The usefulness of CDH1 methylation as a gastric cancer peritoneal metastasis biomarker
China Gastric Cancer Research Highlight

The usefulness of CDH1 methylation as a gastric cancer peritoneal metastasis biomarker

Wallax Augusto Silva Ferreira1, Danilo do Rosário Pinheiro2, Symara Rodrigues-Antunes1, Mariceli Baia Leão Barros1, Bárbara do Nascimento Borges3

1Molecular Biology Laboratory, Biological Science Institute, Federal University of Pará, Belém, Pará, Brazil;2Master Program of Animal Health and Production, Federal Rural University of Amazonia, Belém, Pará, Brazil;3Socio-environmental and Hydric Resources Institute, Federal Rural University of Amazonia, Belém, Pará, Brazil

Corresponding to: Bárbara do Nascimento Borges. Universidade Federal Rural da Amazônia (UFRA), Instituto Socioambiental e dos Recursos Hídricos (ISARH), Avenida Presidente Tancredo Neves 2501, Zip Code: 66077-530, Bairro: Montese, Belém, Pará, Brazil. Email: barbara.borges@ufra.edu.br or pithecia@gmail.com.

Submitted May 08, 2013. Accepted for publication May 28, 2013.

doi: 10.3978/j.issn.2224-4778.2013.05.22

Gastric cancer (GC) remains one of the most prevalent malignant diseases worldwide, being considered the second leading cause of global cancer deaths, affecting close to one million people per year (1). Although some recent advances in molecular biology, surgery, chemotherapy, and radiotherapy have been made, the poor prognosis and high mortality rate continue to make gastric cancer an attractive target of active clinical and basic scientific research (2).

Due to GC heterogeneity, some classifications have been proposed over the years, based on histopathology, clinical aspects, and endoscopic characteristics (3-5). However, the most widely used is the one proposed by Laurén (4), which classifies GC into intestinal and diffuse types, according to structural characteristics of the tumors. Some studies point out differences in the clinicopathological characteristics between these two types, indicating that they are a result of distinct molecular pathways (6).

The etiology of GC is considered multifactorial as many inherited and environmental factors, like diet, lifestyle, genetic and socioeconomic factors, play a role in its carcinogenesis. However, it is clear that the major etiologic risk factor for GC is Helicobacter pylori (H. pylori), which is responsible for more than 80% of cases (7).

A number of studies provide evidences that both genetic and epigenetic alterations play critical roles in GC. Although the role of genetic alterations has long been recognized, in the last decade epigenetic modifications have also been considered as an important factor in GC pathway (7). Accumulating evidence indicates that aberrant promoter methylation is one of the most common molecular alterations in GC, being considered as a sensitive and very promising biomarker in early diagnosis of tumors (8).

A number of tumor-suppressor and tumor-related genes, including APC, CDH1, MHL1, CDKN2A, CDKN2B and RUNX3 are commonly methylated in GC (6), suggesting the potential clinical value of DNA methylation as a marker for risk prediction and prognosis (9). Among those, CDH1 deserves special attention as is widely reported as silenced in GC, mainly of the diffuse type, especially by promoter methylation (10-12).

CDH1, a suppressor gene located on chromosome 16q22.1 and member of the APC pathway, codifies for the E-cadherin protein and belongs to a family of cell surface glycoproteins that mediates the cell-cell adhesion playing an important role in the maintenance of the tissue architecture (13,14). The inactivation of E-cadherin results in a decreased cell adhesion, an increased cell motility and abnormal polarity, which favors the infiltrative ability and promotes tumor metastasis (8,15,16).

Various degrees of methylation in the CDH1 promoter CpG islands and the consequent loss of E-cadherin expression were reported in GC (8,17), including the Hereditary Diffuse Gastric Cancer (HDGC) as 25-40% of the cases are caused by heterozygous silence of E-cadherin (12,18).

The main consequence of CDH1 inactivation is the loss of cell-cell adhesion which is correlated with an infiltrative and metastatic ability in GC (12,19). CDH1 inactivation is so strongly correlated with GC prognosis and survival that patients with E-cadherin-positive gastric cancers showed statistically significant prolonged 3- and 5-year survival rates, compared to patients with E-cadherin-negative tumors (20).

Frequently, GC is diagnosed in advanced stage where the surgical resection is the only option for treatment (21). Considering this information and the high level of metastasis, including in the peritoneum, the identification of biomarkers for early detection and/or presence of GC metastasis is a very important task for its prevention and treatment (22).

Peritoneal metastasis is an important event in the GC prognosis as it may be responsible for resistance to various chemotherapeutic drugs and causes ascites and intestinal obstruction. This type of metastasis has a difficult identification as it may occurs in cases with negative cytological examination (23,24). The methylation pattern of several genes was evaluated in peritoneal washes in order to identify possible biomarkers of abdomen metastasis. The methylation observed in the peritoneum fluid (PF) was successful in the detection of occult neoplastic cells on the peritoneum, and that its use along with a cytological examination might increase the positive detection of cancer cells in PF (24).

Recently, Yu et al. (25) published an important paper in this subject, reporting that alterations in the methylation pattern of CDH1 in preoperative peritoneal washes were significant correlated with abdomen metastasis and poor prognosis, suggesting that this marker could be used for the diagnosis of tumor invasion, metastasis and progression of GC.

In conclusion, even with few studies focusing the search for peritoneal metastasis biomarkers which can be predictive of poor prognosis, we can speculate that studies in this field are extremely important as they have great utility for the medical community and consequently for the patients’ survival.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

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Cite this article as: Silva Ferreira WA, do Rosário Pinheiro D, Rodrigues-Antunes S, Leão Barros MB, do Nascimento Borges B. The usefulness of CDH1 methylation as a gastric cancer peritoneal metastasis biomarker. Transl Gastrointest Cancer 2013;2(S1):116-118. doi: 10.3978/j.issn.2224-4778.2013.05.22