Considerations about gastric cancer proteomics

Gastric Cancer (GC) is the third leading cause of death from cancer throughout the world1. Its incidence varies substantially among different countries. In Brazil, GC corresponds the fifth major cause of cancer mortality among men and the sixth among women. It is estimated that Brazil will have 20,520 new GC cases in 2016, 12,920 in men and 7,600 in women2. The stomach is classically divided into four anatomical regions: cardia, fundus, corpus and pylorus. Each has different glands, cells and functions, showing a heterogeneity in the morphological, cytological and molecular levels3.Based on this heterogeneity, some classification systems have been proposed to evaluate the gastric tumor’s pathological characteristics. For gastric adenocarcinoma, the Lauren’s classification is one of the most used systems, in which two major histologic subtypes are the intestinal and the diffuse, the indeterminate subtype being an uncommon one4. The World Health Organization (WHO) 2010 classification describes four major histologic patterns of gastric adenocarcinoma: tubular, papillary, mucous and poorly cohesive (including signet ring cell carcinoma), plus uncommon histologic variants5. GC is considered a multifactorial disease. However, the factors involved in tumor development and progression, especially in the genetic pathways, remain unclear. Among the risk factors involved are: genetic predisposition6, diet7, alcohol consumption, smoking8, and chronic Helicobacter pylori or Epstein-Barr virus (EBV) infection.The International Agency for Research on Cancer (IARC) classifies H. pylori and EBV as a class-I carcinogen9,10 , and both are known to up-regulate DNA methyltransferases (DNMT)11. GC lesions have shown to display hypermethylation of CDH1, which expresses E-cadherin protein, associated with DNMT1 protein overexpression by EBV infection12. The frequency of molecular studies aimed to analyze promoter methylation of tumor suppressor genes (TSG) and global proteomics in gastric carcinogenesis is increasing. Nonetheless, only a few13 consider important characteristics, such as: the different types of stomach cells, the tumor location and the influence of H. pylori and EBV infection. The molecular differences relating to anatomical and histological tumor areas were recently described14. The authors propose a molecular classification of gastric cancer, dividing it into four subtypes: tumors positive for EBV; microsatellite unstable tumors; genomically stable tumors and tumors with chromosomal instability. This classification may be important in future proteomics studies. A meta-analysis15 revealed differences based on gender and anatomic location in EBV-positive

G astric Cancer (GC) is the third leading cause of death from cancer throughout the world 1 .Its incidence varies substantially among different countries.In Brazil, GC corresponds the fifth major cause of cancer mortality among men and the sixth among women.It is estimated that Brazil will have 20,520 new GC cases in 2016, 12,920 in men and 7,600 in women 2 .
The stomach is classically divided into four anatomical regions: cardia, fundus, corpus and pylorus.
Each has different glands, cells and functions, showing a heterogeneity in the morphological, cytological and molecular levels 3 .Based on this heterogeneity, some classification systems have been proposed to evaluate the gastric tumor's pathological characteristics.For gastric adenocarcinoma, the Lauren's classification is one of the most used systems, in which two major histologic subtypes are the intestinal and the diffuse, the indeterminate subtype being an uncommon one 4 .The World Health Organization (WHO) 2010 classification describes four major histologic patterns of gastric adenocarcinoma: tubular, papillary, mucous and poorly cohesive (including signet ring cell carcinoma), plus uncommon histologic variants 5 .
GC is considered a multifactorial disease.The molecular differences relating to anatomical and histological tumor areas were recently described 14 .
The authors propose a molecular classification of gastric cancer, dividing it into four subtypes: tumors positive for EBV; microsatellite unstable tumors; genomically stable tumors and tumors with chromosomal instability.This classification may be important in future proteomics studies.

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gastric cancer compared with EBV-negative ones, and emphasized the importance of investigating the significance of EBV in GC.Another study analyzed the protein profiles of paired surgical specimens from primary gastric tumor with non-tumor mucosa 16 .Aquino et al. 17 showed that the non-tumor surgical margins presented several proteins previously correlated with cancer, but also other overexpressed proteins that may be related to tumor nourishment and metastasis.Lima et al. 18 However, the factors involved in tumor development and progression, especially in the genetic pathways, remain unclear.Among the risk factors involved are: genetic predisposition 6 , diet 7 , alcohol consumption, smoking 8 , and chronic Helicobacter pylori or Epstein-Barr virus (EBV) infection.The International Agency for Research on Cancer (IARC) classifies H. pylori and EBV as a class-I carcinogen 9,10 , and both are known to up-regulate DNA methyltransferases (DNMT) 11 .GC lesions have shown to display hypermethylation of CDH1, which expresses E-cadherin protein, associated with DNMT1 protein overexpression by EBV infection 12 .The frequency of molecular studies aimed to analyze promoter methylation of tumor suppressor genes (TSG) and global proteomics in gastric carcinogenesis is increasing.Nonetheless, only a few 13 consider important characteristics, such as: the different types of stomach cells, the tumor location and the influence of H. pylori and EBV infection.
observed that gastric carcinogenesis has different pathways depending on the presence of the H.pylori or EBV, suggesting a possible involvement of H. pylori with the apoptotic process; and the low expression of c-Myc and Bax in the EBV-positive groups suggests that EBV may inhibit the expression of these proteins.The molecular and cytological heterogeneity of GC indicate that proteomics interpretations should not be generalized.One must consider individual factors such as: genetics and epigenetics, gender, environmental factors and pathological characteristics.In this context, the analysis of individual tumor tissue may show more straight results when compared with a pool of samples as tissues or liquid biopsies, where specific information of some patients can be missed.