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Promoter methylation of CDKN2A and lack of p16 expression characterize patients with hepatocellular carcinoma.

Csepregi A, Ebert MP, Röcken C, Schneider-Stock R, Hoffmann J, Schulz HU, Roessner A, Malfertheiner P - BMC Cancer (2010)

Bottom Line: Hypermethylation of the CDKN2A promoter was found in 23 HCCs (69.7%; mean PMR = 42.34 +/- 27.8%), six (20.7%; mean PMR = 31.85 +/- 18%) liver metastases and in the extralesional tissue of only one patient.Correspondingly, nuclear p16 expression was found immunohistochemically in five (10.9%, mean IRS = 0.5) HCCs, 23 (92%; mean IRS = 4.9) metastases and only occasionally in hepatocytes of non-lesional liver tissues (mean IRS = 1.2).The difference of CDKN2A-methylation and p16 protein expression between HCCs and liver metastases was statistically significant (p < 0.01, respectively).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany. csepregia@yahoo.de

ABSTRACT

Background: The product of CDKN2A, p16 is an essential regulator of the cell cycle controlling the entry into the S-phase. Herein, we evaluated CDKN2A promoter methylation and p16 protein expression for the differentiation of hepatocellular carcinoma (HCC) from other liver tumors.

Methods: Tumor and corresponding non-tumor liver tissue samples were obtained from 85 patients with liver tumors. CDKN2A promoter methylation was studied using MethyLight technique and methylation-specific PCR (MSP). In the MethyLight analysis, samples with > or = 4% of PMR (percentage of methylated reference) were regarded as hypermethylated. p16 expression was evaluated by immunohistochemistry in tissue sections (n = 148) obtained from 81 patients using an immunoreactivity score (IRS) ranging from 0 (no expression) to 6 (strong expression).

Results: Hypermethylation of the CDKN2A promoter was found in 23 HCCs (69.7%; mean PMR = 42.34 +/- 27.8%), six (20.7%; mean PMR = 31.85 +/- 18%) liver metastases and in the extralesional tissue of only one patient. Using MSP, 32% of the non-tumor (n = 85), 70% of the HCCs, 40% of the CCCs and 24% of the liver metastases were hypermethylated. Correspondingly, nuclear p16 expression was found immunohistochemically in five (10.9%, mean IRS = 0.5) HCCs, 23 (92%; mean IRS = 4.9) metastases and only occasionally in hepatocytes of non-lesional liver tissues (mean IRS = 1.2). The difference of CDKN2A-methylation and p16 protein expression between HCCs and liver metastases was statistically significant (p < 0.01, respectively).

Conclusion: Promoter methylation of CDKN2A gene and lack of p16 expression characterize patients with HCC.

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Results of Methylight analysis. Frequency of promoter methylation of CDKN2A gene is shown in patients with liver tumors detected by Methylight assay.
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Figure 1: Results of Methylight analysis. Frequency of promoter methylation of CDKN2A gene is shown in patients with liver tumors detected by Methylight assay.

Mentions: Using Methylight assay, methylation status of 8 CpG islands of the first exon of CDKN2A was evaluated in 33 HCCs and the corresponding non-tumor liver samples. The mean PMR of HCC samples was 31.41 ± 27.63% (range 0.01 to 100%) (Table 1). Twenty-three patients with HCC (69.7%) showed a PMR > 4% and were regarded as hypermethylated. The CDKN2A hypermethylation positive HCCs showed a mean PMR of 42.34 ± 27.8% (range 7.91 to 100%) (Table 1). A methylation of CpG islands was detected in 4 (57%) of 7 well-differentiated, 15 (79%) of 19 moderately differentiated, and 4 (57%) of 7 poorly differentiated HCCs. The frequency of promoter hypermethylation between patients with non-HCV induced HCC and those with HCV-induced HCC was not different (69% vs. 70%; ns). The mean PMR of the corresponding non-cancer liver tissues was 1.15 ± 1.64% (range 0.01 to 22.41). All but one (HCC patient No. 21) corresponding non-tumor samples obtained from patients with HCC were found to have an unmethylated CDKN2A promoter (Figure 1).


