An estimated 1-3% of cases of stomach cancer are caused by inherited syndromes. Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome that leads to an increased risk for both diffuse gastric cancer and lobular breast cancer. Patients who inherit the genetic mutation for HDGC are at high risk for developing stomach cancer at a young age.
History of HDGC
In 1964, stomach cancer was noted in a Maori tribal family in New Zealand, following an autosomal dominant pattern of inheritance. CDH1 gene mutations were first described in patients from three Maori families in 1998. At this time, the International Gastric Cancer Linkage Consortium (IGCLC) was formed, and the name “Hereditary Diffuse Gastric Cancer” was introduced. Families with multiple cases of diffuse gastric cancer, lobular breast cancer, or both may be affected by hereditary diffuse gastric cancer syndrome.
Diffuse Gastric Cancer
HDGC leads to a cancer called diffuse-type, signet ring cell gastric adenocarcinoma. These signet ring cells appear as isolated cells or in small clusters in the lining of the stomach. Unfortunately, the diffuse type of gastric cancer associated with HDGC is difficult to diagnose because the cancer is not visible on upper endoscopy (looking into the stomach with a small camera). For this reason, most cases of diffuse gastric cancer are diagnosed at late stages (III or IV), and associated with a lower survival rate.
Lobular Breast Cancer
Women from HDGC families should be followed by oncologists or breast surgeons and have clinical breast exams regularly. Screening with yearly breast MRI, which can be combined with mammograms, is recommended starting at age 30. There is a possible role for preventive hormone-blocking medications to reduce the risk of lobular breast cancer in CDH1 mutation carriers. If there are many cases of breast cancer in the family, prophylactic mastectomy may also be considered, but mastectomy is not routinely recommended.
Future of HDGC
Research on the genetics, diagnosis, and treatment of HDGC is ongoing. Centers of Excellence have been established worldwide and experts from the International Gastric Cancer Linkage Consortium continue to work together to develop new guidelines and recommendations for patients and families affected by HDGC.
Ford JM. Inherited susceptibility to gastric cancer: advances in genetics and guidelines for clinical management. American Society of Clinical Oncology Educational Sessions. 2002:116-125.
Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. The New England Journal of Medicine. June 2001;344(25):1904-1909.
Francis WP, Rodrigues DM, Perez NE, Lonardo F, Weaver D, Webber JD. Prophylactic laparoscopic-assisted total gastrectomy for hereditary diffuse gastric cancer. Journal of the Society of Laparoendoscopic Surgeons. 2007;11:142-147.
Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, et al. Familial gastric cancer: overview and guidelines for management. Journal of Medical Genetics. 1999;36:873-880.