About 25 to 30 % of patients meeting current clinical criteria for HDGC are found to have germline mutations in CDH1, meaning that up to 70 % of families have no identifiable mutation [7]. Using the nomenclature reported by Blair et al., families that fulfil the IGCLC criteria for HDGC (see below) but have no identified CDH1 mutation are designated familial diffuse gastric cancer (FDGC) , HDGC refers only to families with a pathogenic CDH1 mutation [10]. CDH1 genetic testing involves sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large deletions. While this testing is currently the gold standard, there may still be mutations that are missed due to technological limitations. Families without identified CDH1 mutations have been investigated for other potential candidate genes involved in FDGC. In a Dutch kindred with FDGC, a mutation has recently been identified in CTNNA1, which encodes alpha-E-catenin, making this a potential causative mutation in FDGC [80]. Alpha-E-catenin, in a complex with beta-catenin, binds the cytoplasmic domain of E-cadherin to the cytoskeleton [32, 81, 82]. Loss of CTNNA1 in animal models induces altered cell polarity, hyperproliferation, and increase in Ras- and mitogen-activated kinase (MAPK) activity—features which are consistent with the potential to induce a malignant phenotype [83]. While the CTNNA1 mutation in this family is suspicious of pathogenicity for HDGC, the phenotype suggests older onset of DGC and mutations in CTNNA1 have not been found in other families to validate the result. It is likely that some families with FDGC may harbour mutations in other genes that have yet to be identified.

Other malignancies have shown higher prevalence in families with HDGC, the most prominent of which is LBC [10, 16, 18, 48]. The risk for developing LBC for females with CDH1 mutations is approximately 60 % by age 80 [7]. Therefore, LBC is considered a cancer in the HDGC syndrome that warrants specific management. Colorectal cancer has been identified in some HDGC kindreds [19, 20, 41], although the numbers are small and given this is such a common cancer in the community, direct pathogenesis from a CDH1 mutation has not been established [18].

Other hereditary syndromes are associated with increased risk for GC, including Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) , hereditary breast and ovarian cancer, familial adenomatous polyposis (FAP), Cowdens syndrome and Peutz–Jeghers syndrome. Table 6.2 describes the associated risk of GC , which can be intestinal or diffuse type, with selected syndromes where it is known. Patients with hereditary breast and ovarian cancer syndrome have increased risks of malignancies in addition to breast and ovarian cancer, including gastric cancer although the risks are not well quantified [84, 85]. Patients with Lynch syndrome, in addition to colorectal cancer, are at risk of GC, other gastrointestinal malignancies, endometrial carcinoma and transitional cell carcinomas of the renal tract [6, 86, 87].

Polyposis of the gastrointestinal (GI) tract is associated with a number of familial cancer syndromes. Upper GI polyposis is frequently found associated with FAP. In the stomach this is manifested as fundic gland polyposis [89, 90]. Although sporadic fundic gland polyps are considered to be non-neoplastic, in FAP patients some have been found to harbour dysplasia which may evolve into invasive GC [89, 91, 92]. Peutz–Jeghers and Cowden syndrome patients present with polyposis of multiple organs. Only rare cases of GC have been reported in Cowden syndrome, suggesting this is not a common manifestation of this disease [93, 94]. The risk of cancer in Peutz–Jeghers syndrome is higher, with a life-time risk of GC of 29 % [88]. Juvenile polyposis syndrome is another syndrome associated with hamartomatous polyp formation of the GI tract, with associated increased risk of GI malignancy mainly related to colorectal cancer, but GC has also been documented [95, 96]. GC has also been seen in families with Li–Fraumeni syndrome [97, 98], and some FDGC families have been identified with TP53 mutations suggesting GC is a component of Li–Fraumeni syndrome spectrum [57]. Although there appears to be no significant increase in the incidence of GC in patients with MUTYH-associated polyposis, a autosomal recessive disorder caused by germline mutations in the base excision repair gene MUTYH [99], monoallelic MUTYH mutation carriers have been reported to have a higher incidence of GC than the general population [100]. There are reports of an increased incidence of GC in relatives of patients with Fanconi’s anaemia [101]. In 2012 a new autosomal dominant condition associated with gastric polyposis and intestinal GC was described. This featured proximal polyposis of the stomach and GC and was named gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) [102, 103]. The causative gene for this syndrome is unknown.