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HEREDITARY DIFFUSE GASTRIC CANCER (HDGC)
Stomach cancer, also known as gastric cancer, is cancer that starts in any part of the stomach.
Worldwide, gastric cancer is the fifth leading cause of cancer and the third most common cause of death from cancer. The vast majority of gastric cancers are sporadic, meaning that they appear in scattered or isolated instances.
There are several types of stomach cancer. Most stomach cancers (90-95%) are adenocarcinomas. They arise from the mucosal tissue lining the inside of the stomach and are further classified as intestinal type or diffuse type based upon the appearance of the cancer cells. An experienced pathologist can identify the type of cancer found. This information is critical in assessing hereditary cancer risk.
It has been established that 1-3% of gastric cancers result from inherited cancer syndromes, the majority of them being Hereditary Diffuse Gastric Cancer.
Hereditary Diffuse Gastric Cancer (HDGC) is an inherited cancer syndrome that leads to a higher than average risk of developing diffuse gastric cancer and lobular breast cancer. Families with one or more cases of diffuse gastric cancer, lobular breast cancer, or both may be affected by hereditary diffuse gastric cancer syndrome. HDGC is most frequently caused by inherited mutations in the CDH1 gene, although other genes may be involved in some families.
Dr. Parry Guilford discovered the connection of the CDH1 gene mutation to gastric cancer and lobular breast cancer in a family from New Zealand’s Maori population in 1998.
HDGC is now estimated to have a population incidence of approximately 5-10/100,000 births. (2020)
The CDH1 gene is a tumor suppressor gene located on chromosome 16 and encodes for a protein called E-cadherin. The normal function of E-cadherin is to allow cells and tissues to adhere to one another in a normal manner. When there is a pathogenic variant (mutation) in the CDH1 gene, the normal function of the gene is disrupted. Pathogenic variants directly contribute to the development of disease. In a small minority of cases, HDGC is caused by a pathogenic variant in a gene called CTNNA1, which is found on chromosome 5 and has a similar function to the CDH1 gene.
Everyone is born with two copies of the CDH1 gene, one from each of their mother and father. HDGC is diagnosed when a person or family tests positive for a pathogenic variant in the CDH1 or (rarely) the CTNNA1 gene. Only one mutated copy of the gene (from one parent) is needed to be affected by HDGC. Since everyone has two copies of each gene, each person has a 50% random chance of inheriting the mutated copy from their affected parent. This does not mean that 50% of the family members will inherit it – each person’s risk is 50%.
In some families, a pathogenic variant in CDH1 is found, but there is only a family history of breast cancer. In this case, the term Hereditary Lobular Breast Cancer (HLBC) is used. If someone in the family is later diagnosed with diffuse gastric cancer, the diagnosis changes to HDGC.
Exact risks of cancer are difficult to estimate, and may vary between families with HDGC. Some studies have shown that men with a pathogenic CDH1 gene variant, and a strong family history of stomach cancer, have up to a 70% lifetime risk of developing diffuse gastric cancer. The estimated lifetime risk for women with a pathogenic CDH1 gene variant and a strong family history of stomach cancer is 56%. Women also have a significantly elevated risk of developing lobular breast cancer in their lifetime. People with pathogenic CDH1 variants and little or no family history of stomach cancer seem to have a lower risk of this cancer. The distinction between HDGC and HLBC acknowledges the likelihood that not all families with pathogenic CDH1 variants are equally at risk of DGC.
Criteria have been established to select families for screening (genetic testing) for CDH1 mutations. Not all families are found to have a CDH1 mutation. With the exception of CTNNA1, other genes that may lead to HDGC are not known at this time. Genetic test results provide information that will help identify the recommended course of treatment in each case. Updated HDGC Clinical Practice Guidelines lay out paths for management of families with pathogenic CDH1 gene mutations with family history of gastric cancer, only a family history of lobular breast cancer, families found to have a CDH1 variant of unknown significance, and ‘HDGC-like’ families who have met genetic testing criteria but no CDH1 or CTNNA1 pathogenic variants have been found.
Diffuse Gastric Cancer (DGC), also known as signet ring cell adenocarcinoma or linitis plastica, grows rapidly in the lining of the stomach wall. These aggressive cancer cells do not form a mass; rather they are diffused (scattered widely or thinly) throughout the lining of the stomach wall, appearing as isolated cells or in small clusters. Diffuse gastric cancer is difficult to detect because the cancer is not visible on upper endoscopy (looking into the stomach with a small camera). For this reason, most cases of DGC are diagnosed at late stages (III or IV), when the cancer is incurable and when survival rates are significantly lower. Prophylactic total gastrectomy (preventive removal of the stomach) is generally recommended for those individuals found to have proven pathogenic CDH1 mutations.
Women in HDGC families have a higher risk of lobular breast cancer. Recommended screening or surveillance protocols are more comprehensive for this group of women. While prophylactic mastectomy may be considered, it is not routinely recommended.
HDGC research is ongoing, and a group of experts comprising the International Gastric Cancer Linkage Consortium (IGCLC) convene periodically to review and update the Hereditary Diffuse Gastric Cancer Clinical Guidelines, providing expert guidance and recommendations for the clinical care of patients and families affected by HDGC worldwide, and to determine the future direction of HDGC research. The most recent HDGC Clinical guideline update was published in 2020.
Every Family Tells a Story
60 Second Lecture Series
“Every Family Tells a Story”
March 20, 2015
Cancer Bytes, Yale Cancer Center
Johanna D’Addario shares her HDGC experience in this three part series.