Development and validation of immune-related genomics nomogram for prognostic prediction in left- and right-side colorectal cancer

Abstract

Abstract Background: Previous studies have reported that the tumor heterogeneity and immune molecular mechanisms of proximal and distal colorectal cancer (CRC) are divergent. Therefore, our study aims to analyze the difference between left-sided CRC (LCC) and right-sided CRC (RCC), and respectively develop the nomograms based on prognostic immune-related genes for LCC and RCC. Methods: We enrolled 443 colon cancer patients (220 LCC patients and 223 patients) from The Cancer Genome Atlas (TCGA) datasets. Firstly, the differential expressed immune-related genes (DE-IRGs), overall survival (OS), and biological functions between LCC and RCC groups were identified. Then, we analyzed the differences between the two groups in the immune microenvironment, immune checkpoint, and tumor mutation burden (TMB). Next, the LCC and RCC data from TCGA dataset are randomly divided into training and internal validation sets at a 7:3 ratio respectively. Additionally, 566 colon cancer patients (342 LCC patients and 224 RCC patients) in the GSE39582 dataset were downloaded from the Gene Expression Omnibus (GEO) database as the external validation set. Then, survival and Lasso Cox regression analyses were applied to identify hub immune-related genes and respectively establish two prognostic gene signatures of LCC and RCC groups. The prognostic signatures were validated by the 10-fold cross-validation, internal validation set, and external validation set. Further, combined with clinical features, we constructed two clinical predictive nomograms and validated them. Results: RCC patients have lower survival than LCC. RCC patients have higher proportions of T cells CD8, T cells follicular helper, and lower macrophages M0, T cells CD4 naive. RCC patients have higher ESTIMATE and immune scores and lower tumor purity. The immune checkpoint expression levels and TMB values are higher in RCC patients than in LCC. We respectively selected 10 immune-related genes for LCC and 7 genes for RCC groups to develop and validate the prognostic model and calculate a risk score for each patient. The AUC values of the risk score for OS in LCC were 0.735 in the training set, 0.711 in the internal validation set, and 0.744 in the external validation set, and in RCC were 0.704 in the training set, 0.738 in the internal validation set, and 0.705 in the external validation set. The AUC values of the 10-fold cross-validation range from 0.564 to 0.808 in LCC and from 0.589 to 0.792 in RCC. The nomogram of LCC of RCC includes risk based on prognostic genes, age, pathological T, N, M, stage, and gender. the AUC values of the LCC nomogram were 0.722 in the training set, 0.696 in the internal validation set, and 0.739 in the external validation set, and of the RCC nomogram were 0.774 in the training set, 0.744 in the internal validation set, and 0.737 in the external validation set. We also found that were significantly different between high- and low-risk patients in the immune score, ESTIMATE score, tumor purity, immune checkpoint expression levels, and TMB values. Conclusions: We found significant differences in the multidimensional insight between LCC and RCC patients in clinical features, DE-IRGs, TMB, immune checkpoint expression levels, and immune microenvironment landscape. Our study respectively established two prognostic nomograms based on DE-IRGs in combination with clinical features to provide a basis for personalized and precise treatment of LCC and RCC patients.