Status of p16<SUP>INK4a</SUP> and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

Abstract

Aberrant methylation of tumor suppressor gene promoters has been extensively investigated in cervical cancer. Transcriptional silencing, as a main consequence of hypermethylation of CpG islands, is the predominant mechanism of p16 INK4a and E-cadherin gene inactivation in malignant epithelial tumors. This study was conducted to evaluate the promoter methylation status of p16 INK4a and E-cadherin genes in 22 specimens of cervical carcinomas, four cervical cancer cell lines (HeLa, SiHa, Caski, C33A), and 20 human papillomavirus negative specimens, obtained from normal cervical swabs, using the methylation-specific PCR approach. Hypermethylation of the 5′ CpG island of the p16 INK4a and E-cadherin genes were found in 13 (59.1%) and 10 (45.5%) of 22 cervical cancer samples, respectively. Furthermore, our findings did not show any correlation between promoter methylation of p16 INK4a and E-cadherin genes and clinicopathological parameters, including HPV infection, phenotypic distribution, and stage of the disease. However, hypermethylation of E-cadherin gene promoter appears to be age related in cervical cancer, whereas the frequency of aberrant methylation of p16 INK4a gene promoter is unchanged according to the age of patients. Thus, caution must be made to use these markers in the diagnosis of cervical cancer. However, dietary or pharmaceutical agents that can inhibit these epigenetic events may prevent or delay the development of cervical cancer.

p16INK4a and p15INK4b gene promoter methylation in cervical cancer patients

“…INK4a gene promoter to be unchanged according to the patient age (28). Similar observations were also obtained in the present study, suggesting that age is not associated with the increase in the risk of cervical cancer with respect to p16 hypermethylation.…”

p16 (INK4a) has clinicopathological and prognostic impact on oropharynx and larynx squamous cell carcinoma

“…The loss of p16 (INK4a) through homologous deletion, point mutation or methylation-induced promoter silencing has also been widely observed in cancer cell lines and some malignant tumors, such as acute lymphoblastic leukemia (3,4,7), melanomas (8), pancreatic cancer (9), esophagus (10), lung (11), bladder (1), cervical (12), and head and neck squamous cell carcinomas (HNSCC) (6,13). Additionally, the absence of p16 (INK4a) is an early and often critical event in tumor progression, once that deletion in at least one copy is quite high in premalignant lesions giving selective advantage to neoplastic cells (14).…”

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).…”

“…A total of 388 LSIL [13, 15–18, 22, 24, 25, 27, 33–35, 38, 39], 636 HSIL [13, 15–18, 22–25, 27, 28, 32–35, 37, 38] and 1439 CC [11–13, 15, 17–26, 29–31, 33–38] specimens were included in this meta-analysis. As summarized in Table 2, the pooled rates of P16 INK4a hypermethylation showed an increasing trend ( p < 0.001 for the differences in pooled rates) from LSIL tissues (21.4%, 95% confidence interval (CI): 15.0-29.7%) to HSIL tissues (30.9%, 95% CI: 21.9-41.7%) and ultimately to CC specimens (35.0%, 95%CI: 27.6-43.3%).…”

“…Eighteen studies [13, 17, 19, 21–26, 30, 31, 33–38] with 950 CC patients and 732 controls were included to appraise the effect of P16 INK4a promoter hypermethylation on CC risk. There was a significant association between P16 INK4a promoter hypermethylation and increased CC risk, with an OR of 12.17 (95% CI: 5.86-25.27) and a p value of < 0.001 (Figure 4 and Table 5).…”