Crohn’s disease (CD) and ulcerative colitis (UC) are the main subtypes of inflammatory bowel disease (IBD), which are chronic inflammatory disorders that primarily affect the gastrointestinal tract (1–3). It is characterized by periods of remission and flare-ups, leading to impaired quality of life for patients and substantial costs for health care (4, 5).

The risk of intestinal cancer in CD and UC has been analyzed deeply (6, 7), but the potential association of CD and UC with extraintestinal cancer has received relatively little attention. However, extraintestinal manifestations are observed in up to 35% of IBD patients (8, 9), highlighting the importance of studying the risk of extraintestinal cancer in this population.

Several observational studies have shown that IBD patients were positively associated with the risk of extraintestinal cancer. A meta-analysis of population-based cohort studies, involving 17,052 IBD patients, indicated that CD patients exhibited increased risks of cancer in the upper gastrointestinal tract, lung, and skin, while UC patients had a higher risk of liver-biliary cancer (10). Another meta-analysis suggested a significant association between IBD, especially UC, and an increased risk of cervical cancer (11). Moreover, a 20-year prospective follow-up study in Norway has reported an increased incidence of breast cancer in patients with CD and UC (12). Results from some cohort and case-control studies have reported an elevated risk of pancreatic cancer and skin cancer in patients with IBD (13–15). However, there are currently no specific guidelines for extraintestinal cancer screening or surveillance in patients with CD and UC. Additionally, it is not easy to assess the real risk and causality of extraintestinal cancer in CD and UC due to the residual confounding commonly encountered in traditional observational studies.

Mendelian randomization (MR) is a new method of etiological investigation that uses genetic variations closely linked to a particular exposure as instrumental variables (IVs) (16). This approach can avoid the limitations of traditional epidemiological studies and permit us to draw causal inferences about the impact of specific exposures on outcomes (17). Because alleles follow the principle of random allocation during gametogenesis, the offspring have random genetic variations; thus, the results are not affected by confounding factors or reverse causation (18, 19).

Our study aimed to appraise causal associations of CD and UC with extraintestinal cancers through MR analysis. Furthermore, we tried to analyze the differences between European and East Asian ethnic groups. Significantly, our findings have the potential to inform more effective and targeted cancer surveillance programs for patients with CD and UC, facilitating early cancer detection and alleviating the burden on healthcare systems.

There is evidence from many studies that patients with CD and UC are at an increased risk of developing intestinal cancer (6, 7, 44, 45). Interestingly, a growing body of research evidence indicates that these patients are at significantly elevated risk of extraintestinal cancers (46). Our MR study may provide some new evidence on the extraintestinal cancer risk in patients with CD and UC.

During analyses of causal effects between CD and extraintestinal cancers, we discovered that the incidence of pancreatic cancer in patients with CD is 1.10 times higher in the European population and 1.19 times higher in the East Asian population compared to individuals without CD. Similarly, Yu’s MR study showed a causal effect between CD and pancreatic cancer risk (OR: 1.111; 95% CI: 1.015-1.213) in Europeans (47). Two studies, one involving Scandinavians and the other Koreans, also consistently reported that CD increases the risk of pancreatic cancer (48, 49). A previous study found that IL-18 played a key role in the pathogenesis of both CD and pancreatic cancer through a common pathogenic pathway, affecting the immune response and tumor microenvironment by activating immune cells (50). As for breast cancer, our MR analysis showed that the risk was slightly increased in CD patients in Europe (OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015). Pellino et al. reported that CD was an independent risk factor for developing breast cancer (OR: 2.76; 95% CI: 1.2-6.2; P=0.017) (51). Existing studies indicated that CD and breast cancer may share common molecular mechanisms (52–54). However, we found that the risk of breast cancer was reduced by 5.48% in CD patients (OR: 0.9452; 95% CI: 0.9096-0.9822) in East Asia. Although previous cohort studies have shown a decreased risk of breast cancer in patients with CD (55, 56), future research is needed to explore the underlying mechanisms that influence cancer risk variation across diverse populations. The genetic profiles of CD patients may differ between European and East Asian populations, leading to varied susceptibility to developing breast cancer.

In our MR study, the effect size of CD on the risk of breast cancer in Europeans was relatively small (OR=1.0208), suggesting that the elevated risk is just modest. Furthermore, in East Asians, the risk of breast cancer may even be reduced. Therefore, it is not recommended for CD patients to conduct earlier or more frequent breast cancer screening compared to the general screening programs currently in place.

