Hypermethylation of promoter regions of the APC1A and p16INK4a genes in relation to prognosis and tumor characteristics in cervical cancer patients

Abstract

Abstract. Hypermethylation of the O 6 -MGMT, p14ARF , p16 INK4a, RASSF1A and APC1A genes are unfavourable prognostic markers in colorectal cancer (CRC). We hypothesized that they could be related to prognosis also in cervical cancer. Methylation was studied in DNA extracts from surgical specimens of cancer tissue by novel pyrosequencing methods. In 109 patients (90 squamous cell carcinomas, 19 adenocarcinomas), we found that hypermethylation of the APC1A gene promoter occurred in 8.3% of patients, and of p16 INK4a in 1.8%. APC1A hypermethylation was significantly related to more advanced FIGO stage of the tumor (P=0.013), larger tumor diameter (P=0.049) and distant recurrence-free survival (P=0.0007), but not with locoregional recurrence rate, age, HPV status, DNA ploidy, tumor grade or malignancy grading score. We conclude that methylation of the APC1A promoter in cervical cancer, as diagnosed by pyrosequencing, is significantly related to major biological characteristics of the tumor, and may be a new predictor of poor prognosis in cervical cancer.

DNA methylation of the p14ARF, RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients

“…3). Employing the same Pyrosequencing assays (13) as in the present paper, we recently showed that APC1A promoter methylation was associated with poor prognosis also in cervical cancer (39). …”

Associations of P16INK4a promoter hypermethylation with squamous intra-epithelial lesion, cervical cancer and their clinicopathological features: a meta-analysis

“…Hence, 28 articles with 29 studies were finally included [11–13, 15–39]. Among these studies, all studies were eligible to estimate the P16 INK4a hypermethylation rates; 20 studies (1 cross-sectional [13] and 19 case-control designs [16, 17, 19, 21–28, 30–35, 37, 38]) investigated the associations of P16 INK4a methylation status with the risk of LSIL, HSIL and CC; 1254 SIL/CC patients from 18 studies (11 case-control studies [19, 21, 23, 25, 26, 31, 32, 35–38] and 7 case-only studies [11, 12, 15, 18, 20, 29, 39]) were eligible to assess the associations between P16 INK4a methylation status and clinicopathological features. For most of these studies (26 studies), the methylation detection was based on methylation-specific PCR (MSP) (including MSP, nested MSP and MSP with another method (sequencing, prosequencing and BSP) for quality control).…”

“…Thereafter, numerous studies were carried out to assess the associations of P16 INK4a hypermethylation with the development of SIL and CC. However, most of these studies only included relatively small sample size, leading to inconsistent results and a broad range of P16 INK4a hypermethylation rates (from 2% to 93%) in cancer tissues [12, 13]. Moreover, the effect of P16 INK4a promoter hypermethylation on different phases of cervical carcinogenesis (from LSIL to CC) is less summarized.…”

Impact of DNA methylation on trophoblast function

“…Thus, methylation status of the APC1A tumor suppressor gene promoter has been suggested as a novel marker of an unfavourable outcome in cervical cancer, i.e. prognosis is worse with an increase in promoter methylation [9]. The relationship between APC1A methylation and cervical cancer clinical outcome may be explained by known functions of the APC1A in cell adhesion and β-catenin inactivation.…”