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Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis.

ABSTRACT: BACKGROUND:Bladder cancer displays a broad mutational spectrum and intratumor heterogeneity (ITH), which results in difference in molecular phenotypes and resistance to therapies. However, there are currently no clinically available measures to predict patient prognosis using ITH. We aimed to establish a clinically relevant biomarker by using ITH for informing predictive of outcomes. METHODS:We used the Bioconductor R package Maftools to efficiently and comprehensively analyze somatic variants of muscle-invasive bladder cancer (MIBC) from The Cancer Genome Atlas (TCGA). We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters as well as mutational subtypes. RESULTS:We observed a broad range of somatic mutations in MIBC from TCGA. MATH value was higher for the high-grade group than for the low-grade group (p < 0.05). There was a strong correlation between higher MATH value and presence of TP53 mutations (p = 0.008), as well as between lower MATH value and presence of FGFR3 mutations (p = 0.006). Patients with FGFR3 mutation and low MATH value exhibit longer overall survival time than that of all BLCA patients (p = 0.044), which was replicated in another bladder cancer database composed of 109 BLCA patients. CONCLUSION:Measures of tumor heterogeneity may be useful biomarkers for identifying patients with bladder cancer. Low MATH value was an independent risk factor that predicted better prognosis for patients with FGFR3 mutation compared to all BLCA patients.

SUBMITTER: Han Y

PROVIDER: S-EPMC7694425 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis.

Han Yuying Y Liu Xu X Ye Haihong H Tian Ye Y Ji Zhengguo Z

World journal of surgical oncology 20201126 1

<h4>Background</h4>Bladder cancer displays a broad mutational spectrum and intratumor heterogeneity (ITH), which results in difference in molecular phenotypes and resistance to therapies. However, there are currently no clinically available measures to predict patient prognosis using ITH. We aimed to establish a clinically relevant biomarker by using ITH for informing predictive of outcomes.<h4>Methods</h4>We used the Bioconductor R package Maftools to efficiently and comprehensively analyze som ...[more]

PMID: 33243261

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Project description:Background:Uterine corpus endometrial carcinoma (UCEC) is a clinically heterogeneous disease, and this heterogeneity is associated with tumor development, clinical characteristics, and prognostic outcomes. Mutant-allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative measure to assess intra-tumor heterogeneity based on next-generation sequencing data. We aimed to explore the use of MATH as a measure for tumor heterogeneity and its prognostic role in UCEC patients. Methods:We calculated MATH scores from the available data of 560 UCEC patients from The Cancer Genome Atlas (TCGA) and investigated their correlations with clinical characteristics, genetic alterations, and overall survival. Predictive accuracy was quantified using the area under the receiver operating characteristic curve (AUC) and the index of concordance (C-index). Results:In total, 242 MATH scores were obtained from the UCEC cohort. MATH scores were significantly related to age, race, cancer type, clinical stage, histological grade, molecular type, targeted molecular therapy, and hormonal therapy. Furthermore, the genomic pattern on the basis of MATH scores showed that mutation rates of TP53 (tumor protein p53) and ARID1A (AT-rich interaction domain 1A) were independently associated with MATH scores. Correlation analysis revealed a significantly positive association of MATH scores with the fraction of somatic copy number alteration (SCNA). Importantly, a high MATH score was significantly associated with shorter overall survival [hazard ratio (HR), 2.342; 95% confidence interval (CI), 1.110-4.942]. Multivariate Cox regression combined with stratified analysis revealed that the MATH score is an independent prognostic factor in UCEC patients under 60 years old, and predictive quantification showed the MATH score had an AUC of 0.756 and a C-index of 0.845. Conclusions:Our results suggest that MATH, a practical and useful way to measure intra-tumor heterogeneity, may serve as a significant biomarker for the prognosis of patients with UCEC, enabling more accurate prediction of clinical outcomes.

Project description:BackgroundThioesterase superfamily member 6 (THEM6) has been implicated in the development and progression of various cancers. However, prior research emphasized on its regulatory role merely, we aim to investigate the effect of THEM6 gene on the immunological role and its relationship with molecular subtype in bladder cancer (BLCA).MethodsThrough pan-cancer analysis, we explored the THEM6 expression pattern and immunological role using The Cancer Genome Atlas (TCGA) database. In addition, we performed a correlation of THEM6 and its immunological functions, including immunomodulators, immune checkpoints, cancer immunity cycles, T cell inflamed score, and tumor-infiltrating immune cells in the BLCA tumor microenvironment (TME) based on TCGA and BLCA microarray cohort from Xiangya Hospital. We also assessed the accuracy of THEM6 in predicting the molecular subtype and its response to different interventions in BLCA. Finally, we computed and validated a prediction model established by THEM6-related different expressed immune-related genes that might help in BLCA prognosis.ResultsTHEM6 led to immunosuppression in BLCA TME. Furthermore, there was a downregulation in the immunological functions. Besides, THEM6 could effectively distinguish BLCA molecular subtypes, and THEM6 low expression implied basal subtype that was more effective to several interventions, such as immune checkpoint blockade (ICB) therapies, neoadjuvant chemotherapy, and radiotherapy. While THEM6 high expression indicated luminal subtype, hyperprogression and better response to targeted therapies, such as blocking THEM6 and several immune-inhibited oncogenic pathways.ConclusionsTHEM6 may be with potential immune-modulating properties and may become a potential new immunotherapy target for BLCA. THEM6 could accurately predict the molecular subtype of BLCA, which was helpful for guiding the treatment. Simultaneously, the prediction model may exhibit an excellent predictive value in patients with BLCA.

Dataset Information

Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis.

Publications

Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis.

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