Hereditary Diffuse Gastric Cancer (HDGC)
Stomach (gastric) cancer is the fifth most common cause of cancer worldwide, and the third leading cause of cancer deaths worldwide. The American Cancer Society has estimated that 24,590 new cases of gastric cancer will be diagnosed in the United States in 2015, and that more than 10,000 Americans would die of gastric cancer during the year.1 Because gastric cancer is difficult to diagnose, it is often diagnosed at a late stage with a poor prognosis. The treatment for gastric cancer is surgery and chemotherapy.2 The overall 5-year survival rate is 29%.1
An estimated 1-3% of cases of gastric cancer are caused by inherited syndromes.2 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 gastric cancer at a young age.3
History of HDGC
In 1964, gastric cancer was noted in a Maori tribal family in New Zealand, following an autosomal dominant pattern of inheritance.4 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 the hereditary diffuse gastric cancer syndrome.
The CDH1 gene, located on chromosome 16, normally encodes for a protein called E-cadherin. The normal function of E-cadherin is to allow cells and tissues to adhere to one another. 4
When there is a mutation in the CDH1 gene, the function of the E-cadherin protein is disrupted, and cancer often results.3,4 The exact mechanism by which this mutation ultimately causes gastric cancer is not entirely known. 4
Inheritance of the CDH1 gene mutation follows an autosomal dominant pattern, meaning that offspring of mutation carriers have a 50% chance of inheriting the mutant gene.3,4 It is estimated that up to three out of every four CDH1 gene mutation carriers will go on to develop gastric cancer.3,5,6
It is important to note, however, that not all HDGC families have a mutation in the CDH1 gene. Other genes that may lead to HDGC are currently being studied.7
Diffuse Gastric Cancer
HDGC leads to a cancer called diffuse-type, signet ring cell gastric adenocarcinoma.4,5 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.5
Management of HDGC Family Members
Hereditary Diffuse Gastric Cancer testing criteria has been established and is considered in families who meet any of the following criteria.
- Two or more cases of gastric cancer in first- or second-degree relatives, with at least one case confirmed to be diffuse gastric cancer
- One case of diffuse gastric cancer diagnosed under age 40
- A personal or family history of both diffuse gastric cancer and lobular breast cancer, with one diagnosis under age 507
In addition, families in whom testing could be considered are those who meet any of the following criteria.
- Bilateral lobular breast cancer or family history of two or more cases of lobular breast cancer under age 50
- A personal or family history of cleft lip/palate in a patient with diffuse gastric cancer
- In situ signet ring cells and/or pagetoid spread of signet ring cells7
Affected patients from families meeting the criteria are referred for genetic counseling and testing for a CDH1 gene mutation. The genetic testing is performed in two stages, diagnostic testing and predictive testing. Diagnostic testing is done using a blood sample from a patient affected with gastric cancer, to identify if a mutation in the CDH1 gene exists to cause the cancer. If a mutation is identified, healthy family members who are at risk for inheriting the same mutation may choose to undergo predictive testing for the same mutation.5
People from HDGC families are at an increased risk of developing diffuse-type gastric cancer and lobular breast cancer. It is estimated that the risk of developing gastric cancer by ate 80 is 70% in men and 56% in women. Additionally, female carriers are at an increased risk (42% by age 80) for lobular breast cancer.7
Diffuse Gastric Cancer
Patients from HDGC families should be followed by physicians, genetic counselors, gastroenterologists, surgeons, pathologists, oncologists, dieticians, and other health professionals.2 Upper endoscopy with random gastric biopsies (small samples of tissue) is currently the best method to screen for gastric cancer.2 Unfortunately, diffuse gastric cancer often is not apparent on endoscopy, and biopsies are often negative.3
The current screening recommendations are upper endoscopy with biopsies on an annual basis.2,7,9 If possible, biopsies should be reviewed by pathologists who are knowledgeable about hereditary diffuse gastric cancer. Because hereditary diffuse gastric cancer is nearly impossible to detect at an early stage, however, the recommended procedure to prevent gastric cancer is a total gastrectomy, or complete removal of the stomach.3,7,8 Although this procedure is complicated and commonly leads to weight loss, diarrhea, altered eating habits, and vitamin deficiency, it is possibly the only method to prevent stomach cancer in these families.2,4,5,9
Lobular Breast Cancer
Women from HDGC families should be followed by oncologists or breast surgeons and have clinical breast exams regularly.7,9 Screening with yearly breast MRI, which can be combined with mammograms, is recommended starting a age 30.7 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.6,7,10
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.
1.) American Cancer Society Statistics. Available at www.cancer.org.
2.) 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.
3.) 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.
4.) 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.
5.) 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.
6.) Kaurah P, MacMillan A,Boyd N, Senz J, De Luca A, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. Journal of the American Medical Association. 2007;297(21):2360-2372.
7.) Vogelaar IP, van der Post RS, Carneiro F, Guilford P, Huntsman D, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;00:1-14.
8.) Norton JA, Ham CM, Van Dam J, Jeffrey RB, Longacre TA, et al. CDH1 truncating mutations in the E-cadherin gene: An indication for total gastrectomy to treat hereditary diffuse gastric cancer. Annals of Surgery. 2007;245(6):873-879.
9.) Chun, YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, et al. Germline E-cadherin gene mutations: Is prophylactic total gastrectomy indicated? Cancer. 2001;92(1):181-187.
10.) Schrader KA, Masciari S, Boyd N, Wiyrick S, Kaurah P, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Familial Cancer. 2008;7:73-82.