Exploring Genetic Associations of Crohn's Disease and Ulcerative Colitis with Extraintestinal Cancers in European and East Asian Populations

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Feb 26

PMID 38404590

Authors

Chengdong Yu

Jiawei Xu

Siyi Xu

Lei Tang

Qinyuan Han

Xiaoqiang Zeng

Yanxiao Huang

Tenghua Yu

Zhengkui Sun

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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), 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) 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).

Conclusions: 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.

References

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

. The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022; 400(10352):563-591. PMC: 9395583. DOI: 10.1016/S0140-6736(22)01438-6. View

Olen O, Erichsen R, Sachs M, Pedersen L, Halfvarson J, Askling J . Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study. Lancet Gastroenterol Hepatol. 2020; 5(5):475-484. DOI: 10.1016/S2468-1253(20)30005-4. View

Kaplan G . The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015; 12(12):720-7. DOI: 10.1038/nrgastro.2015.150. View

Pedersen N, Duricova D, Elkjaer M, Gamborg M, Munkholm P, Jess T . Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am J Gastroenterol. 2010; 105(7):1480-7. DOI: 10.1038/ajg.2009.760. View

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

Kilic Y, Kamal S, Jaffar F, Sriranganathan D, Quraishi M, Segal J . Prevalence of Extraintestinal Manifestations in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2023; 30(2):230-239. DOI: 10.1093/ibd/izad061. View

Nounu A, Kar S, Relton C, Richmond R . Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study. Breast Cancer Res. 2022; 24(1):66. PMC: 9548139. DOI: 10.1186/s13058-022-01553-9. View

Bhaskaran K, Douglas I, Forbes H, Dos-Santos-Silva I, Leon D, Smeeth L . Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014; 384(9945):755-65. PMC: 4151483. DOI: 10.1016/S0140-6736(14)60892-8. View

10.

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

11.

The Lancet Diabetes Endocrinology . The obesity-cancer link: of increasing concern. Lancet Diabetes Endocrinol. 2020; 8(3):175. DOI: 10.1016/S2213-8587(20)30031-0. View

12.

Singh S, Nagpal S, Murad M, Yadav S, Kane S, Pardi D . Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013; 12(2):210-8. DOI: 10.1016/j.cgh.2013.04.033. View

13.

Olen O, Erichsen R, Sachs M, Pedersen L, Halfvarson J, Askling J . Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020; 395(10218):123-131. DOI: 10.1016/S0140-6736(19)32545-0. View

14.

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

15.

Yuan F, Pfeiffer R, Julian-Serrano S, Arjani S, Barrett M, Koshiol J . Autoimmune conditions and pancreatic cancer risk in older American adults. Int J Cancer. 2022; 152(2):172-182. PMC: 11260175. DOI: 10.1002/ijc.34235. View

16.

Hovde O, Hoivik M, Henriksen M, Solberg I, Smastuen M, Moum B . Malignancies in Patients with Inflammatory Bowel Disease: Results from 20 Years of Follow-up in the IBSEN Study. J Crohns Colitis. 2017; 11(5):571-577. DOI: 10.1093/ecco-jcc/jjw193. View

17.

Ungaro R, Mehandru S, Allen P, Peyrin-Biroulet L, Colombel J . Ulcerative colitis. Lancet. 2016; 389(10080):1756-1770. PMC: 6487890. DOI: 10.1016/S0140-6736(16)32126-2. View

18.

Richmond R, Davey Smith G . Mendelian Randomization: Concepts and Scope. Cold Spring Harb Perspect Med. 2021; 12(1). PMC: 8725623. DOI: 10.1101/cshperspect.a040501. View

19.

Nguyen T, Do D, Nguyen T, Nguyen T, Nguyen-Thanh T, Nguyen H . Immune-related biomarkers shared by inflammatory bowel disease and liver cancer. PLoS One. 2022; 17(4):e0267358. PMC: 9032416. DOI: 10.1371/journal.pone.0267358. View

20.

Saich R, Chapman R . Primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes in inflammatory bowel disease. World J Gastroenterol. 2008; 14(3):331-7. PMC: 2679122. DOI: 10.3748/wjg.14.331. View