Considerations about gastric cancer proteomics

CARVALHO, CARLOS EDUARDO; MCCORMICK, THAÍS MESSIAS; CARVALHO, PAULO COSTA; FISCHER, JULIANA DE SALDANHA DA GAMA; AQUINO, PRISCILA FERREIRA DE; BRAVO NETO, GUILHERME PINTO; CARVALHO, MARIA DA GLÓRIA DA COSTA

doi:10.1590/0100-69912016005016

ABSTRACT

The frequency of molecular studies aimed to analyze promoter methylation of tumor suppressor genes and global proteomics in gastric carcinogenesis is increasing. Nonetheless, only a few considered the different types of stomach cells, the tumor location and the influence of Helicobacter pylori and Epstein Barr virus infection (EBV). Molecular differences relating to anatomical and histological tumor areas were also recently described. 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.

Keywords: Stomach Neoplasms; Proteome; Helicobacter pylori; Herpesvirus 4, Human; Methylation

RESUMO

A frequência de estudos moleculares visando a analisar os promotores de metilação de genes supressores de tumor e proteômica globais na carcinogênese gástrica está aumentando. No entanto, apenas alguns consideraram os diferentes tipos de células do estômago, a localização do tumor e a influência da infecção por Helicobacter pylori e pelo vírus Epstein-Barr (EBV). Diferenças moleculares relacionadas com áreas tumorais anatômicas e histológicas também foram recentemente descritas. Os autores propõem uma classificação molecular de câncer gástrico, dividindo-o em quatro subtipos: tumores positivos para o EBV; tumores microssatélite instáveis; tumores genomicamente estáveis e tumores com instabilidade cromossômica.

Descritores: Neoplasias Gástricas; Proteoma; Helicobacter pylori; Herpesvirus Humano 4; Metilação

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 infection¹ ².

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 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 mucosa¹⁶. 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 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.

REFERENCES

¹ Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.
² Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Estimativa 2016: Incidência de Câncer no Brasil. Rio de Janeiro: INCA; 2015. Disponível em: <http://www.inca.gov.br/estimativa/2014/estimativa-24042014.pdf>
³ Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.
⁴ Hwang SW, Lee DH, Lee SH, Park YS, Hwang JH, Kim JW, et al. Preoperative staging of gastric cancer by endoscopic ultrasonography and multidetector-row computed tomography. J Gastroenterol Hepatol. 2010;25(3):512-8.
⁵ Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC; 2010.
⁶ McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11(11):664-74.
⁷ Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10(2):75-83.
⁸ Moy KA, Fan Y, Wang R, Gao YT, Yu MC, Yuan JM. Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2287-97.
⁹ de Aquino PF, Carvalho PC, da Gama Fischer JS, de Souza AQ, Viana JS, et al. Epstein-Barr virus DNA associated with gastric adenocarcinoma and adjacent non-cancerous mucosa in patients from Manaus, Brazil. Genet Mol Res. 2012;11(4):4442-6.
¹⁰ Yakirevich E, Resnick MB. Pathology of gastric cancer and its precursor lesions. Gastroenterol Clin North Am. 2013;42(2):261-84.
¹¹ Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol. 2014;20(14):3916-26.
¹² Etoh T, Kanai Y, Ushijima S, Nakagawa Y, Nakanishi Y, Sasako M, et al. Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol. 2004;164(2):689-99.
¹³ Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg. 2005;241(1):27-39.
¹⁴ Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-9.
¹⁵ Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137(3):824-33. Erratum in: Gastroenterology. 2011;140(3):1109.
¹⁶ He QY, Cheung YH, Leung SY, Yuen ST, Chu KM, Chiu JF. Diverse proteomic alterations in gastric adenocarcinoma. Proteomics. 2004;4(10):3276-87.
¹⁷ Aquino PF, Fischer JS, Neves-Ferreira AG, Perales J, Domont GB, Araújo GD, et al. Are gastric cancer resection margin proteomic profiles more similar to those from controls or tumors? J Proteome Res. 2012;11(12):5836-42.
¹⁸ Lima VP, de Lima MA, André AR, Ferreira MV, Barros MA, Rabenhorst SH. H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression. World J Gastroenterol. 2008;14(6):884-91.

Source of funding:
CAPES, CNPq and Fundação do Câncer.

Publication Dates

Publication in this collection
Sep-Oct 2016

History

Received
13 Sept 2016
Accepted
19 Oct 2016

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹ Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.

[2] ² Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Estimativa 2016: Incidência de Câncer no Brasil. Rio de Janeiro: INCA; 2015. Disponível em: <http://www.inca.gov.br/estimativa/2014/estimativa-24042014.pdf>

[3] ³ Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.

[4] ⁴ Hwang SW, Lee DH, Lee SH, Park YS, Hwang JH, Kim JW, et al. Preoperative staging of gastric cancer by endoscopic ultrasonography and multidetector-row computed tomography. J Gastroenterol Hepatol. 2010;25(3):512-8.

[5] ⁵ Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC; 2010.

[6] ⁶ McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11(11):664-74.

[7] ⁷ Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10(2):75-83.

[8] ⁸ Moy KA, Fan Y, Wang R, Gao YT, Yu MC, Yuan JM. Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2287-97.

[9] ⁹ de Aquino PF, Carvalho PC, da Gama Fischer JS, de Souza AQ, Viana JS, et al. Epstein-Barr virus DNA associated with gastric adenocarcinoma and adjacent non-cancerous mucosa in patients from Manaus, Brazil. Genet Mol Res. 2012;11(4):4442-6.

[10] ¹⁰ Yakirevich E, Resnick MB. Pathology of gastric cancer and its precursor lesions. Gastroenterol Clin North Am. 2013;42(2):261-84.

[11] ¹¹ Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol. 2014;20(14):3916-26.

[12] ¹² Etoh T, Kanai Y, Ushijima S, Nakagawa Y, Nakanishi Y, Sasako M, et al. Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol. 2004;164(2):689-99.

[13] ¹³ Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg. 2005;241(1):27-39.

[14] ¹⁴ Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-9.

[15] ¹⁵ Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137(3):824-33. Erratum in: Gastroenterology. 2011;140(3):1109.

[16] ¹⁶ He QY, Cheung YH, Leung SY, Yuen ST, Chu KM, Chiu JF. Diverse proteomic alterations in gastric adenocarcinoma. Proteomics. 2004;4(10):3276-87.

[17] ¹⁷ Aquino PF, Fischer JS, Neves-Ferreira AG, Perales J, Domont GB, Araújo GD, et al. Are gastric cancer resection margin proteomic profiles more similar to those from controls or tumors? J Proteome Res. 2012;11(12):5836-42.

[18] ¹⁸ Lima VP, de Lima MA, André AR, Ferreira MV, Barros MA, Rabenhorst SH. H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression. World J Gastroenterol. 2008;14(6):884-91.