HDGC is a hereditary condition causing an increased risk for diffuse or signet ring gastric (stomach) cancer. This type of cancer gets into the stomach wall causing thickening of the wall (linitis plastica) without forming a mass or tumor. HDGC is defined clinically as the presence of two or more documented cases of diffuse gastric cancer in first- or second-degree relatives with at least one case diagnosed prior to age 50 years OR three or more documented cases of diffuse gastric cancer in first- or second-degree relatives, regardless of age of onset. The average age of onset of hereditary diffuse gastric cancer is 38 years, with a range of 14-69 years. The majority of the cancers in individuals with CDH1 mutations occur before the age of 40 years. The estimated cumulative risk of gastric cancer by age 80 years is 67% for men and 83% for women. Women also have between a 39-52% lifetime risk for lobular breast cancer.
In addition there is an increase in colon cancers in the families with CDH1 mutations. CDH1 is the only gene known to be associated with hereditary diffuse gastric cancer and sequence analysis of the CDH1 gene is available on a clinical basis. Mutations in CDH1 account for approximately one-half of hereditary diffuse gastric cancers and are inherited in an autosomal dominant manner, meaning each first degree relative (parent, child, and sibling) of an individual with this condition has a 50% chance of inheriting the disease causing mutation.
Multidisciplinary care should be incorporated pre- and post-surgery and should include the gastroenterologist, surgeon, pathologists, and nutritionists. The individual’s physical and psychological fitness, as well as age, nutrition, lifestyle, and family support, must be considered along with an assessment of the emotional effects a total gastrectomy will have.
Upper endoscopy is proposed for those with HDGC who do not opt for prophylactic gastrectomy or for whom gastrectomy has been deferred. Endoscopic screening including a detailed, 30-minute endoscopic examination of the gastric mucosa with multiple random biopsies and biopsies of subtle lesions is recommended at six- to twelve-month intervals. It is recommended that this procedure be performed at a center that has experience with HDGC. Microscopic tumor foci have been detected on most prophylactic gastrectomy pathology in those with HDGC who have recently undergone endoscopic screening, highlighting the limitations of endoscopic screening in these high-risk individuals. Affected individuals should be counseled of the high risks of mortality from delaying prophylactic gastrectomy.
There is currently no conclusive evidence that the risk for colorectal cancer is elevated in those with a pathogenic variant in CDH1. However, one study has suggested enhanced colorectal surveillance for the subset of HDGC families with colorectal cancer diagnoses. Specifically, they recommend colonoscopy screening beginning at age 40 or 10 years younger than the youngest diagnosis of colon cancer, whichever is younger, and repeated at intervals of 3–5 years.
CDH1 is a tumor-suppressor gene that provides instructions for making epithelial cadherin, or E-cadherin. This protein is found within the membranes surrounding epithelial cells. E-cadherin belongs to a family of proteins called cadherins that play a role in cell adhesion, signal transduction, controlling cell maturation and movement, and regulating the activity of certain genes.
No Stomach for Cancer http://www.nostomachforcancer.org/gastric-cancer/hereditary-diffuse-gastric-cancer
Stanford Cancer Institute: Hereditary Diffuse Gastric Cancer Syndrome http://cancer.stanford.edu/patient_care/services/geneticCounseling/HDGC.html
American Society of Clinical Oncology http://www.cancer.net/cancer-types/hereditary-diffuse-gastric-cancer
* Screening recommendations based on National Comprehensive Cancer Network Guidelines Version 1.2017 Genetic/Familial High Risk Assesment: Breast and Ovarian Cancer and National Comprehensive Cancer Network Guidelines Version 3.2016 Gastric Cancer.