Does inflammatory bowel disease have a causal relationship with extracolonic tumors?

In a recent study published in BMC Medicine, researchers investigated whether inflammatory bowel disease (IBD) is causally related to extracolonic cancers.

Study: Causal association between inflammatory bowel disease and 32 site-specific extracolonic cancers: a Mendelian randomization study. Image Credit: Orawan Pattarawimonchai/Shutterstock.com

Background

Extracolonic cancer is connected with IBD, a persistent inflammation of the intestines. However, the causal link between extracolonic cancer and inflammatory bowel disease has not been extensively investigated.

There is no expert agreement or recommendation for IBD screening or surveillance, and no extensive Mendelian randomization (MR)- based studies have examined the causal link between region-specific extracolonic malignancies and IBD at an individual’s body level.

About the study

In the present study, researchers performed a Mendelian randomization analysis to comprehensively evaluate the causal link between inflammatory bowel disease and extracolonic tumors.

The International IBD Genetics Consortium (IIBDGC) data were retrieved to determine instrumental variables (IVs) genetic variations strongly related to IBD from a genome-wide association study (GWAS) involving 12,882 individuals with IBD, 5,956 individuals with Crohn’s disease (CD), and 6,968 individuals with ulcerative colitis (UC).

As outcome data, three cancer GWAS sources were used. Mendelian randomization was performed to determine the causative impact of IBD subtypes on 32 extracolonic malignancies, including oral cavity tumors, pharyngeal tumors, respiratory tumors, gastrointestinal tumors, genital tumors, breast tumors, skin tumors, and hematological cancers.

The researchers initially investigated the relationship between inflammatory bowel disease and extracolonic tumors using GWAS summary statistics information from the United Kingdom (UK) Biobank, followed by replication studies using the FinnGen trial data and other genome-wide association studies undertaken by global consortiums and independent research teams.

Lastly, the researchers conducted meta-analytical research to evaluate the cumulative causal influence of several MR datasets.

Genome-wide significant single-nucleotide polymorphisms (SNPs) were removed from GWAS data to create IVs. In contrast, those with a larger physical distance (equal to or more than 5,000 kb) and low linkage disequilibrium chances were kept.

The inverse variance weighted (IVW) approach was utilized as the primary estimating method to evaluate the causal link between exposures and outcomes. Furthermore, random-effects modeling was used, and odds ratios (ORs) were determined.

Results

In total, 167, 154, and 111 SNPs were utilized as instrument variables for IBD, Crohn’s disease, and ulcerative colitis, respectively. The F statistics for each instrument surpassed 10, suggesting that the genetic instruments utilized were quite powerful.

Inflammatory bowel disease, Crohn’s disease, and ulcerative colitis showed probable causative correlations with oral cancers (OR, 1.2 for IBD, 1.1 for CD, and 1.2 for UC).

Based on merging several MR results from different data sources (BCAC and UK Biobank), the meta-analysis revealed a significantly positive causal link between inflammatory bowel disease and breast malignancy (OR, 1.1) and a probable causal link between Crohn’s disease and breast malignancy (OR, 1.0).

Even when three SNPs were removed, there was still a plausible causative connection between Crohn’s disease and breast tumor (OR, 1.0).

The robustness of the data was further established by leave-one analysis. SNPs in tumor information from the FinnGen database and the United Kingdom biobank revealed significant pleiotropy and heterogeneity between IBD, ulcerative colitis, Crohn’s disease, and malignant non-melanoma cancers.

The study found no causal association between inflammatory bowel disease and malignant-type melanoma (OR: 1.0), although UC and IBD showed positive relationships with cutaneous melanoma in FinnGen data. 

The researchers discovered inconsistencies in the causal links between inflammatory bowel disease and certain cancers in separate datasets. Brain cancer, for example, showed a potential causal linkage to IBD in the United Kingdom biobank but not in FinnGen data.

Similarly, a causal connection between CD and multiple myeloma was present in the FinnGen data but not in the UK biobank data. This phenomenon might be explained by the following: although both UK biobank and FinnGen recruits were of European descent, there are variances in the genetic pool.

The altered immunological environment in breasts and generalized inflammatory responses might lead to breast cancer resistance protein (BCRP) downregulation and G-protein-coupled estrogen receptor (GPER) upregulation on the membranes of breast cells, according to one possible mechanism for the link between breast cancer development and inflammatory bowel disease. Breast cancer develops as a result of a succession of subsequent signaling alterations.

Conclusions

Overall, the study findings highlighted IBD as a possible cause of oral cancer and a significant cause of breast malignancy.

In addition, there were probable links between Crohn’s disease, ulcerative colitis, and oral cancer and between Crohn’s disease and breast cancer. The elevated risk of these two extracolonic malignancies in IBD patients should not be overlooked.

Endoscopic monitoring on a regular and consistent basis can successfully avoid the development of IBD into colorectal cancer. However, the extracolonic malignancy risk in IBD may have been overestimated thus far.

The study findings might support extracolonic cancer screening and monitoring in IBD patients. Regular dental health screening may lower oral cancer risk among IBD patients, while breast cancer incidence may be higher in CD and UC patients. The findings, however, may have low generalizability and should be verified in more varied populations.