Abstract
BackgroundBladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response.MethodsWe mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC.ResultsWe found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency o KDM6A mutations in the TCGA and ICGC datasets was 25.97 and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating immune cells (TIICs) and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A mRNA level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response.ConclusionOverall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response.
Highlights
Bladder cancer (BC) is considered to be the fourth most prevalent neoplasm in men [1]
Lysine-specific demethylase 6A (KDM6A) mutation is frequent in BC We downloaded the data, including follow-up profiles and gene expression levels, of 411 and 103 BC tissues from the The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, respectively
KDM6A mutation is associated with higher mutation counts BC samples with KDM6A mutations had higher overall mutation counts than wild-type samples in the TCGA cohort (Fig. 1)
Summary
Bladder cancer (BC) is considered to be the fourth most prevalent neoplasm in men [1]. BC is associated with high rates of tumour recurrence and progression, which represent major challenges in treatment. Lysine-specific demethylase 6A (KDM6A) is a member of the histone H3 lysine 27 demethylase gene family, which is reported to exert pro-tumorigenic effects in some cancer types [2, 3] but is considered a tumour suppressor in other contexts [4]. Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; its effects on tumour progression and clinical outcome in BC remain unclear. We explored the potential role of KDM6A in regulating the antitumor immune response
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