Dataset Information

Particular gene upregulation and p53 heterogeneous expression in TP53-mutated maxillary carcinoma.

ABSTRACT: It has been demonstrated that tumor protein p53 (TP53) mutation in maxillary squamous cell carcinoma, is more treatment-resistant compared with the carcinoma without TP53 mutation. However, the association between TP53 mutation and treatment resistance remains unclear. As a first step in understanding the biological differences between tumors with and without TP53 mutation, a comprehensive gene expression analysis of maxillary squamous cell carcinoma with or without TP53 mutation was performed. A total of 42 genes were identified to be differentially expressed by >4-fold. Quantification of their mRNA using quantitative polymerase chain reaction indicated 18 genes with high expression and three genes with low expression in TP53 mutated tumors vs. TP53 wild-type tumors. The 18 genes included eight cell adhesion (DSC3, GRHL1, EPPK1, PROM2, ANXA8, DSP, JUP, and KRT6B) and four cell growth inhibition (SFN, CLCA2, SAMD9 and TP63) genes. Among these genes, DSC3, SFN, and CSTA, whose expression was markedly increased, also demonstrated high protein expression in immunohistochemical staining of TP53 mutated tumors. The TP53 mutated tumors demonstrated high nuclear staining of the TP53 protein only in tumor cells at the tumor margins adjacent to the stroma, whereas the tumor interior was negative for TP53. However, all tumor cells of TP53 wild-type tumors exhibited positive nuclear staining for the TP53 protein. The combined findings suggest that TP53 mutated tumors possess a phenotype opposite to that associated with cancer progression and malignant transformation, and exhibit tumor cell heterogeneity between the tumor interior and margins.

SUBMITTER: Kudo I

PROVIDER: S-EPMC5649615 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Particular gene upregulation and p53 heterogeneous expression in TP53-mutated maxillary carcinoma.

Kudo Itsuhiro I Esumi Mariko M Kusumi Yoshiaki Y Furusaka Tohru T Oshima Takeshi T

Oncology letters 20170814 4

It has been demonstrated that tumor protein p53 (TP53) mutation in maxillary squamous cell carcinoma, is more treatment-resistant compared with the carcinoma without TP53 mutation. However, the association between TP53 mutation and treatment resistance remains unclear. As a first step in understanding the biological differences between tumors with and without TP53 mutation, a comprehensive gene expression analysis of maxillary squamous cell carcinoma with or without < ...[more]

PMID: 29085461

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Project description:TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.

Dataset Information

Particular gene upregulation and p53 heterogeneous expression in TP53-mutated maxillary carcinoma.

Publications

Particular gene upregulation and p53 heterogeneous expression in <i>TP53</i>-mutated maxillary carcinoma.

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