Cancer Res Treat.  2020 Jul;52(3):925-937. 10.4143/crt.2019.533.

Prognostic Value of TP53 Mutation for Transcatheter Arterial Chemoembolization Failure/Refractoriness in HBV-Related Advanced Hepatocellular Carcinoma

• Xue M
• Wu Y
• Fan W
• Guo J
• Wei J
• Wang H
• Tan J
• Wang Y
• Yao W
• Zhao Y
• Li J

• KMID: 2504471
• DOI: http://doi.org/10.4143/crt.2019.533

Abstract

Purpose
This study aimed to investigate the clinicopathologic features and mutational landscape of patients with hepatitis B virus (HBV)–related advanced hepatocellular carcinomas (HCC) undergoing transcatheter arterial chemoembolization (TACE).
Materials and Methods
From January 2017 to December 2018, 38 patients newly diagnosed with HBV-related advanced HCC were enrolled in the final analysis. Their pathological tissues and corresponding blood samples before TACE treatment were collected for whole-exome sequencing. Response to TACE was evaluated at 1-3 months after two consecutive use of TACE. Predictive factors were analyzed by univariate and multivariate analyses in a bivariate Logistic regression model. Enrichment of related pathways of all driver genes were acquired using the gene set enrichment analysis (GSEA).
Results
Among 38 patients, 23 (60.5%) exhibited TACE failure/refractoriness. Patients with TACE failure/refractoriness showed higher frequency of TP53 mutation than their counterparts (p=0.020). Univariate and multivariate analyses showed that only vascular invasion and TP53 mutation were significantly correlated with TACE failure/refractoriness in HBV-related advanced HCC. Of the 16 patients without vascular invasion, eight (50.0%) had TP53 mutations, and TP53 mutation was associated with TACE failure/refractoriness (p=0.041). Moreover, GSEA showed that mitogen-activated protein kinase and apoptosis pathways induced by TP53 mutation were possibly associated with TACE failure/refractoriness.
Conclusion
Our study suggested that TP53 mutation was independently related with TACE efficacy, which may work via mitogen-activated protein kinase and apoptosis pathways. These findings may provide evidence to help distinguish patients who will particularly benefit from TACE from those who require more personalized therapeutic regimens and rigorous surveillance in HBV-related advanced HCC.

Keyword

Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Whole-exome sequencing; Treatment outcome; Tumor response; Tumor protein p53

Figure

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  Fig. 1. Flow chart of enrolled patients. HCC, hepatocellular carcinoma; WES, whole-exome sequencing; TACE, transcatheter arterial chemoembolization; CT, computed tomography; MRI, magnetic resonance imaging.

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  Fig. 2. Heatmap of somatic genetic alterations in significant variation genes between groups A and B. Group A is defined as a group where transcatheter arterial chemoembolization (TACE) failure/refractoriness. And group B is defined as a group which can benefit from TACE therapy. Top and right panel shows the frequency of somatic mutation, middle panel shows patients ID, mutational spectra of single-nucleotide variants in different group, and types of mutation are indicated in the legend at the bottom (n=38). We found that the occurrence probability of TP53 and FLG mutations in the invalid group was significantly higher than that in group A. T>G mutation did not occur in group A during the transformation and alteration.

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  Fig. 3. Distribution of somatic mutations in the TP53 gene. The structural domains of TP53 mutations were different between the two groups, and the occurrence probability of TP53 R249S mutation in group A was higher than that in group B. Alteration frequency was represented as a percentage of significant variation genes in two groups: the left box represents group A and the right represents group B. Alteration types and frequencies were represented by different colors and color gradients, respectively.

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  Fig. 4. TP53 mutated and wild-type cases were compared before and after transcatheter arterial chemoembolization (TACE) by using computed tomography (CT) scan. For TP53 mutated case in A, plain sweep, augmentation, and portal phase were shown respectively in a, b, and c before TACE, while they were shown in d, e, and g after TACE. We found that TACE failure/refractoriness was assessed in the TP53 mutated case. Meanwhile, the TP53 wild-type case was shown in B and effective for TACE. The two cases were evaluated according to the criteria mentioned above.

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  Fig. 5. Frequently altered cancer pathways for TP53 using gene set enrichment analysis pathway enrichment in hepatocellular carcinoma. Core pathway analysis identified frequent genomic alterations in multiple cancer pathways including mitogen-activated protein kinase and apoptosis. MAPK, mitogen-activated protein kinase.

Reference

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