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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 an increased risk of diffuse gastric cancer and lobular breast cancer. Families with multiple 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 are likely to 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.
There are about 450 known HDGC families worldwide. (2018)
The CDH1 gene is 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 mutation in the CDH1 gene, the normal function of the gene is disrupted, which often leads to cancer.
Everyone is born with two copies of the CDH1 gene, one from each of their mother and father. People are at risk of HDGC if they inherited a mutation in CDH1 from either of their parents. The risk of diffuse gastric cancer for CDH1 mutation carriers by age 80 is reported to be 70% for men, 56% for women, with additional risk of lobular breast cancer in women of 42%.
Criteria have been established to select families for screening (genetic testing) for CDH1 mutations. Not all families are found to have a CDH1 mutation. 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.
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.
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.