Journal Article

Comprehensive characterization of PKHD1 mutation in human colon cancer

Wang, Yue, Tang, Wanxiangfu, Gong, Fangming, Li, Peng, Han, Lu, Wang, Daizhenru, Sun, Yulan, Wu, Xuxiaochen, Bao, Hua

2024

Overview

Introduction The PKHD1 (Polycystic Kidney and Hepatic Disease 1) gene is essential for producing fibrocystin or polyductin, which is crucial in various cellular functions. Mutations in PKHD1 have been found to be involved in the development and progression of colorectal cancer (CRC). Along with APC, TP53, and KRAS, PKHD1 is one of the most frequently mutated genes in CRC. PKHD1 expression is governed by the Wnt/PCP pathway, often dysregulated in CRC. Targeting this pathway, crucial for CRC progression, could unveil potential therapeutic strategies for colon cancer treatment. Methods This study examined an in‐house dataset of 3702 colon cancer samples, analyzing mutation landscapes, clinical features, tumor mutational burden (TMB), microsatellite instability (MSI), and chromosomal instability (CIN) score. For the survival analysis of PKHD1 patients, survival data of 436 colon adenocarcinoma samples were obtained from TCGA dataset. Additionally, 433 samples from TCGA with RNA‐seq data were used for the assessment of immune cell infiltration and gene set enrichment analysis. Results Polycystic Kidney and Hepatic Disease 1 mutation was detected in 424 colon cancer patients from our in‐house cohort and was associated with increased TMB, higher MSI, and lower CIN score. Importantly, within the TCGA dataset, PKHD1 mutations were identified as an independent prognostic factor, not merely correlated with established prognostic biomarkers, and were associated with poorer overall survival outcomes. In terms of immune response, these mutations correlated with increased enrichment scores for 12 immune cell types, including B cell plasma, macrophages, and naive CD4+ T cells. Additionally, interferon alpha and interferon‐gamma gene sets were significantly down‐regulated in patients with PKHD1 mutations (FDA q‐value < 0.1). Conclusions Overall, these findings suggest that PKHD1 may be a potential biomarker for the prognosis of colon cancer and provide some insight for personalized immunotherapy. In this study of 3702 samples, mutations in the PKHD1 gene, frequently observed in colorectal cancer (CRC), were correlated with increased tumor mutational burden and microsatellite instability, but decreased chromosomal instability. These mutations also serve as an independent prognostic biomarker, associated with poorer overall survival outcomes in TCGA COAD patients. These critical findings reinforce the potential of PKHD1 as a pivotal biomarker for colon cancer prognosis and may facilitate the emergence of personalized immunotherapy strategies.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenocarcinoma / Adenomatous polyposis coli / Aged / Antigen-presenting cells / Biomarkers / Biomarkers, Tumor - genetics / Cancer therapies / CD4 antigen / Cell cycle / Colon cancer / Colonic Neoplasms - genetics / Colonic Neoplasms - mortality / Colonic Neoplasms - pathology / Colorectal cancer / Colorectal carcinoma / Female / Gene set enrichment analysis / Genes / Genomes / Genomic instability / Humans / Immune response / Immunotherapy / Liver diseases / Lymphocytes T / Macrophages / Male / Medical prognosis / Metastases / Microsatellite Instability / Middle Aged / Mutation / mutations / p53 Protein / Patients / Polycystic kidney / Prognosis / Receptors, Cell Surface - genetics / Signal transduction / Statistical analysis / Survival analysis / Trends / tumor‐infiltration immune cell / Wnt protein / γ-Interferon