Attenuated Promoter-Methylation Control of SLC7A11 in KRAS-Mutant Colorectal Cancer: A Paired Methylation-Expression Analysis of TCGA-COAD

Abstract Background. SLC7A11 (xCT), the cystine transporter that sustains glutathione synthesis and ferroptosis resistance, is upregulated in KRAS-mutant colorectal cancer (CRC). Its promoter is regulated both by DNA methylation and by the KRAS-activated transcription factor NRF2, but whether these two controls interact in KRAS-mutant tumours has not been examined at the level of paired patient data. Methods. We assembled paired DNA-methylation (Illumina 450K) and RNA-sequencing data for TCGA-COAD primary tumours, retaining 193 tumours with both SLC7A11 promoter methylation and expression. We computed the Spearman methylation-expression correlation overall and within KRAS wild-type and KRAS-mutant strata, tested the between-stratum difference with a Fisher r-to-z test, and repeated the analysis for GPX4 as a comparator. Results. Across all 193 tumours, SLC7A11 promoter methylation correlated inversely with expression (Spearman r = − 0.254, p = 0.0004), as expected for methylation-mediated repression. Stratifying by KRAS status, the correlation was clear in wild-type tumours (r = − 0.327, p = 0.0006) and weaker and non-significant in KRAS-mutant tumours (r = − 0.149, p = 0.168). The difference between the two correlations was not itself statistically significant (Fisher r-to-z, p ≈ 0.20), so the data are suggestive of, but do not establish, a loss of methylation control in mutant tumours. SLC7A11 promoter methylation was lower in mutant tumours (Δβ = −0.042, p = 0.0002), a statistically significant difference. GPX4 showed no methylation difference (Δβ = +0.002, p = 0.96), indicating its lower expression in mutant tumours is not methylation-driven. Conclusions. In KRAS-mutant CRC, the inverse coupling between SLC7A11 promoter methylation and expression is weaker than in wild-type tumours, consistent with a model in which NRF2 activation partly overrides methylation-based repression, though the between-group difference does not reach significance in this cohort and needs confirmation in a larger paired dataset. The SLC7A11 promoter hypomethylation (Δβ = −0.042, p = 0.0002) is statistically significant but modest in absolute magnitude and requires functional validation.