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Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma.

ABSTRACT: BACKGROUND & AIMS:Mutations in TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic values of TP53 mutation sites are not known for patients with hepatocellular carcinoma (HCC) because of heterogeneity in their geographic and etiologic backgrounds. METHODS:TP53 mutations were investigated in a total of 409 HCC patients, including Chinese (n = 336) and white (n = 73) patients, using the direct sequencing method. RESULTS:A total of 125 TP53 mutations were found in Chinese patients with HCC (37.2%). HCC patients with TP53 mutations had a shorter overall survival time compared with patients with wild-type TP53 (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.37-2.52; P < .001). The hot spot mutations R249S and V157F were significantly associated with worse prognosis in univariate (HR, 2.11; 95% CI: 1.51-2.94; P < .001) and multivariate analyses (HR, 1.79; 95% CI: 1.29-2.51; P < .001). Gene expression analysis revealed the existence of stem cell-like traits in tumors with TP53 mutations. These findings were validated in breast and lung tumor samples with TP53 mutations. CONCLUSIONS:TP53 mutations, particularly the hot spot mutations R249S and V157F, are associated with poor prognosis for patients with HCC. The acquisition of stem cell-like gene expression traits might contribute to the aggressive behavior of tumors with TP53 mutation.

SUBMITTER: Woo HG

PROVIDER: S-EPMC3057345 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma.

Woo Hyun Goo HG Wang Xin Wei XW Budhu Anuradha A Kim Yun Hee YH Kwon So Mee SM Tang Zhao-You ZY Sun Zongtang Z Harris Curtis C CC Thorgeirsson Snorri S SS

Gastroenterology 20101119 3

<h4>Background & aims</h4>Mutations in TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic values of TP53 mutation sites are not known for patients with hepatocellular carcinoma (HCC) because of heterogeneity in their geographic and etiologic backgrounds.<h4>Methods</h4>TP53 mutations were investigated in a total of 409 HCC patients, including Chinese (n = 336) and white (n = 73) patients, using the direct sequencing method.<h4>Results</h4>A tota ...[more]

PMID: 21094160

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Project description:Background:Stratification of tumors is necessary to achieve better clinical outcomes. Hepatocellular carcinoma (HCC) is commonly associated with mutation of the TP53 gene and heterogeneity in immune cell content. However, TP53 mutation-associated immunotype of HCC has not been reported yet. This study aimed to identify the TP53 mutation-associated immunotype in HCC. Methods:The mutation annotation format (MAF) document, mRNA expression data, and clinical data of HCC patients were downloaded from the publicly available The Cancer Genome Atlas (TCGA) data portal. Data from 332 HCC patients were analyzed in this study. Infiltrating immune cells were evaluated by the well-known CIBERSORT method. Additional mutation data of HCC patients were downloaded from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Results:The TP53 gene harbored the highest frequency of mutations in HCC patients. Consequently, five lethal features, including TP53 mutations, were screened by least absolute shrinkage and selector operation (LASSO)-COX regression, according to TP53 mutations and 22 infiltrating immune cells. Two distinct subgroups of HCC were identified, namely, immunotypes A and B. Furthermore, the expression levels of co-inhibitory immune checkpoints were significantly upregulated, and the gene ontology (GO) terms or pathways to boost immune responses were found to be inhibited in the immunotype B subgroup compared to that in the immunotype A subgroup. Finally, we proved immunotype to be an independent adverse prognostic factor that contributed to improvement in the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment. Conclusions:Two distinct immunotypes of HCC, in terms of prognosis, phenotype, and function, were identified and the traditional understanding of intratumoralCD8+ T cells was subverted. Moreover, the identified immunotypes contributed to improving the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment in some HCC patients.

Project description:Background: Hepatitis B virus (HBV) infection is one of the major causes of chronic liver disease, which progresses from chronic hepatitis B (CHB) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Early detection and laboratory-based screening of hepatocellular carcinoma are still major challenges. This study was undertaken to determine whether the cancer hallmark gene signatures that are released into circulation as circulating tumour DNA (ctDNA) can be used as a liquid biopsy marker for screening, early detection, and prognosis of HCC. Methods: A total of 130 subjects, including HBV-HCC (n = 80), HBV-cirrhotic and non-cirrhotic (n = 35), and healthy (n = 15) controls, were evaluated for TP53 and beta-catenin (CTNNB1) gene hotspot mutations in ctDNA by Sanger-based cycle sequencing and droplet digital PCR (ddPCR) assays. Mutation detection frequency, percentage mutant fractions, and their association with tumour stage, mortality, and smoking habits were determined. Results: Sanger-based cycle sequencing was carried out for 32 HCC patients. Predict SNP Tools analysis indicated several pathogenic driver mutations in the ctDNA sequence, which include p.D228N, p.C229R, p.H233R, p.Y234D, p.S240T, p.G245S, and p.R249M for TP53 gene exon 7 and p.S33T for CTNNB1 gene exon 3. The TP53 c.746G>T (p.R249M) mutation was detected predominately (25% cases) by sequencing, but there was no dominant mutation at position c.747G>T (p.R249S) that was reported for HBV-HCC patients. A dual-probe ddPCR assay was developed to determine mutant and wild-type copy numbers of TP53 (p.R249M and p.R249S) and CTNNB1 (p.S45P) and their percentage mutant fraction in all 130 subjects. The TP53 R249M and CTNNB1 S45P mutations were detected in 31.25% and 26.25% of HCC patients, respectively, with a high mutant-to-wild-type fraction percentage (1.81% and 1.73%), which is significant as compared to cirrhotic and non-cirrhotic patients. Poor survival was observed in HCC patients with combined TP53 and CTNNB1 gene driver mutations. The TP53 R249M mutation was also significantly (p < 0.0001) associated with smoking habits (OR, 11.77; 95% CI, 3.219-36.20), but not the same for the TP53 R249S mutation. Conclusion: Screening of ctDNA TP53 and CTNNB1 gene mutations by ddPCR may be helpful for early detection and identifying the risk of HCC progression.

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Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma.

Publications

Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma.

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