A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer

Abstract

Background Although the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients. Methods EOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis. Results The cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age. Conclusion In this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.

Construction and validation of a nomogram for predicting overall survival of patients with stage III/IV early−onset colorectal cancer

“…Second, there was no detailed information on CEA, radiotherapy, chemotherapy, and surgical treatment in the SEER database. Third, the SEER database did not include potential prognostic factors for EO-CRC, such as systemic immune inflammation index ( 33 ), geriatric nutrition risk index ( 33 ), symptom duration of 3 months or more ( 34 ), carbohydrate antigen 19-9 ( 35 ), and cell cycle-related genes ( 36 ). Fourth, our data was exclusively from the SEER database, representing only a portion of the US population, potentially limiting the applicability of our results to other regions or countries.…”

Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

“…CGREF1 mRNA has high expressions in HCT116, H1299 and HepG2 cells while expressing at low levels in other cell lines including Raji, Jurkat, BT325, PC12 [32]. Mechanistically, CGREF1 is regulated by p53 [33], and the overexpression of CGREF1 significantly inhibits the transcriptional activity of AP-1, reduces the phosphorylation of ERK (extracellular signal-regulated kinases) and p38 MAPK (mitogen-activated protein kinases), and suppresses the proliferation of HEK293T and HCT116 cells [32]. Furthermore, CGREF1 can decrease the percent of G2/M and S phase and repress cell proliferation while overexpressing [32].…”

“…We found that the increased expression of CGREF1 is significantly related to the decreased risk of dorsopathies. In the research of Xiang et al, the colorectal cancer patients with higher expression of CGREF1 were found to have significantly better overall survival than patients with lower expression, and the role of CGREF1 in the prognosis of Early-onset colorectal cancer was reported [33]. Furthermore, Xie et al observed that CGREF1 expression were high in the tissue of osteosarcoma patients while it were lowly expressed in normal tissue, and speculated that CGREF1 can predict drug resistance to osteosarcoma [34].…”