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. 2011 Mar;140(3):1063-70.
doi: 10.1053/j.gastro.2010.11.034. Epub 2010 Nov 19.

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

Hyun Goo Woo  1 , Xin Wei Wang, Anuradha Budhu, Yun Hee Kim, So Mee Kwon, Zhao-You Tang, Zongtang Sun, Curtis C Harris, Snorri S Thorgeirsson
Affiliations

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

Hyun Goo Woo et al. Gastroenterology. 2011 Mar.

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.

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Figures

Figure 1
Figure 1. Prognostic values of TP53 mutation sites
(A) Kaplan-Meir plot for survival between the tumors of mutation-type (MT) and wild-type (WT) TP53. (B). Kaplan-Meir plot for survival between the tumors with R249S and V157F mutations. (C) Kaplan-Meir plot for survival between the tumors with hotspot (i.e. R249S and V157F) and non-hotspot mutations. The + symbols in panel indicate censored data.
Figure 2
Figure 2. Prognostic value of combined status of TP53 mutation and other clinical features
(A–D) Kaplan-Meir plots for survival between patients with mutation-type (MT) and wild-type (WT) TP53 in subpopulations of patients who have a low tumor grade (I, II) (A), low serum AFP level (< 300 ng/ml) (B), large tumor size (> 5cm), (C), or liver cirrhosis (D). The + symbols in panel indicate censored data.
Figure 3
Figure 3. Expression of stem cell-like traits in TP53 mutated tumors
(A) The enrichment scores for the ES signatures and HB signatures in the compiled HCC data set are shown on the left; the enrichment in groups of mutation-type (MT) and wild-type (WT) is shown in the middle; and the enrichments of ES signature without the proliferation-related genes (noprol) are shown on the right. The enrichment scores in each sample and group represent −log10 (P-value) calculated by hypergeometric test. (B) Based on the expression status of ES1 (upper) or HB (lower) signatures and the hotspot TP53 mutation status, the 366 patients were stratified into four groups. 42 cases of non-hotspot mutations were not included in the analysis. ES+ represent the tumors which were enriched with ES1 signature (P<0.01), while other tumors were indicated as ES−. HB+ represents the tumors which were positively enriched with HB_UP and negatively enriched with HB_DOWN signatures (P<0.01), while other tumors were indicated as HB−. (C) The plots showed the enrichment scores (ES) for the ES1 signature in breast cancers (upper) and lung cancers (lower) were calculated by GSEA method.
Figure 4
Figure 4. Validation of CD24 and AFP expression by quantitative PCR
(A, B) Expression of CD24 (A) and AFP (B) levels in mutant type (MT, n=31) and wild-type (WT, n=44) HCCs were measured by quantitative PCR. Statistical significance was tested by two-tailed Mann-Whitney U test. Median and interquartile ranges were indicated by horizontal lines.
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