Identification of predictive biomarkers for chemoradiation response in rectal cancer

Chemoradiotherapy (CRT) is a standard treatment for rectal cancer, yet patients show marked variability in response. Identifying biomarkers that predict CRT response is an unmet need. A study at Keimyung University and Dongsan Hospital (Daegu, South Korea) investigated differentially expressed genes (DEG) between responders and nonresponders. A total of 1477 DEGs were detected, including 729 upregulated and 748 downregulated genes in responders. Functional enrichment analysis indicated immune activation and epithelial polarity in responders, whereas nonresponders showed enrichment of extracellular matrix organization, focal adhesion, and phosphoinositide 3-kinase-protein kinase B signaling. Gene-set enrichment analysis further identified four pathways associated with CRT response: antigen presentation, extracellular matrix-receptor interaction, focal adhesion, and drug metabolism. Among these, the antigen presentation pathway consistently predicted treatment response across data sets. Elastic net regression defined a six-gene signature (KLRC1, CTSS, HLA-DMA, HLA-DQB1, HLA-DQB2, and CIITA) with strong predictive performance, with AUCs ranging from 0.76-0.81. These gene participate in major histocompatibility complex class II antigen-processing and immune-regulatory pathways that enhance CD4 T-cell activation. The authors conclude that these findings indicate that an immune-active, antigen presentation phenotype underlies chemoradiosensitivity in rectal cancer. The six-gene signature may serve as biomarker to guide personalized treatment strategies.