Journal
CANCERS
Volume 15, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/cancers15010158
Keywords
epigenetics; stage II colon cancer biomarkers; LINE1; oncogene signalling; immune contexture; transforming growth factor beta (TGF beta)
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Using DNA methylation-based screening, researchers have developed a classifier that can segregate stage II colon cancer into four sub-classes. They identified hypermethylation at specific CpG sites in CDH17 and LRP2 genes that independently confer increased or reduced risk of cancer recurrence. Functional enrichment and immune cell infiltration analyses revealed distinct molecular features in each sub-class.
Stage II colon cancer (CC), although diagnosed early, accounts for 16% of CC deaths. Predictors of recurrence risk could mitigate this but are currently lacking. By using a DNA methylation-based clinical screening in real-world (n = 383) and in TCGA-derived cohorts of stage II CC (n = 134), we have devised a novel 40 CpG site-based classifier that can segregate stage II CC into four previously undescribed disease sub-classes that are characterised by distinct molecular features, including activation of MYC/E2F-dependant proliferation signatures. By multivariate analyses, hypermethylation of 2 CpG sites at genes CDH17 and LRP2, respectively, was found to independently confer either significantly increased (CDH17; p-value, 0.0203) or reduced (LRP2; p-value, 0.0047) risk of CC recurrence. Functional enrichment and immune cell infiltration analyses, on RNAseq data from the TCGA cohort, revealed cases with hypermethylation at CDH17 to be enriched for KRAS, epithelial-mesenchymal transition and inflammatory functions (via IL2/STAT5), associated with infiltration by 'exhausted' T cells. By contrast, LRP2 hypermethylated cases showed enrichment for mTORC1, DNA repair pathways and activated B cell signatures. These findings will be of value for improving personalised care paths and treatment in stage II CC patients.
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