Unraveling the Causal Links and Novel Molecular Classification of Crohn’s Disease in Breast Cancer: A Two-Sample Mendelian Randomization and Transcriptome Analysis with Prognostic Modeling

Abstract

Background Crohn’s disease (CD), a prominent manifestation of chronic gastrointestinal inflammation, and breast cancer (BC), seemingly disparate in the medical domain, exhibit a shared characteristic. This convergence arises from their involvement in chronic inflammation and immune responses, an aspect that has progressively captivated the attention of investigators but remain controversy. Methods We used two-sample Mendelian Randomization (MR) and transcriptomics to explore the relationship between CD and BC. MR assessed causality of CD on different BC subtypes and reverse causality of BC on CD. We identified CD-related differentially expressed genes and their prognostic impact on BC, and developed a new molecular BC classification based on these key genes. Results MR revealed a causal link between CD and increased BC risk, especially in estrogen receptor-positive (ER+) patients, but not in ER-negative (ER-) cases. BC showed no causal effect on CD. Transcriptomics pinpointed genes like B4GALNT2 and FGF19 that affected BC prognosis in CD patients. A nomogram based on these genes predicted BC outcomes with high accuracy. BC patients were reclassified into three prognostically distinct subtypes using these genes. Conclusions CD is a risk factor for ER + BC but not for ER- BC. BC does not causally affect CD. Our prognostic model and new BC molecular classifications offer insights for personalized treatment strategies.