Similar to other gastric carcinomas, patients with HDGC are often asymptomatic in the early stages and tend to present late with symptoms such as weight loss, abdominal pain, nausea, anorexia, dysphagia, melaena and early satiety. The median age at diagnosis is 38 years, with the range varying greatly from 14-82 years[10,16].

Majority of HDGCs are inherited in an autosomal dominant pattern. It exhibits high penetrance and invasive disease often manifests before age 40. Therefore, one should have a high clinical suspicion when a family history reveals two or more cases of gastric cancer in first or second degree relatives, especially with one case diagnosed before age 50. The lifetime cumulative risk for diffuse GC reaches > 80% in men and women by age 80 years[11].

There is an association of HDGC with lobular breast cancer (LBC) and it can be the presentating pathology[17]. Data based on 11 HDGC families, estimated the cumulative risk for LBC for female CDH1 mutation carriers to be 39% (95%CI: 12%-84%) by 80 years of age[18]. Thus, personal or family history of multiple LBCs at a young age should also prompt CDH1 screening even if there is no HDGC. There have also been case reports of colorectal, prostate and ovarian carcinomas in HDGC families although these are rare and of uncertain significance[19-22]. Interestingly, cleft-lip, with or without cleft-palate malformations have been reported in several HDGC families, some of whom have specific CDH1 splice site mutations[23,24].

It should be remembered that GC can develop in the setting of other hereditary cancer syndromes aside from HDGC. One example would be Lynch syndrome which more often presents with intestinal-type gastric cancers and also has a high lifetime risk of colorectal and endometrial cancer. Other examples include Familial adenomatous polyposis, Li-Fraumeni syndrome, Peutz-Jegher’s syndrome (PJS) and Juvenile Polyposis Syndrome (JPS) (Table 3). The lifetime risk of GC in these syndromes varies considerably but is generally lower than that in HDGC.

E-cadherin is a cell adhesion protein that is required for development, cell differentiation and maintenance of epithelial architecture[6]. Since the E-cadherin gene CDH1 was identified as a genetic basis for HDGC in 1998, more than 120 CDH1 germline mutations have been published[25]. The most common germline alterations are small frameshifts, splice-site and nonsense mutations[9]. Of note, only two de novo mutations have been reported to date[26,27].

However, newer HDGC-susceptibility genes have been identified (Table 2). In 2012, an alpha-E-catenin (CTNNA1) germline truncating mutation was been found in a large Dutch HDGC pedigree[14] although the evidence presented was not definitive given a number of carriers remained cancer-free and other studies have failed to replicate findings[28]. At time of writing, MAP3K6[15], INSR, FBXO24 and DOT1L[16] have also identified as candidate genes although they remain reports from single families. The insulin receptor (INSR) gene mutation is of special interest given insulin signaling has been reported to affect tumour cell invasion capability by modulating E-cadherin glycosylation[29] and is known to play a role in a variety of cancers[30]. There has also been a reported possibility of an association of early onset gastric cancer with IL12RB1 mutation carriers[31] although this is mainly of the intestinal-type.

Guilford et al[10] has suggested HDGC develops from multiple foci of signet ring cell carcinomas (SRCC) in mutation carriers before 30 years of age. These SRCC, which have been termed “early HDGC”[32], develop after loss of the second CDH1 allele via a 2^nd-hit mechanism[33-36]. The same patient may present with distinct 2^nd hit mechanisms in different lesions. Promoter methylation is the most common 2^nd-hit mechanism in primary HDGC tumours although loss of heterozygosity was found to be the most prevalent in lymph node metastases[37].

Interestingly, other studies are starting to look at oncogenic pathways involved in metastatic progression in HDGC and have found one such candidate driver in a transforming growth factor beta receptor 2 loss-of-function mutation[38].

The identification of germline mutations in families fulfilling the criteria for HDGC relies on information from pathology reports from at least one proband. A report by Hebbard et al[39] on 23 patients who underwent prophylactic total gastrectomy showed 21 of them had evidence of diffuse/signet-ring carcinoma on final standardized pathological evaluation which was not picked up by preoperative endoscopic screening. Thus, for adequate pathological sampling, IGCLC recommends targeting any endoscopically visible lesions as well as random sampling of six biopsies for each of the following anatomical zones: antrum, transitional zone, body, fundus, cardia. This would give a minimum of 30 biopsies[11].

