Affiliations of authors: J.-G. Park, H.-K. Yang, W. H. Kim, Cancer Research Institute, Seoul National University, College of Medicine, South Korea; C. Caldas, University of Cambridge, U.K.; J. Yokota, National Cancer Center Research Institute, Tokyo, Japan; P. J. Guilford, University of Otago, New Zealand.
Correspondence to: Jae-Gahb Park, M.D., International Collaborative Group on Hereditary Gastric Cancer, c/o Cancer Research Institute, Seoul National University, College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea (e-mail: jgpark{at}plaza.snu.ac.kr).
Gastric cancer is the second leading cause of cancer death worldwide (1). Although hereditary gastric cancer is estimated to account for 5%10% of all gastric adenocarcinomas (2,3), the paucity of consistent clinical criteria available to identify families with the disease has hindered the description of its genetic heterogeneity, prevalence, natural history, and clinical expression. Moreover, the existence of two distinct histopathologic subtypes, intestinal and diffuse, adds to the complexity of definitions.
The International Collaborative Group on Hereditary Gastric Cancer (ICG-HGC) was founded in April 1999 in Seoul, South Korea, during the 3rd International Gastric Cancer Congress. The ICG-HGC was established to define the clinical criteria for hereditary gastric cancer, to develop strategies for the management of affected families, and to promote international collaborative studies. The inaugural meeting of the ICG-HGC was held in Seoul on August 22, 1999, with 110 participants from six countries. Coincident with the organization of the ICG-HCG, the International Gastric Cancer Linkage Consortium (IGCLC) hosted its first workshop in Cambridge, U.K., in June 1999. The consensus statements agreed on for hereditary gastric cancer during the IGCLC workshop have been recently published as an "overview and guidelines for management" (4). Because the aims of these two independent groups were concordant, they have merged under the IGCLC designation. Here we describe the criteria proposed by ICG-HGC for the ascertainment of hereditary gastric cancer families and summarize the recommendations for the clinical management of these families.
MOLECULAR GENETICS OF HEREDITARY GASTRIC CANCER
Until recently, no predisposing genetic factors to gastric cancer had been identified. However, using a genetic linkage approach, Guilford et al. (5) identified inactivating germline mutations in the E-cadherin gene (CDH-1) in three New Zealand Maori families affected by diffuse gastric cancer. Subsequent studies (69) have described 18 different CDH-1 germline mutations in hereditary gastric cancers. Fifteen of the 18 mutations are truncating mutations, and the remainder are missense mutations. CDH-1 germline mutations are associated with the diffuse form, but not the intestinal form, of gastric cancer (69). A germline CDH-1 mutation, therefore, genotypically defines an autosomal dominant cancer syndrome known as hereditary diffuse gastric cancer (4,10).
CDH-1 mutations account for a currently unknown proportion (probably <25%) of hereditary diffuse gastric cancer families. Moreover, the CDH-1 gene is not genetically linked to the locus predisposing to a second autosomal dominant form of diffuse gastric cancer, hyperplastic polyposis and diffuse carcinoma (4,6). Therefore, mutations in genes other than CDH-1 are also likely to predispose to diffuse gastric cancer.
To date, no specific germline mutations have been identified that predispose to the intestinal type of gastric cancer. In one recent Japanese study (8), familial clustering of gastric cancer was detected in approximately 1% of gastric cancer patients, including a number of families with the intestinal type. The familial clustering in the Japanese retrospective study could not be attributed to germline mutations in CDH-1, in p53, or in DNA mismatch repair genes.
A germline mutation has, however, been identified in a family with a history of gastrointestinal stromal tumors through four generations (11). The mutation is specific for gastrointestinal stromal tumors and is a gain of function mutation in the c-kit gene that would be predicted to lead to constitutive activation of the encoded receptor tyrosine kinase.
Gastric cancer has also been seen as part of the tumor spectrum in four hereditary cancer susceptibility syndromes: hereditary nonpolyposis colorectal cancer (HNPCC), Li-Fraumeni syndrome, familial adenomatous polyposis, and Peutz-Jeghers syndrome (4,12-15).
