Key points

Introduction

Gastric cancer is a major health burden worldwide. It is the second cause of cancer deaths after lung cancer. More than 90% of the tumors are adenocarcinomas, the main focus of this review. The prognosis is dismal, with an average 5-year survival rate of less than 20%, mainly because of late diagnosis, because the early stages are clinically silent. Only a few countries, especially Japan, have set up extensive programs of early detection. If the tumor is detected and treated before it invades the muscular layer of the stomach, the 5-year survival rate can reach 90%. The highest incidence rates are reported for East Asia (Korea, Mongolia, Japan, and China) with annual incidence rates between 40 and 60 per 100,000 inhabitants. In Latin America, pockets of high risk are reported in the Andes Mountains, with rates between 20 and 30 per 100,000, in contrast to the much lower rates reported for the coastal and river valley regions. Lower rates are found in Africa (∼0.3 to 3 per 100,000, and in affluent populations of North America). The incidence rate in African Americans is about double that seen in white American. In general, the incidence rate for men is double that for women.

In recent decades, there has been a gradual decrease in gastric cancer rates in many populations. It has been proposed that this decrease reflects trends in food handling, especially refrigeration and the abundance of fresh fruit and vegetables in the diet, as well as a decrease in the use of tobacco and dietary salt. However, not all types of gastric cancer are declining; tumors of the cardia and esophagogastric junction are becoming more frequent. Recently, an unexplained increase in gastric cancer incidence in younger individuals, mostly less than 40 years of age, has been reported.

Introduction

Gastric cancer is a major health burden worldwide. It is the second cause of cancer deaths after lung cancer. More than 90% of the tumors are adenocarcinomas, the main focus of this review. The prognosis is dismal, with an average 5-year survival rate of less than 20%, mainly because of late diagnosis, because the early stages are clinically silent. Only a few countries, especially Japan, have set up extensive programs of early detection. If the tumor is detected and treated before it invades the muscular layer of the stomach, the 5-year survival rate can reach 90%. The highest incidence rates are reported for East Asia (Korea, Mongolia, Japan, and China) with annual incidence rates between 40 and 60 per 100,000 inhabitants. In Latin America, pockets of high risk are reported in the Andes Mountains, with rates between 20 and 30 per 100,000, in contrast to the much lower rates reported for the coastal and river valley regions. Lower rates are found in Africa (∼0.3 to 3 per 100,000, and in affluent populations of North America). The incidence rate in African Americans is about double that seen in white American. In general, the incidence rate for men is double that for women.

In recent decades, there has been a gradual decrease in gastric cancer rates in many populations. It has been proposed that this decrease reflects trends in food handling, especially refrigeration and the abundance of fresh fruit and vegetables in the diet, as well as a decrease in the use of tobacco and dietary salt. However, not all types of gastric cancer are declining; tumors of the cardia and esophagogastric junction are becoming more frequent. Recently, an unexplained increase in gastric cancer incidence in younger individuals, mostly less than 40 years of age, has been reported.

Etiology

The cause of gastric cancer is multifactorial, although infection with Helicobacter pylori is considered to be the primary cause; its effects are modulated by microbial, environmental, and host factors.

Gastric cancer is one of a few types of neoplasms directly linked to an infectious agent. In 1994, the International Agency for Research on Cancer (IARC) classified infection with H pylori as a class I human carcinogen for gastric cancer. The same infectious agent is recognized as the primary cause of gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

H pylori is a gram-negative bacterium capable of colonizing the gastric mucosa and eliciting an immune response in the host. The infection is predominantly acquired in early infancy and remains present for life if not treated with antibiotics. One type of gastritis associated with the infection, namely multifocal atrophic gastritis, may be linked to the precancerous process. Nonatrophic antral gastritis is not associated with the precancerous process but may be linked to duodenal ulcer. Reactive oxygen species (ROS) may be generated by the infection and may induce DNA mutations. H pylori is also able to induce hypermethylation of DNA, especially the CpG islands, thereby silencing genes associated with tumor suppression. A study on subjects infected with H pylori reported that a population at high risk for gastric cancer from the Colombian Andes (Tuquerres) had significantly greater hypermethylation of the RPRM gene (a tumor suppressor gene) in the gastric mucosa compared with those in a low-risk population on the Pacific coast (Tumaco).

H pylori strains vary considerably in their pathogenicity and carcinogenicity. More virulent strains carry the cytotoxic-associated gene cagA , encoding an oncogenic protein that can be injected directly into gastric epithelial cells by a type IV secretion system. Most strains in East Asia and in the high-risk area of the Colombian Andes are cagA positive. After entering the cytoplasm of the gastric epithelial cells, CagA becomes phosphorylated in motifs that contain the EPIYA sequences and starts a chain of molecular events linked to carcinogenesis. The EPIYA sequences are classified as A, B, C, or D according to the amino acids flanking them. The number and type of EPIYA motifs vary in different H pylori strains. In western countries, H pylori strains contain EPIYA motifs A, B, and C. In East Asia, the strains contain the D motif instead of the C motif. Strains with more than 3 EPIYA motifs induce significantly more gastric atrophy, intestinal metaplasia, and gastric cancer. In vivo and in vitro studies have shown that CagA induces disruption of intercellular junctions, loss of epithelial polarity, increased proliferation, reduced apoptosis, and eventually carcinogenicity. Another virulence-associated gene is vacA, which induces cytoplasmic vacuoles, pores in the cell membrane, and apoptosis. Although all H pylori strains contain the vacA gene, genetic variations determine its functional activity and cancer risk. The vacA gene has genetic variations in the s (signal) region, which can be s1a, s1b, s1c, or s2. The middle region shows alleles that can be m1 or m2 and the intermediate region can be i1 or i2. Strains vacA s1/m1 or vacA s1/m1/i1 convey a higher risk of progression and cancer than strains vacA s2/m2 or vacA s2/m2/i2.

Some adhesion proteins of the membrane have been linked to higher virulence. One of them is BabA (blood-group antigen-binding adhesin) encoded by the gene babA , not present in all strains. BabA adheres to the antigen Lewis ^b , present in the epithelial cell membrane. Infections with H pylori strains babA2 -positive are associated with greater cancer risk.