Probands often present with advanced stage GC and treatment consists of palliative chemotherapy (often taxanes, platinum agents or irinotecan), targeted radiotherapy and bypass surgery. While research looks into E-cadherin pathway regulators to increase chemosensitivity to epidermal growth factor receptor inhibitors and cytotoxics[40-42], there are currently no specific targeted therapies for diffuse GCs although there is an ongoing Phase I clinical trial studying everolimus in combination with chemotherapy[43].

As personalized therapy becomes increasingly prominent in cancer care, management of patients with HDGC should involve a multidisciplinary team of geneticists, surgeons and pathologists to address the following aspects of care: (1) genetic counselling and screening for both CDH1 positive and negative patients. This should include a three-generation family pedigree, analysis of CDH1/other candidate gene mutation and translation into lifetime risks of diffuse GC and LBC[11]; and (2) discussion of prophylactic gastrectomy vs surveillance.

Guidelines for the clinical management of CDH1 mutation carriers have been reviewed by the IGCLC (2010) and are outlined in clinical utility cards for HDGC[44]. Figure 1 summarises the management algorithm.

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Figure 1 Clinical management of individuals suspected to have hereditary diffuse gastric cancer. Adapted from Pinheiro et al[9]. ¹Analyses recommended include: mutation frequency in healthy control population, co-segregation of mutation within pedigree, recurrence of mutation in independent families, in-silico predictions and in vitro functional assays[45,65-68].

It is suggested that these individuals go on to have their mutations assessed for pathogenicity via functional in-vitro testing (aggregation and invasion assays) and in-silico models that have been developed[45]. These techniques have found a significant number of pathogenic missense variants and should be carried out by molecular diagnostic laboratories with appropriate expertise.

Mutation screening in the research setting of HDGC families without CDH1 mutations can be considered. Approaches needed would include high density single-nucleotide polymorphism (SNP) genotyping, non-parametric and parametric linkage analysis, whole exome sequencing as well as aforementioned pathogenicity assessments[14,15].

There is currently no reliable screening test for early diagnosis of diffuse GCs in mutation carriers. While IGCLC guidelines suggest annual endoscopic surveillance in specific settings, it should be known that direct visualization with endoscopy tends to detect lesions late in the disease process[46] and multiple random endoscopic samples often returns false negatives[39]. Other screening methods like chromoendoscopy and positron emission tomography have not been deemed to be consistently effective[47,48].

Due to the lack of reliably sensitive surveillance methods, prophylactic total gastrectomy should be considered in the early 20s and is usually advised before age 40 for those carrying CDH1 mutations. Some authors suggest consideration of gastrectomies in CDH1 mutation carriers at an age 5 years younger than the youngest family member who developed gastric cancer[49].

There are currently no recommendations with regards to prophylactic gastrectomy in CDH1-negative individuals. Prospective studies evaluating prophylactic gastrectomy in HDGC have offered the surgery only to CDH1 positive individuals[50], while a systematic retrospective review of 28 articles on prophylactic gastrectomy found a small sample of 11 CDH1-negative individuals who had undergone the gastrectomy before CDH1 testing all had negative histopathology results for cancer[51].

Patients may refuse or decide to postpone the procedure due to young age, fertility concerns or fear of surgical complications. Fortunately, there have been reports of successful pregnancies post-prophylactic gastrectomy[52] and the youngest known carrier to date to undergo gastrectomy was 16 years of age[53].

A significant proportion of HDGC families are likely to be CDH1 negative. Further study to identify other genetic causes is needed before their risk and therefore management measures such as prophylactic gastrectomy can be assessed. As more cases of HDGC are identified, two lines of study are especially valuable. First, pathogenicity and penetrance of new germline mutations need to be documented to improve genetic counselling and decision-making. This is especially so for missense mutations. Second, prophylactic gastrectomy specimens provide material to identify molecular mechanisms that may predict progression from SRCC lesions to HDGC. In particular, elucidating epigenetic mechanisms, such as analysis of hypermethylation of cell cycle or DNA repair genes[54-57], may provide useful insights into possible environmental or pharmaceutical chemoprevention strategies.

Better surveillance methods could reduce morbidity by picking up target lesions earlier such that they are amenable to endoscopic therapies. While detection of diffuse GCs has proven difficult and surveillance frequency remains challenging, one paradigm to guide further research would be to assume that microfoci of SRCC will be present in all adult mutation carriers. Thus, rather than trying to detect all microfoci, the aim of surveillance should be geared towards detecting “high risk” SRCC. While this will require further elucidation of mechanisms of carcinogensis, it is plausible to imagine current surveillance methods, combined with genetic data, as a reliable alternative to prophylactic total gastrectomy.