What Is Gastric Adenocarcinoma and Proximal Polyposis of the Stomach?

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare hereditary gastric cancer syndrome. It is defined by the formation of lesions, known as polyps, within the inner lining of the stomach wall.

While some polyps are benign (non-cancerous), others can become malignant and turn into cancer. Polyps caused by GAPPS have a higher likelihood of developing into intestinal-type adenocarcinomas, a specific type of gastric cancer. For this reason, if you have GAPPS, or have a family history of the condition, it is encouraged that you undergo screening or genetic testing as you have an elevated risk of getting early-onset gastric cancer.

The process by which a disease or disorder develops is called its pathogenesis. In the pathogenesis of GAPPS, some of the earliest gastric lesions are called hyperproliferative aberrant pits (HPAPs). These are described as disorganized and abnormally rapid growths of fundic (or oxyntic) glands around gastric pits in the stomach mucosa. HPAPs subsequently give rise to gastric epithelial polyps that appear as many tiny bumps within the stomach’s inner lining.

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There are various types of epithelial polyps in the stomach, which include:

• Fundic gland polyps (FGPs): These are the most prevalent form of gastric polyps and are commonly found in Western populations. They affect fundic (or oxyntic) glands in the proximal stomach. FGPs appear as several small, smooth and flat bumps. These polyps are usually associated with the use of proton pump inhibitors, which are a class of medication prescribed for the treatment of heartburn and acid-related conditions.
• Adenomatous polyps: These polyps are more likely to become cancerous than others. They can be found in the distal stomach, near the bottom of the organ. Adenomatous polyps usually signal the beginning of gastric cancer and may suggest a higher risk of other gastrointestinal cancers. For these reasons, all adenomatous polyps need to be removed. Removal can be done with an endoscope or surgery if there are many of these growths.
• Hyperplastic polyps: These polyps occur in bunches throughout the stomach. They are strongly associated with conditions that inflame or irritate the stomach, such as chronic gastritis and H. pylori infection. If left untreated, hyperplastic polyps can turn cancerous.

GAPPS is mainly characterized by numerous (more than 100) small polyps carpeting the gastric fundus and body. It does not affect the distal stomach (antrum and pylorus), small intestine and colon. While most of these polyps are FGPs, adenomatous and hyperplastic polyps have occasionally been found in the stomachs of people with GAPPS.

Some FGPs contain areas of increased abnormal cell growth. This is known as dysplasia, which can be classified into low- or high-grade dysplasia based on how quickly the abnormal cells change and grow. GAPPS-associated FGPs can display both low- and high-grade dysplasia. However, regions of fundic gland polyposis with high-grade dysplasia and adenomatous polyps are more likely to develop into intestinal-type gastric adenocarcinoma. This rapid progression of polyposis to high-grade dysplasia and gastric cancer is rarely observed in other polyposis syndromes, which makes it unique to GAPPS.

GAPPS is a rare and newly discovered hereditary gastric cancer syndrome whose genetic basis remained unknown for several years. It's now been found that the disease is caused by a mutation in the adenomatous polyposis coli (APC) gene.

This gene provides instructions for the production of the APC protein, which acts as a tumor suppressor and, therefore, has a critical role in regulating numerous tumorigenic processes. Examples include uncontrolled cell growth and cell-cell adhesion. The APC protein achieves this through association with other proteins involved in cellular signaling.

Scientists have found that the underlying genetic cause of GAPPS is a point mutation in the promoter region of the APC gene. A promoter is a sequence of DNA located upstream of a gene. When specific proteins, called transcription factors, bind to a promoter, it initiates the transcription of the corresponding gene and, therefore, the production of the gene product (often a protein).

When the promoter IB region is mutated, it significantly reduces the binding of a transcription factor called Yin Yang 1 (YY1). This in turn lowers the promoter’s transcriptional activity and alters the expression of the APC protein such that it loses its tumor suppressor function. As a result, it can no longer prevent the uncontrolled growth of cells in the gastric epithelium, ultimately leading to the formation of FGPs that define GAPPS.

As shown above, GAPPS’ key clinical features are:

• carpet-like fundic gland polyposis of the stomach with occasional adenomatous and hyperplastic polyps,
• sparing of the stomach antrum, small intestine and colon,
• an increased predisposition to intestinal-type gastric adenocarcinoma and
• an autosomal dominant mode of inheritance.

Click here to find out more about the symptoms associated with GAPPS and how this rare hereditary syndrome is diagnosed and managed.