Comprehensive characterization of PKHD1 mutation in human colon cancer

Abstract

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.

Keywords: biomarkers; colon cancer; mutations; tumor‐infiltration immune cell.

FIGURE 1

Genomic landscape and biomarkers of colon cancer patients with PKHD1 mutations. (A) The oncoprint of co‐occurring somatic mutations in patients with PKHD1 mutations. Genes are ordered by prevalence in the cohort. (B) TMB comparison between PKHD1 and wild‐type groups. (C) MSI comparison between PKHD1 and wild‐type groups. (D) CIN comparison between PKHD1 and wild‐type groups. All TMB are calculated using non‐synonymous mutations and undergoing log2 transformation. Significance was determined using Wilcoxon signed‐rank test.

FIGURE 2

Comparison of overall survival between PKHD1 and wild‐type groups. (A) Kaplan–Meier survival curve for overall survival of PKHD1‐mutated versus wild‐type patients. The 0 denoted PKHD1 wild type, and 1denoted PKHD1 mutation. (B) Multivariate Cox analysis of PKHD1 mutation presence in addition to sex, age, stage, MSI, TMB, and prognostic biomarkers.

FIGURE 3

Comparison of immune and stromal cell infiltrating between PKHD1 and wild‐type groups. Twelve cell types with significantly different xCell scores are shown. Significance was determined by Wilcoxon signed‐rank test. *** = <0.001; ** = <0.01; * = <0.05.

FIGURE 4

Comparison of gene set enrichment between PKHD1 and wild‐type groups. (A) Schematic diagram comparing gene set enrichment between PKHD1 mutant and wild‐type groups. Two gene sets with significantly different (FDA q‐value < 0.1) enrichment scores are shown: (B) Interferon Alpha and (C) Interferon Gamma are significantly down‐regulated in PKHD1 samples.