Gastric cancer is the second leading cause of cancer death worldwide.1 Environmental agents, including Helicobacter pylori and diet, are the primary risk factors; however, 10% of cases show familial clustering suggestive of a genetic predisposition.2 Histologically, gastric cancers have been classified by Lauren as either diffuse or intestinal.3 The intestinal type pathology is linked to environmental factors and advanced age, whereas the diffuse type occurs in younger patients and is characterized by multifocal signet ring cell infiltrates.4 Overall rates of gastric cancer have declined significantly over the last 50 years despite a simultaneous, dramatic increase in the subset of proximal gastric and distal esophageal cancers.5 Diffuse gastric cancers (DGCs) represent a smaller percentage of gastric cancers that have not declined in incidence.4
Hereditary DGC (HDGC) is an autosomal-dominant, inherited cancer syndrome that is characterized clinically by either 1) ≥2 documented cases of DGC in first- or second-degree relatives with at least 1 diagnosed before age 50 years; or 2) ