Previous studies have reported associations of Crohn\'s disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear.
Using genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.
In the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10-5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10-5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).
Our study provided evidence 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.

Patients with Crohn\'s disease (CD) and ulcerative colitis (UC) are at increased risk of developing intestinal cancer. However, less is known about the risk of extraintestinal cancers (EICs). The aim of this study was to conduct a systematic review and meta-analysis of population-based cohorts assessing the risk of EICs in inflammatory bowel disease (IBD) patients.
Only population-based studies reporting on the prevalence or incidence of EICs were included. In total, 884 studies were screened and those included were assessed for quality. Eligible studies were pooled for length of follow-up evaluation, events in the IBD population, and events or expected events in a control population for the meta-analyses.
In total, 40 studies were included in the systematic review and 15 studies were included in the meta-analysis. The overall risk of EICs was found to be increased in both CD (incidence rate ratio [IRR]: 1.43 [CI, 1.26, 1.63]) and UC (IRR: 1.15 [1.02, 1.31]) patients. Both CD and UC patients presented with an increased risk of skin (IRR: CD, 2.22 [1.41-3.48]; UC, 1.38 [1.12-1.71]) and hepatobiliary (IRR: CD, 2.31 [1.25-4.28]; UC, 2.05 [1.52-2.76]) malignancies. Furthermore, CD patients showed an increased risk of hematologic (IRR, 2.40 [1.81-3.18]) and lung (IRR, 1.53 [1.23-1.91]) cancers. These increased risks were present despite treatment with immunosuppressives.
This systematic review and meta-analysis shows that both CD and UC patients are at an increased risk of developing EICs, both overall and at specific sites. However, additional studies with longer follow-up evaluation are needed to assess the true risk of EICs posed by IBD.

BACKGROUND: Patients with inflammatory bowel disease are at increased risk of extracolonic cancers. Little is known regarding this risk following total colectomy [TC].
METHODS: Patients who underwent TC for inflammatory bowel disease in Denmark during 1977-2013 were identified from the Danish National Patient Registry. Incidence rates of extracolonic cancers were determined through record linkage to the Danish Cancer Registry and compared with expected incidence rates in the general population. Standardized incidence ratios [SIRs] were calculated as the observed vs expected cancer incidence.
RESULTS: In total, 4430 patients (3441 with ulcerative colitis [UC]; 989 with Crohn\'s disease [CD]) were followed for 54,183 person-years after TC. Following their surgery, 372 patients were diagnosed with extracolonic cancer compared to 331 expected [SIR = 1.1 (95% confidence interval {CI}: 1.0-1.2)]. The risk of extracolonic cancer overall was increased among patients with CD and TC (SIR = 1.5 [95% CI: 1.2-1.8]), but not among patients with UC and TC (SIR = 1.0 [95% CI: 0.9-1.2]). Patients with UC and TC had a higher risk of intestinal extracolonic cancer (SIR = 2.0 [95% CI: 1.4-2.7]). Patients with CD and TC had a higher risk of smoking-related cancers (SIR = 1.9 [95% CI: 1.2-2.9]), intestinal extracolonic cancer (SIR = 3.1 [95% CI: 1.6-5.5]) and immune-mediated cancers (SIR = 1.5 [95% CI: 1.0-2.1]).
CONCLUSIONS: Patients with CD and TC had a higher risk of extracolonic cancer overall compared to the general population, while patients with UC and TC did not. Site-specific cancer risk varied according to inflammatory bowel disease type.