Characterization of the gene signature correlated with favorable response to chemoradiotherapy in rectal cancer: A hypothesis-generating study.

Abstract

This study aimed to define the gene signature associated with response to neoadjuvant chemoradiotherapy (nCRT), or chemoradiosensitivity (CRS) signature, in rectal cancer, and investigate the correlation between the CRS signature and characteristics of tumor. Three public microarray datasets of pre-nCRT rectal cancer were used to discover and validate the CRS signature, and the pathway analysis of the CRS signature was performed. Patients in The Cancer Genome Atlas (TCGA) dataset were stratified according to the CRS signature enrichment score, and mutational profile and proportions of infiltrated immune cells were compared. In the discovery dataset (GSE53781), 95 genes were upregulated in complete responders compared to non-complete responders and defined as the CRS signature. Pathways regarding DNA replication and repair processes as well as inflammatory response were enriched in the CRS signature. In the validation datasets (GSE35452 and GSE45404), patients with favorable response to nCRT exhibited higher enrichment score of the CRS. In TCGA-READ cohort, patients with high CRS signature harbored KRAS mutation in lower frequency than those with low CRS signature. In addition, proportions of proinflammatory immune cells were higher, but proportion of immunosuppressive M2 macrophages was lower in patients with high CRS signature than those with low CRS signature. The current integrative bioinformatic analysis suggests the CRS signature and showed that the CRS signature is associated with dissimilar mutational profile and increased immune response. The discovered CRS signature and related characteristics may serve as candidate of stratification factor in upcoming studies for rectal cancer.