The incidence of gastric cancer (which is adenocarcinoma in 97 % of cases) shows marked geographical variation, being 88 per 100,000 males in Japan and 22 and 11 per 100,000 in the UK and USA, respectively. Women have about half the male incidence. There is a twofold to threefold excess risk of gastric cancer in the first-degree relatives of affected patients, particularly in cases diagnosed under the age of 50 years of age. Two major histological variants of gastric cancer are recognized: a diffuse type containing signet ring cells and intestinal-type gastric cancer which is associated with the presence of H. pylori. The latter is preceded by chronic gastritis, atrophy, and metaplasia. However, the diffuse histological type does not have recognized precursor changes (Correa and Shiao 1994). An association between blood group A and gastric cancer (particularly the diffuse type) has long been recognized. This could in part be due to the association of this blood group with pernicious anemia, which itself carries a higher than expected risk of gastric cancer (McConnell 1966). The risk of gastric cancer in relatives of index cases appears to be much more pronounced when the histological type in the index case is diffuse (seven times the risk in matched controls) rather than of the intestinal type (1.5 times higher than in control families) (Macklin 1960), but only a small proportion of diffuse gastric cancers occurs in families with an autosomal dominant gastric cancer susceptibility (reviewed in González et al. 2002).
The diffuse type of gastric carcinoma demonstrates a nearly equal sex ratio (compared with a male preponderance in the intestinal type), a younger patient age distribution, and little change with geographical migration, relative to the intestinal type. Chronic atrophic gastritis is found with increased frequency in relatives of index cases with pernicious anemia and gastric adenocarcinomas, but, specifically, it has been demonstrated to be more frequent in the relatives of index cases with diffuse spreading carcinoma than in controls; this has not been seen with other gastric cancer types (Kekki et al. 1987). Evidence suggests there may be an association between chronic H. pylori infection and intestinal-type chronic gastritis and cancer susceptibility: an increased frequency of infection with this organism has been reported in stomach cancer patients (Scott et al. 1990). Chronic gastritis may have a hereditary component, but the nature of this and its relationship to Helicobacter infection have not been clearly elucidated (Kekki et al. 1987). Ménétrier’s disease is also associated with an increased risk (10%) of gastric cancer – possibly because atrophic gastritis occurs in this etiologically obscure disease.
Most gastric cancers are sporadic, although up to 3 % occur in predisposed individuals. Nevertheless, there are many reports of families in which there is a strikingly high incidence of gastric cancer, following an autosomal dominant pattern of inheritance (Triantafillidis et al. 1993; Villanueva et al. 2010). Napoleon Bonaparte came from such a family (Creagan and Fraumeni 1973). Gastric cancer is a component of Lynch syndrome. An increased incidence of stomach cancer has also been noted in the close relatives of women with the medullary or tubular histological types of breast cancer. Some of these families may have Li– Fraumeni syndrome (Burki et al. 1987), and gastric carcinoma has also been described in some families with p53 mutations (Varley et al. 1995). Lobular breast cancer is increased in families with germline CDH1 mutations.
Adenocarcinoma of the stomach is reported in familial adenomatous polyposis (Jagelman et al. 1988) and is also reported to be more frequent in ataxia telangiectasia (Haerer et al. 1969; Gylling et al. 2007; Ohue et al. 1996) and in patients with immune deficiency. IgA deficiency is associated with an increased risk of intestinal metaplasia and of gastric cancer. The inheritance of IgA deficiency is not clear-cut and may be multifactorial (Grundbacher 1972). Gastric cancer occurs with increased relative risk in carriers of germline BRCA2 mutations (Breast Cancer Linkage Consortium 1997; Jakubowska et al. 2002). Gastric carcinoma (particularly of the intestinal type) is also part of the spectrum of cancers found in Lynch syndrome and displays replication errors (RER) characteristic of the condition in such families. The average age at diagnosis of gastric carcinoma in Lynch syndrome has been reported to be 56 years of age (Arnio et al. 1997; Watson et al. 2008).
The International Gastric Cancer Linkage Consortium (IGCLC) defined hereditary diffuse gastric cancer (HDGC) as (a) families with two or more cases of diffuse gastric cancer in first- or second-degree relatives with one affected aged <50 years or (b) three cases or more cases of diffuse gastric cancer in first- or second-degree relatives at any age (Caldas et al. 1999; Pharoah et al. 2001). Overall, about 25–50 % of patients with HDGC will have germline CDH1 mutations, and this rises to about 50 % in younger- onset cases (<50 years) with a positive family history (Gayther et al. 1998; Guilford et al. 1998; Richards et al. 1999). However isolated early-onset cases of diffuse gastric cancer are unlikely to have germline CDH1 mutations (Brooks-Wilson et al. 2004). Recently, it was suggested that families meeting the HDGC criteria should be offered testing for CDH1 mutations, and in addition, CDH1 molecular genetic testing also should be considered in (a) families with two cases of gastric cancer in the family with one confirmed case of diffuse gastric cancer <50 years, (b) cases of diffuse gastric cancer aged <40 years, and (c) a personal or family history of diffuse gastric cancer and lobular breast cancer (with one diagnosed <50 years of age). About 4 % of CDH1 mutation-positive families have exonic deletions.
The lifetime risk of gastric cancer in CDH1 mutation carriers was originally estimated to be >80 %, and prophylactic gastrectomy should be offered to mutation carriers aged 20 years or older (Fitzgerald et al. 2010), and multiple foci of gastric cancer have been found in gastrectomy specimens from affected individuals (Huntsman et al. 2001). If gastrectomy is delayed, then intensive annual endoscopy with multiple biopsies should be performed, but the efficacy of such screening is uncertain, as multiple foci of gastric cancer have been detected in gastrectomy specimens from affected individuals previously screened in this way (Huntsman et al. 2001).
Chromoendoscopic surveillance has also been advocated (Shaw et al. 2005), but is generally thought to be too insensitive to replace preventive surgery.
Further large-scale studies of penetrance are required as the long-term effects of total gastrectomy remain uncertain.
There is an increased risk of breast cancer, particularly lobular, in women with germline CDH1 mutations, and it has been recommended that such women should have annual mammogram and breast MRI and biannual clinical breast examination from 25 years of age (Fitzgerald et al. 2010). In CDH1 mutation-positive families with a history of colorectal cancer, mutation carriers might be offered colonoscopy from 40 years of age or, if younger, 10 years younger than the earliest age of onset of colorectal cancer in the family (Fitzgerald et al. 2010).
For individuals at risk for familial gastric cancer without CDH1 mutations, endoscopy with eradication of H. pylori infection is performed as an initial step. Subsequent endoscopies may be performed annually.