Transcriptomics and Mendelian randomization studies reveal the critical role of Stanniocalcin-2 in linking perfluorinated compound-exposure to colorectal cancer

Colorectal carcinoma (CRC) represents a major gastrointestinal malignancy with substantial global incidence, marked by elevated morbidity and mortality rates. Despite advancements in treatment, there is still considerable variation in prognosis, particularly with high recurrence rates, emphasizing the need for more precise prognostic tools. The present study is aimed at identifying central prognostic biomarkers linked to perfluorinated compound (PFCs) exposure and construct a prognostic risk model for CRC based on transcriptomic data. We analyzed transcriptome data from 638 CRC samples and 51 normal control samples from The Cancer Genome Atlas (TCGA) database, then identified a total of 3,230 PFC-associated genes. Candidate genes related to CRC prognosis were found by analyzing differences in gene expression, doing functional enrichment, and building a protein–protein interaction (PPI) network. We built a LASSO model with PRAME, CDKN2A, and STC2 and checked it using Kaplan–Meier analysis and ROC curves over time, while STC2 was further identified as the key mediator linking PFC exposure to CRC risk based on Mendelian randomization and experimental validation. This model could put patients into high-risk or low-risk groups, which gives doctors a new tool to plan personalized treatments. We also checked the immune setting, tumor mutation load, and likely response to immunotherapy, which further proved the model’s usefulness in the clinic. A Mendelian randomization (MR) analysis in two steps showed that higher levels of genetic risk for Perfluorooctanoic acid (PFOA) and Perfluorooctanesulfonic acid (PFOS) exposure raised CRC risk. STC2 was found to partly explain the mediator from PFOA to CRC, making up about 8.6% of the overall effect. We ran sensitivity checks, and the results still held, which means these cause-and-effect findings are strong. Finally, In vitro analyses verified that PFOA upregulates STC2 transcription in CRC cells. Our results suggest new ways to assess CRC prognosis and give scientific backing for treating cancers linked to the environment, based on how PFCs work in the body.