Stomach cancer (SC) is one of the most common cancers and the third leading cause of cancer-related deaths; however, it is often diagnosed at later stages. Literature data on epigenetic changes in stomach cancer and precancer, in particular on hypermethylation of tumor suppressor genes, indicate its important role in gastric tissue malignization.
Bisulfite pyrosequencing was used to study the CpG methylation in promoter sites of 6 tumor suppressor genes (APC, CDH13, MLH1, MGMT, P16 and RASSF1A). The study included paired bioptates of tumors and intact tissues obtained from 35 patients (25 men, 10 women, median age 67 years) with stomach cancer (G2-3 adenocarcinoma, T3-4N0-2M0).
The rates of hypermethylation of the MGMT, P16 and RASSF1A genes amounted to 23%, 14% and 11% respectively. Increased methylation in the promoter site of the MLH1 gene was observed in one case only (11% vs 4%). Regulatory sites of CDH13 and APC genes in intact tissues were atypically hypermethylated in 80% of cases, which was obviously associated with functional characteristics of the gastric mucosa. However, the methylation of the promoter site of the CDH13 gene in non-tumor tissue was 2 times lower compared to the local tumor (p = 0.002) and 1.5 times lower compared to the tumor with lymph node metastases (p = 0.012). An association between the methylation of the P16 and RASSF1A genes and higher tumor grade G (p = 0.046) and increasing tumor sizes (T-classification, p = 0.028) was registered.
We observed hypermethylation of the promoter sites of the MGMT, P16 (CDKN2A) and RASSF1A genes in malignant stomach tissues compared to intact tissues which demonstrated the importance of disorders of repair processes (MGMT and RASSF1A) and mechanisms of regulation of the cell cycle (CDKN2A) in the malignization of stomach tissues. The methylation status of these genes can be a useful biomarker for early diagnosis of stomach cancer or possible therapeutic targets.
Clinical trial identification
Legal entity responsible for the study
Ministry of Health of the Russian Federation.
Has not received any funding.
All authors have declared no conflicts of interest.