CRITERIA FOR ASCERTAINMENT OF HEREDITARY GASTRIC CANCER
The ICG-HCG recommends two complementary sets of clinical criteria for the screening of suspected hereditary gastric cancer families. The first criterion (9) provides a simple, broad screen that is suitable for preliminary use in a clinical setting. The second criteria is suited to the screening of families prior to linkage studies and mutation searching and is recommended by the IGCLC. The IGCLC criteria include histologic verification of tumor types as well as separate criteria for countries with high and low incidences of the intestinal form of gastric cancer.
Broad Screen Criteria
The criteria for a broad screen suitable for preliminary use in a clinical setting include the following: 1) two or more cases of gastric cancer of any histologic type in first- and/or second-degree relatives, with at least one diagnosed before age 50 years, or 2) three or more cases of gastric cancer in first- and/or second-degree relatives at any age. With the use of these criteria, a prospective analysis identified 51 Korean families from 421 (12.1%) consecutive gastric cancer patients treated at the Department of Surgery, Seoul National University Hospital, from March 1999 through September 1999.
IGCLC Screen Criteria
These criteria are suitable for screening families for familial gastric cancer prior to linkage studies and mutation searching. The criteria for hereditary diffuse gastric cancer include the following: 1) two or more documented cases of diffuse gastric cancer in first- and/or second-degree relatives, with at least one diagnosed before age 50 years, or 2) three or more cases of documented diffuse gastric cancer in first- and/or second-degree relatives at any age. By contrast, the criteria for hereditary intestinal gastric cancer for use in countries with high incidence, such as Japan, South Korea, Portugal, and Italy, are analogous to the Amsterdam criteria for HNPCC and include the following: 1) at least three cases of intestinal gastric cancer in first- and/or second-degree relatives, one of whom is a first-degree relative of the other two; 2) cases of intestinal gastric cancer in at least two successive generations; and 3) diagnosis of intestinal gastric cancer in one relative before age 50 years. Finally, the criteria for hereditary intestinal gastric cancer in countries with low incidence, such as the United States and the U.K., include the following: 1) at least two first- and/or second-degree relatives affected by intestinal gastric cancer, one diagnosed before age 50 years, or 2) three or more relatives with intestinal gastric cancer at any age.
CLINICAL IMPLICATIONS OF GENETIC SUSCEPTIBILITY TESTING
Prospective recruitment of hereditary gastric cancer patients with complete pedigree ascertainment and blood sampling is essential for improving the accuracy of studies on 1) the worldwide prevalence of hereditary gastric cancer, 2) natural history, 3) the tumor spectrum, 4) the genotype-phenotype association, 5) the environmental triggers, 6) clinical surveillance (including the upper and lower ages of screening), and 7) the penetrance of mutations that predispose to the disease.
The current estimates of gene penetrance (according to IGCLC data, around 70% by age 75 years) and associated lifetime cancer risk are likely to be refined as more hereditary gastric cancer families are described. Families fitting the IGCLC criteria for hereditary diffuse gastric cancer should be screened for germline CDH-1 mutations, although, currently, CDH-1 mutation screening should still be considered a research endeavor (4). CDH-1 germline mutation carriers should be referred to a clinical screening program. Endoscopies should be repeated every 6 months to 1 year and combined with Helicobacter pylori strain typing and eradication. If a tumor is identified by endoscopy, the patient should probably be offered a complete, but not a partial, gastrectomy, as recommended by the IGCLC (4). The option of prophylactic gastrectomy in carriers of CDH-1 mutations will need careful consideration, particularly because the risk of extragastric cancers is largely unknown. Moreover, prophylactic gastrectomy is of totally unproven efficacy and carries a high risk of complications, such as anastomotic leakage, significant weight loss, and dumping syndrome (4). The role of E-cadherin in wound repair raises the possibility that some CDH-1 mutation carriers may be compromised in their ability to heal at the anastomosis (16,17), a possible effect that would be important for surgeons to consider.
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Manuscript received December 15, 1999; revised July 27, 2000; accepted August 18, 2000.
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