Genetic variants reduced POPs-related colorectal cancer risk via altering miRNA binding affinity and m⁶A modification

Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC-MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m⁶A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.