Characterization and clinical implications of CpG island methylator phenotypes of resistant tumors.

BACKGROUND

Drug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized.

RESULTS

DNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide.

CONCLUSIONS

This study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.