Work

Integrated Multiomics Analysis Links PAH‐Associated Molecular Features to Somatic Mutation and Genomic Complexity in Pancreatic Ductal Adenocarcinoma

Year: 2026

Type: article

Abstract: Background Polycyclic aromatic hydrocarbons (PAHs) have mutagenic and carcinogenic potential, but their relationships with genomic alterations and epithelial and stromal heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Methods We integrated network toxicology, pathomics, bulk, single cell, and spatial transcriptomics, immune phenotyping, protein expression, virtual knockout analysis, genomic profiling, and molecular docking. PAH‐associated PDAC target genes were linked to ductal epithelial cell (DEC) and cancer associated fibroblast (CAF) states. RAC1 associated somatic mutations, tumor mutation burden (TMB), copy number alterations (CNAs), and mutational signatures were further characterized. Results Ninety‐one PAH‐associated PDAC target genes were identified. CTSG, PRKCB, PTPN7, and SMO formed a four‐gene PAH‐associated PDAC target derived protective gene set (PPTP gene set) associated with favorable prognosis and a stable DEC state, whereas high RAC1 expression was associated with poor prognosis and CAF remodeling. Tumors with high RAC1 expression showed higher TMB and enrichment of KRAS, TP53, CDKN2A, and SMAD4 alterations. RAC1 expression was positively associated with TMB, CNA burden, and mutational signature contributions and was higher in tumors with KRAS, TP53, or CDKN2A mutations. PPTP expression showed inverse associations with genomic complexity. Single‐cell and spatial analyses linked RAC1 to CAF, DEC, and immune remodeling. Conclusion RAC1 expression and the PPTP signature identify distinct PDAC states with contrasting somatic mutation burden, driver alterations, copy number changes, mutational signature activity, and epithelial and stromal organization. These findings link somatic mutation and genomic complexity with microenvironmental heterogeneity in PDAC.

Source: Human Mutation

DOI: 10.1155/humu/9549681

Authors: Peng Wang, Shi Huang, Wenjing Chen, Guanghui Tao, Yicheng Shen, Xuebing Shi

Institutions: Taizhou Second People's Hospital, Yangzhou University, Southwest Medical University, The People's Hospital Tongling

Language: English

Topic: Pancreatic and Hepatic Oncology Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,740