (46-48), while skin-derived inflammatory mediators may exacerbate gut inflammation (49,50). Furthermore, immune cell trafficking between the gut and skin is increasingly recognized as a mechanism for disease spread (45). Aberrant migration of gut-educated T cells has been implicated in both cutaneous and gastrointestinal inflammation (51,52), even extending to other inflammatory diseases such as ankylosing spondylitis and primary sclerosing cholangitis (52,53).

While gut and skin leukocytes are typically directed to their respective tissues, the presence of inflammation may alter homing patterns. For instance, intestinal T cells may acquire skin-homing characteristics during chronic gut inflammation, leading to secondary cutaneous disease (54). Conversely, skin-resident memory T cells may enter circulation and contribute to systemic inflammation, as observed in graft-vs.-host disease (55). These insights also have therapeutic implications for modulating gut-skin immune cell trafficking. For example, the use of vedolizumab, a gut-selective integrin blocker used in IBD, has been hypothesized to modulate binding of α₄β₇-MAdCAM1 for gut access and subsequent skin entry (56).

The present study has several important limitations. First, the limited number of CD cases (1,531 in FinnGen R8) resulted in the identification of only five genome-wide significant SNPs available for MR analysis post-harmonization. This small number of instruments significantly weakened the strength of the genetic proxies for CD, therefore increasing the likelihood of weak instrument bias. As a result, no significant causal associations were observed between CD and skin cancer outcomes in our MR analyses. Additionally, while the use of Finnish-specific GWAS data enhances variant detection, the findings may not be fully generalizable to other populations with more diverse genetic backgrounds. Finally, the presence of pleiotropy, as suggested by the MR-EGGER intercept tests, indicates that some genetic variants might influence skin cancer risk through mechanisms that are independent of IBD.

Overall, the present study demonstrates a causal genetic association between UC and SCC in European cohorts distinct from biologic-induced skin cancer in previous literature. The demonstrated genetic associations may provide meaningful implications for clinical practice, particularly in terms of risk stratification, preventative counseling and surveillance strategies for patients with IBD. While UV exposure remains the predominant risk factor for SCC, IBD-related immune dysregulation may create a permissive environment for carcinogenesis. Patients with UC, particularly those with longstanding disease, may benefit from personalized preventative strategies, including education on sun safety, regular dermatologic screenings, and early intervention measures. Further investigation of the IL-23/Th17 axis in UC-associated SCC may elucidate underlying disease mechanisms and inform the development of new targeted therapeutic strategies.