Tumors are related to the accumulation of somatic mutations in cells as a result of carcinogens. Studies have shown that BLCA is a highly mutated tumor type. For example, Zhang et al. found that BLCA patients with higher tumor mutational burden (TMB) had more survival benefits. The mutations of FGFR3, HRAS, KRAS, NRAS and PIK3CA in BLCA can present a companion diagnostic to define patients for targeted therapies [30, 31]. Recognizing the genetic mutations that may allow early genetic screenings for BLCA and new therapies targeting cells with these mutations. The FLG gene encode a related protein that accumulates in the intermediate filaments of mammalian epidermal keratin and shown variability in the frequency variants [11–13]. FLG gene mutation is one of the risk factors for cancer, the associations between FLG loss-of-function mutations and cancer were in subgroup analyses. In this study, it’s the first time to found the survival time of FLG wild-type patients was significantly less than that of FLG mutant patients based on the BLCA gene mutation data in the TCGA database. Furthermore, we found that there were two different types of patients in FLG wild-type patients, sub1 and sub2. Though the sample size of sub2 is 10, the prognosis of sub2 patients was worse than that of sub1 patients, the mortality rate of Sub2 is as high as 90%. Hence, we paid attention to the biological function and pathways of sub2 in the following research.
As one of the most common urinary system cancers worldwide, BLCA ranges from unaggressive and noninvasive tumors to aggressive and invasive tumors with high disease-specific mortality. However, traditional treatments did not make significantly improvement for its the 5-year survival rate. Recently, newer immunotherapy have generated a great deal of interest in BLCA. In this study, the results of functional enrichment analysis of differential genes showed that related pathways such as inflammation, chemokine production, and T cell activation were significantly enriched. GSEA analysis of the BP pathway suggests that the pathways related to immunity and inflammation are significantly down-regulated in Sub2, and the immune response involved in T cell activation was suppressed. Analysis of the T cell subtypes of FLG wild-type patients with different types showed that Sub2 of FLG wild-type was correlated with infiltrating levels of immune cells (CD4 naive, Tcm and NKT cell). The results above indicated that The Sub2 was related to the immune microenvironment of BLCA. The investigation of the relationship and biological mechanisms between FLG subtypes and immune microenvironment will help to better understand the role of immunotherapy in BLCA treatment.
Immune checkpoint inhibitors refer to inhibitory drugs developed for immune checkpoints, which can rejuvenate immune cells and kill tumor cells again . The application of ICB, such as anti-programmed cell death (ligand) 1( anti-PD-(L)1) and cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) , is becoming emerging as a novel treatment strategy for BLCA. Therefore, the prediction of immune checkpoints is of great clinical significance for BLCA. Studies have shown a correlation between specific genetic mutations and the efficacy of immunotherapy[39, 40]. It was reported that TMB, microsatellite instability, mismatch repair gene deficiency, T-cell inflamed and IFN-γ gene expression profiles (GEPs), and DNA damage response (DDR) and antigen presentation defects may serve as potential biomarkers for immune checkpoint of immunotherapy. Zhang et al. identified NTRK3 as a potential prognostic biomarker associated with tumor mutation burden and immune infiltration in BLCA . Lin et al. found the effect of NCOR1 mutations on immune microenvironment and efficacy of ICB in patient with BLCA. In this study, we predicted the immune checkpoints of FLG wild-type patients of different types, and the results showed that Sub2 patients respond is worse to immune checkpoint. The results suggested that FLG mutilation may prove to be a novel detection and contribute to the development of immunotherapy for BLCA.