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Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report.

ABSTRACT: BACKGROUND:In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/?-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals. CASE PRESENTATION:Here, we report the case of a treatment-naïve mixed hepatocellular/cholangiocellular carcinoma (HCC/CCC) with morphological and genetic intratumor heterogeneity. Within the predominant part of the tumor with hepatocellular differentiation, a p.D32V mutation in exon 3 of the CTNNB1 gene occurred concomitantly with a TP53 intron 7/exon 8 splice site mutation. CONCLUSION:Intratumor heterogeneity challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC, which has implications for HCC classification approaches.

SUBMITTER: Friemel J

PROVIDER: S-EPMC4888639 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report.

Friemel Juliane J Rechsteiner Markus M Bawohl Marion M Frick Lukas L Müllhaupt Beat B Lesurtel Mickaël M Weber Achim A

BMC clinical pathology 20160601

<h4>Background</h4>In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/β-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals.<h4>Case presentation</h4>Here, we report the case of a treatment-naïve mixed hepatocellular/cholangiocellular carcinoma (HCC ...[more]

PMID: 27252594

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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.

Dataset Information

Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report.

Publications

Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report.

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