Promoter methylation of CDKN2A and lack of p16 expression characterize patients with hepatocellular carcinoma.

Csepregi A, Ebert MP, Röcken C, Schneider-Stock R, Hoffmann J, Schulz HU, Roessner A, Malfertheiner P - BMC Cancer (2010)

Results of Methylight analysis. Frequency of promoter methylation of CDKN2A gene is shown in patients with liver tumors detected by Methylight assay.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927998&req=5

Figure 1: Results of Methylight analysis. Frequency of promoter methylation of CDKN2A gene is shown in patients with liver tumors detected by Methylight assay.
Mentions: Using Methylight assay, methylation status of 8 CpG islands of the first exon of CDKN2A was evaluated in 33 HCCs and the corresponding non-tumor liver samples. The mean PMR of HCC samples was 31.41 ± 27.63% (range 0.01 to 100%) (Table 1). Twenty-three patients with HCC (69.7%) showed a PMR > 4% and were regarded as hypermethylated. The CDKN2A hypermethylation positive HCCs showed a mean PMR of 42.34 ± 27.8% (range 7.91 to 100%) (Table 1). A methylation of CpG islands was detected in 4 (57%) of 7 well-differentiated, 15 (79%) of 19 moderately differentiated, and 4 (57%) of 7 poorly differentiated HCCs. The frequency of promoter hypermethylation between patients with non-HCV induced HCC and those with HCV-induced HCC was not different (69% vs. 70%; ns). The mean PMR of the corresponding non-cancer liver tissues was 1.15 ± 1.64% (range 0.01 to 22.41). All but one (HCC patient No. 21) corresponding non-tumor samples obtained from patients with HCC were found to have an unmethylated CDKN2A promoter (Figure 1).

Bottom Line: Hypermethylation of the CDKN2A promoter was found in 23 HCCs (69.7%; mean PMR = 42.34 +/- 27.8%), six (20.7%; mean PMR = 31.85 +/- 18%) liver metastases and in the extralesional tissue of only one patient.Correspondingly, nuclear p16 expression was found immunohistochemically in five (10.9%, mean IRS = 0.5) HCCs, 23 (92%; mean IRS = 4.9) metastases and only occasionally in hepatocytes of non-lesional liver tissues (mean IRS = 1.2).The difference of CDKN2A-methylation and p16 protein expression between HCCs and liver metastases was statistically significant (p < 0.01, respectively).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany. csepregia@yahoo.de

ABSTRACT

Background: The product of CDKN2A, p16 is an essential regulator of the cell cycle controlling the entry into the S-phase. Herein, we evaluated CDKN2A promoter methylation and p16 protein expression for the differentiation of hepatocellular carcinoma (HCC) from other liver tumors.

Methods: Tumor and corresponding non-tumor liver tissue samples were obtained from 85 patients with liver tumors. CDKN2A promoter methylation was studied using MethyLight technique and methylation-specific PCR (MSP). In the MethyLight analysis, samples with > or = 4% of PMR (percentage of methylated reference) were regarded as hypermethylated. p16 expression was evaluated by immunohistochemistry in tissue sections (n = 148) obtained from 81 patients using an immunoreactivity score (IRS) ranging from 0 (no expression) to 6 (strong expression).

Results: Hypermethylation of the CDKN2A promoter was found in 23 HCCs (69.7%; mean PMR = 42.34 +/- 27.8%), six (20.7%; mean PMR = 31.85 +/- 18%) liver metastases and in the extralesional tissue of only one patient. Using MSP, 32% of the non-tumor (n = 85), 70% of the HCCs, 40% of the CCCs and 24% of the liver metastases were hypermethylated. Correspondingly, nuclear p16 expression was found immunohistochemically in five (10.9%, mean IRS = 0.5) HCCs, 23 (92%; mean IRS = 4.9) metastases and only occasionally in hepatocytes of non-lesional liver tissues (mean IRS = 1.2). The difference of CDKN2A-methylation and p16 protein expression between HCCs and liver metastases was statistically significant (p < 0.01, respectively).

Conclusion: Promoter methylation of CDKN2A gene and lack of p16 expression characterize patients with HCC.

Show MeSH
Related in: MedlinePlus