Aberrant p16 methylation as an early diagnostic marker in blood of hepatocellular carcinoma patients

Abstract

Background Alpha-fetoprotein (AFP) is currently used for serologic screening in hepatocellular carcinoma (HCC) but with low sensitivity ranging 41–65% with a high rate of false-negative and false-positive results. For the hypermethylation of the p16 inhibitor of cyclin-dependent kinase 4 (p16INK4A), a tumor suppressor gene results in the uncontrolled division of cells. This suggests that the loss of p16INK4A function due to promoter methylation may be an early event in HCC pathogenesis so the study aimed to assess aberrant p16INK4A gene methylation as an early diagnostic marker in HCC patients. Results Our study revealed a highly significant increase of p16INK4A methylation in patients versus controls (Fisher, 36.11; p < 0.01). P16INK4A methylation was detected in 86.6% (26/30) and none of the controls were methylated (100% specificity) compared to the low sensitivity of AFP 65.38% at a cutoff value of 28 ng/mL. Data revealed non-significant difference of p16INK4A methylation status between different HCC Barcelona stages (Fisher, 0.055; p > 0.05). While, AFP levels were statistically significantly higher in stages B and C (median = 243,400 ng/mL, respectively, when compared to stage A (median = 10 ng/mL) (H:16.667, p < 0.01)). Conclusion Early diagnosis of HCC can be achieved through the detection of p16INK4A gene methylation in chronic liver disease (CLD) patients with normal serum AFP especially in known cirrhotic patients that deteriorate clinically without apparent etiology.

Diagnostic performance of RASSF1A and CDKN2A gene methylation versus a-fetoprotein in hepatocellular carcinoma

“…As regards AFP serum levels, there was no significant association with CDKN2A methylation, in contrast to Seif et al, who observed that AFP serum levels were considerably higher in the methylated group of patients than in the non-methylated group [7]. The current study's findings might be related to the diversity of the patient groups evaluated.…”

“…Cell cycle regulation, apoptosis induction, microtubule stability, and cellular adhesion are all functions of the protein encoded by RASSF1A [9]. According to previous research, RASSF1A deactivation by promoter hypermethylation has been found to occur frequently in malignant tumors, including HCC [7].…”

“…RAS association domain family protein 1 transcript A (RASSF1A) and cyclin-dependent kinase inhibitor 2A (CDKN2A) are two cell cycle regulator genes that have previously been shown to be deactivated by hypermethylation in malignant tumors [7].…”