In addition, the result from the IVW method indicated a potential association between CD and skin cancer in the European population (OR: 1.0267; 95% CI: 1.0062-1.0476). The pathogenesis of the enhanced risk of skin cancer in CD is poorly understood and may be associated with underlying immune dysfunction in CD patients, leading to altered tumor surveillance (14, 57). However, the MR-Egger method showed OR<1, inconsistent with the direction of IVW. Consequently, the causal association between CD and skin cancer cannot be definitively established in this study. More studies are needed to further determine the causality.

When analyzing causal associations between UC and extraintestinal cancers, we found that the risk of cervical cancer in UC patients is 1.11‐fold higher in the European population and 1.39‐fold higher in the East Asian population compared to individuals without UC. Similar results were reported in several previous studies, suggesting that UC increased the risk of cervical cancer and recommending that women with UC receive regular cervical cancer screening (11, 49, 58, 59).

In Europeans, similar to CD, UC only slightly increased the risk of breast cancer (OR: 1.0220; 95% CI: 1.0051-1.0393). In East Asians, we did not find any correlation between UC and breast cancer. Therefore, we also do not recommend UC patients to undergo breast cancer screening earlier or more frequently than the general screening programs. Interestingly, UC was significantly positively associated with gastric cancer in the East Asian population. Nissen et al. conducted two case-control studies and found that UC was more likely than CD to be a risk factor for gastric cancer (60). Since studies on the relationship between UC and the risk of gastric cancer are limited in the Asian population, more relevant research should be conducted in the future (61). For bile duct and hepatocellular cancers, a large number of studies have suggested that IBD is positively related to the risk of hepatobiliary cancers (62–64). However, our MR study only identified the effect of UC in increasing the risk of bile duct and hepatocellular cancers in the East Asian population. Notably, a previous study involving 17,052 patients with IBD reported that the risk of hepatobiliary cancers was elevated only in patients with UC (10). Another study also reported a significant positive association between UC and bile duct cancer (65). This observation may be associated with the fact that up to 5% of UC patients develop primary sclerosing cholangitis (PSC), a condition known to carry a lifetime risk of developing bile duct cancer ranging from 10% to 15% (66, 67). As for the potential mechanism of the association between IBD and hepatocellular carcinoma, it may be related to the sharing of immune-related biomarkers (68).

Interestingly, our MR study found a potential positive association between UC and lung cancer risk in the East Asian population. A recent study has demonstrated that the lungs and colon can jointly regulate inflammation and immunity through the lung-gut axis, particularly via the transport of gut microbiota and metabolites (69). This provides a possible mechanism for the correlation between UC and lung cancer. Regrettably, two meta-analyses reported an increased risk of lung cancer in CD, but not in UC (10, 70). Although traditional observational studies can offer some initial insight into the association between IBD and cancer, their findings may be influenced by confounders (71, 72). Moreover, our findings diverged from previous observational studies, potentially attributed to the limited sample size of the GWAS dataset.

Our MR study revealed some differences in the risk of developing extraintestinal cancer in CD and UC between European and East Asian populations. In the European population, we found that both CD and UC slightly increased the risk of breast cancer. However, these findings were not found in East Asians. In addition, we found varying degrees of associations between UC and gastric cancer, bile duct cancer, hepatocellular carcinoma, and lung cancer in the East Asian population, but not in the European population. The reasons for these differences in causality remain unclear. It has been reported that there are significant differences in the phenotypes of IBD between Western and Eastern populations (73). Different ethnic groups may have unique genetic markers and susceptibility genes that influence complex genetic diseases (74). These genetic variants can lead to differences in cancer risk among diverse populations.

The strengths of our study lie in the direct assessment of the causal effects of CD and UC on the risk of extraintestinal cancer using the MR method. This approach allows us to avoid the interference of confounding factors in traditional observational studies. Furthermore, our findings provide new evidence for site-specific cancer screening and intervention in patients with CD and UC.

Nevertheless, this study has several limitations. First, the GWAS data for this study are derived from European and East Asian populations, which limits the application of our findings to other populations. Hence, future studies are required to verify the applicability of our results to different populations. Second, we cannot stratify the analysis by sex due to the lack of sex-specific GWAS data. Finally, the MR study can only analyze the causality and cannot explain the specific biological pathways. Further research is necessary to investigate the mechanisms behind the associations of CD and UC with the risk of extraintestinal cancer.

In summary, based on MR analyses and large-scale GWAS data, our study indicated that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.

In this study, all GWAS data were extracted from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/).

CY: Conceptualization, Investigation, Methodology, Writing – original draft. JX: Data curation, Writing – original draft. SX: Data curation, Writing – review & editing. LT: Writing – review & editing. QH: Writing – review & editing. XZ: Writing – review & editing. YH: Writing – review & editing. TY: Formal analysis, Writing – original draft. ZS: Funding acquisition, Supervision, Validation, Writing – review & editing.