By Johanna Chelcun, MHS, PA-C
Gastric cancer is the second most common cause of cancer-related death in the world. View more statistics.
It is estimated that 1-3% of cases of gastric cancer are caused by Hereditary Diffuse Gastric Cancer.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 in women. Patients who inherit the genetic mutation for HDGC are at high risk for developing gastric cancer at a young age.3
History of HDGC
A familial pattern of gastric cancer actually dates back to 1821, when Napoleon Bonaparte died at age 52 of gastric cancer. His father, grandfather, brother and 3 sisters had all died of gastric cancer.4 In 1964, familial gastric cancer was noted in a Maori tribal family in New Zealand, following an autosomal dominant pattern of inheritance.4 A specific type of gene mutation called a CDH1 mutation was first described in patients from three Maori families in 1998. It was then that the International Gastric Cancer Linkage Consortium (IGCLC) was formed, and the name “Hereditary Diffuse Gastric Cancer” was introduced.
Genetics
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 in a normal fashion. 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.3,4,5 It has been estimated that three out of every four CDH1 gene mutation carriers will go on to develop gastric cancer,3 with an average age at diagnosis of 38.6,7
Diffuse Gastric Cancer
HDGC leads to a cancer called diffuse-type, signet ring cell gastric adenocarcinoma.4,6 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), when the cancer is incurable.6
Management of HDGC Family Members
Hereditary Diffuse Gastric Cancer should be considered in families with either two or more cases of diffuse gastric cancer in first- or second-degree relatives, with at least one case diagnosed before the age of 50, or three or more cases of diffuse gastric cancer in first- or second-degree relatives, regardless of the age at diagnosis. Among families that fit this criteria, it is estimated that 25-40% will have a CDH1 gene mutation.4,6,7
Families in which a CDH1 gene mutation is suspected are referred for genetic counseling and testing for CDH1 gene mutations. The genetic testing is performed in two stages, diagnostic testing and predictive testing. Diagnostic testing uses a blood sample from a patient affected with gastric cancer to identify if a mutation in the CDH1 gene exists that caused the cancer. Once a mutation is identified, healthy family members who are at risk for inheriting the same mutation will undergo predictive testing for the same mutation.6
If a family member tests negative for the CDH1 gene mutation, he or she has the same risk of developing gastric cancer as the general population, and no gastric cancer screening is necessary. Alternatively, a positive test result means that the person is at an increased risk of developing diffuse-type gastric cancer. Males with the gene mutation have up to a 67% risk of developing gastric cancer by age 80, and females have up to an 83% risk of developing gastric cancer by age 80. Additionally, female carriers are at an increased risk (20-40% lifetime risk) for lobular breast cancer.6,7
Gastric Cancer Screening
Patients who have a CDH1 gene mutation 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, however, diffuse gastric cancer often is not apparent on endoscopy, and biopsies may not detect cancer cells.3
The current screening recommendations for people with the CDH1 gene mutation are upper endoscopy with biopsies every 6-12 months, beginning 10 years before the youngest affected patient in the family, or by age 25.2,8 Endoscopic ultrasound (using a device to measure the thickness of the stomach wall) and chromoendoscopy (staining tissue with dye to detect cancerous cells) may also be used to screen for cancer.2,6
Because the type of gastric cancer caused by the CDH1 gene mutation is nearly impossible to detect at an early stage, the recommended procedure to prevent gastric cancer in CDH1 gene mutation carriers is a total gastrectomy, or complete removal of the stomach, with Roux-en-Y esophagojejunostomy (attachment of the esophagus to the small intestine).3 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 CDH1 gene mutation carriers.2,4,6,9 The prognosis after total gastrectomy is excellent for those patients with early stage gastric cancer, with a 5-year survival rate over 90%.5
Breast Cancer Screening
Women with a CDH1 gene mutation should perform self-breast exams and have clinical breast exams every 6 months.10 Screening with yearly mammograms and bilateral breast MRI are also recommended, starting between age 25 and 30.8 There is also a possible role for a medication called Tamoxifen 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 should be considered.7,10
Research
At this time, more research is needed to determine better methods to screen for and detect gastric cancer, so that total gastrectomy can be avoided in people who are at risk of developing gastric cancer. One of the primary goals of the Chelcun Family Fund for Stomach Cancer Research is to help fund researchers in New Zealand, Canada and the United States who are currently working towards finding methods of prevention and improving early cancer detection for families affected by this disease.
References
1.) Cancer Facts and Figures 2008. American Cancer Society. Available at: www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf. Accessed 8/18/08.
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.) Guilford P, Blair V, More H, Humar B. A short guide to hereditary diffuse gastric cancer. Hereditary Cancer in Clinical Practice. 2007;5(4):183-194.
6.) 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.
7.) 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.
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, Guilford PJ, Donahue JH. 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.
