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Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer.

ABSTRACT: BACKGROUND:Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC. METHODS:Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated. RESULTS:Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035). CONCLUSIONS:Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

SUBMITTER: Hwang HJ

PROVIDER: S-EPMC7483024 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer.

Hwang Hye Jung HJ Nam Soo Kyung SK Park Hyunjin H Park Yujun Y Koh Jiwon J Na Hee Young HY Kwak Yoonjin Y Kim Woo Ho WH Lee Hye Seung HS

Journal of pathology and translational medicine 20200701 5

<h4>Background</h4>Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC.<h4>Methods</h4>Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative ex ...[more]

PMID: 32601264

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Project description:AimsThe aim of this study was to establish p53 immunohistochemistry (IHC) patterns to predict TP53 mutations in gastrointestinal neuroendocrine neoplasms (GI-NENs) and to determine whether p53 IHC patterns could be used for the differential diagnosis of neuroendocrine neoplasms.MethodsTP53 gene sequencing and p53 IHC were performed on formalin-fixed paraffin-embedded (FFPE) tissue samples from 92 patients diagnosed with GI-NENs from five medical centers.ResultsThe cohort included 35 well-differentiated neuroendocrine tumors and 57 poorly differentiated neuroendocrine carcinomas. Gene sequencing revealed 38 wild-type TP53 and 54 TP53 mutations. p53 expression was interpreted as follows: pattern A, p53 was absent from all tumor cells; pattern B, scattered and weak p53 expression in 1-20% of tumor cells; and pattern C was subclassified as pattern C1: variable p53 staining intensity in 21-60% of tumor cells and tumor cell nests with focal strong positive p53 staining and pattern C2: strong p53 staining in more than 60% of tumor cells. p53 IHC patterns were evaluated as a binary classifier where pattern B predicted wild-type TP53, and patterns A and C predicted TP53 mutations. The sensitivity, specificity, and overall accuracy of this binary classification to predict TP53 status were 0.963, 0.868, and 0.924, respectively. p53 IHC patterns were also correlated with TP53 mutation types. Most cases with pattern A harboured loss-of-function (LOF) mutations, whereas patterns B and C tended to indicate wild-type TP53 and gain-of-function (GOF) mutations, respectively. Furthermore, most of the well-differentiated NETs showed pattern B, whereas pattern C2 was more common in poorly differentiated NECs. Finally, staining interpretation between different observers also yielded high reproducibility.Conclusionsp53 IHC patterns may be used as predictors of TP53 gene mutations and therefore could be potential surrogate markers for TP53 mutations in GI-NENs and could distinguish between well-differentiated NETs and poorly differentiated NECs.

Project description:Background: Lumican (LUM) is a member of the small leucine-rich proteoglycan family and plays dual roles as an oncogene and a tumor suppressor gene. The effect of LUM on tumors is still controversial. Methods: Gene expression profiles and clinical data of gastric cancer (GC) were downloaded from The Cancer Genome Atlas (TCGA) database. The expression difference of LUM in GC tissues and adjacent nontumor tissues was analyzed by R software and verified by quantitative real-time polymerase chain reaction (qRT-PCR) and comprehensive meta-analysis. The relationship between LUM expression and clinicopathological parameters was assessed by chi-square test and logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards regression model were chosen to assess the effect of LUM expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways involved in GC between the low and the high LUM expression datasets. Results: The expression of LUM in GC tissues was significantly higher than that in adjacent nontumor tissues (P < 0.001) from the TCGA database. qRT-PCR (P = 0.022) and comprehensive meta-analysis (standard mean difference = 0.90, 95% CI: 0.34-1.46) demonstrated that LUM was upregulated in GC. The chi-square test showed that the high expression of LUM was correlated with tumor differentiation (P = 0.024) and T stage (P = 0.004). Logistic regression analysis showed that high LUM expression was significantly correlated with tumor differentiation (OR = 1.543 for poor vs. well or moderate, P = 0.043), pathological stage (OR = 3.149 for stage II vs. stage I, P = 0.001; OR = 2.505 for stage III vs. stage I, P = 0.007), and T classification (OR = 13.304 for T2 vs. T1, P = 0.014; OR = 18.434 for T3 vs. T1, P = 0.005; OR = 30.649 for T4 vs. T1, P = 0.001). The Kaplan-Meier curves suggested that patients with high LUM expression had a poor prognosis. Multivariate analysis showed that a high expression of LUM was an important independent predictor of poor overall survival (HR, 1.189; 95% CI, 1.011-1.400; P = 0.037). GSEA indicated that 14 signaling pathways were evidently enriched in samples with the high-LUM expression phenotype. Conclusions: LUM might act as an oncogene in the progression of GC and could be regarded as a potential prognostic indicator and therapeutic target for GC.

Project description:BackgroundGastric cancer is the sixth most frequently diagnosed cancer and third in causing cancer-related death globally. The most frequently mutated gene in human cancers is TP53, which plays a pivotal role in cancer initiation and progression. In Africa, particularly in Rwanda, data on TP53 mutations are lacking. Therefore, this study intended to obtain TP53 mutation status in Rwandan patients with gastric cancer.ResultsFormalin-fixed paraffin-embedded tissue blocks of 95 Rwandan patients with histopathologically proven gastric carcinoma were obtained from the University Teaching Hospital of Kigali. After DNA extraction, all coding regions of the TP53 gene and the exon-intron boundary region of TP53 were sequenced using the Sanger sequencing. Mutated TP53 were observed in 24 (25.3%) of the 95 cases, and a total of 29 mutations were identified. These TP53 mutations were distributed between exon 4 and 8 and most of them were missense mutations (19/29; 65.5%). Immunohistochemical analysis for TP53 revealed that most of the TP53 missense mutations were associated with TP53 protein accumulation. Among the 29 mutations, one was novel (c.459_477delCGGCACCCGCGTCCGCGCC). This 19-bp deletion mutation in exon 5 caused the production of truncated TP53 protein (p.G154Wfs*10). Regarding the spectrum of TP53 mutations, G:C > A:T at CpG sites was the most prevalent (10/29; 34.5%) and G:C > T:A was the second most prevalent (7/29; 24.1%). Interestingly, when the mutation spectrum of TP53 was compared to three previous TP53 mutational studies on non-Rwandan patients with gastric cancer, G:C > T:A mutations were significantly more frequent in this study than in our previous study (p = 0.013), the TCGA database (p = 0.017), and a previous study on patients from Hong Kong (p = 0.006). Even after correcting for false discovery, statistical significance was observed.ConclusionsOur results suggested that TP53 G:C > T:A transversion mutation in Rwandan patients with gastric cancer is more frequent than in non-Rwandan patients with gastric cancer, indicating at an alternative etiological and carcinogenic progression of gastric cancer in Rwanda.

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Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer.

Publications

Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer.

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