Abstract
Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding to ICI therapy. PBK/TOPK, a serine/threonine kinase, plays a role in cell cycle regulation and mitotic progression. Here, we investigated the correlation between PBK/TOPK expression and tumor immunity and its prognostic value in colon cancer. Based on large-scale bioinformatics analysis, we discovered that elevated PBK/TOPK expression predicted a favorable outcome in patients with colon cancer and was positively associated with immune infiltration levels of CD8+ T cells, CD4+ T cells, natural killer cells, and M1 macrophages. In contrast, a negative correlation was found between PBK/TOPK expression and immune suppressor cells, including regulatory T cells and M2 macrophages. Furthermore, the expression of PBK/TOPK was correlated with the expression of T-cell cytotoxicity genes in colon cancer. Additionally, high PBK/TOPK expression was associated with mutations in DNA damage repair genes, and thus with increased tumor mutation and neoantigen burden. These findings suggest that PBK/TOPK may serve as a prognostic and predictive biomarker for immunotherapy in colon cancer.
Highlights
Colon cancer is a malignant disease ranked third in cancer incidence and second in cancer mortality worldwide [1]
Analysis of The Cancer Genome Atlas (TCGA) data base revealed that the PDZ-binding kinase (PBK) promoter was hypo-methylated in colon cancer tissues compared with normal tissues, indicating that PBK/T-lymphokine-activated killer cell-originated protein kinase (TOPK) can be epigenetically induced in colon cancers (Supplementary Figure S3)
We examined the prognostic value of PBK/TOPK in colon adenocarcinoma (COAD), breast invasive carcinoma (BRCA), bladder urothelial carcinoma (BLCA), esophageal carcinoma (ESCA), glioblastoma multiforme, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), and stomach adenocarcinoma (STAD) of TCGA cohort where its tumorigenic roles are proposed [16,42,43,44,45,46,47,48]
Summary
Colon cancer is a malignant disease ranked third in cancer incidence and second in cancer mortality worldwide [1]. The incidence and mortality have been slowly declining each year, mainly owing to the surgical resection of primary tumors at the early localized stages. The 5-year survival rate at a late stage, remains profoundly low [1]. Targeted therapy, such as cetuximab or bevacizumab, has been shown to prolong overall survival (OS), but it is effective only in a subset of patients with colon cancer [2]. The development of effective predictors of immunotherapeutic response for patients with colon cancer is crucial
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