Curr Top Med Chem. 2026 May 18. doi: 10.2174/0115680266436608260406113212. Online ahead of print.

ABSTRACT

INTRODUCTION: Epidemiological studies indicate a potential link between mental disorders and cancer; however, the role of neurotransmitter-related genes (NRGs) in carcinogenesis remains unclear. In this study, we employed Mendelian randomization utilizing multi-omics data to investigate the causal effects and mechanisms of NRGs in cancer.

METHODS: We assessed the causal relationships between ten mental disorders and fourteen cancer types. NRGs were sourced from GeneCards, and transcriptome data for breast cancer (BC) were obtained from the Gene Expression Omnibus (GEO). Summary-data-based Mendelian Randomization (SMR) integrated genome-wide association study (GWAS) data with expression quantitative trait loci (eQTLs), DNA methylation QTLs (mQTLs), intestinal eQTLs, and fecal microbiota QTLs (mbQTLs). Colocalization analyses were conducted to explore the relationships between host genes and gut microbiota, with sensitivity assessments performed using two additional Mendelian randomization methods.

RESULTS: Mendelian randomization confirmed a causal association between mental disorders and BC. A meta-analysis of five BC datasets identified 821 differentially expressed genes (DEGs) among 829 non-redundant genes. SMR highlighted KRTCAP2 as a potential causal gene in blood, and cg24674445 as a significant methylation site. The expression of KRTCAP2 was found to be inversely correlated with BC, while methylation at cg24674445 downregulated KRTCAP2, suggesting that cg24674445 may promote BC progression.

DISCUSSION: This study advances beyond established epidemiological correlations by providing genetically validated evidence for a causal link between mental disorders and breast cancer. Its primary significance lies in delineating a plausible biological pathway-epigenetic regulation of neurotransmitter-related genes-that may mechanistically elucidate this connection. By integrating multi-omics data, we transition from mere association to a testable model of disease etiology, where genetic predispositions to mental illness and cancer converge upon shared regulatory mechanisms within the genome.

CONCLUSION: Multi-omics Mendelian randomization demonstrates that DNA methylation modulates the association between neurotransmitter-related genes and breast cancer.

PMID:42163732 | DOI:10.2174/0115680266436608260406113212

Cancer Discov. 2026 Apr 15. doi: 10.1158/2159-8290.CD-25-1663. Online ahead of print.

ABSTRACT

Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via CXCL12-CXCR4 axis, and induced time course-dependent T cell exhaustion within the brain microenvironment. Clinically, elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 were significantly associated with BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

PMID:41973996 | DOI:10.1158/2159-8290.CD-25-1663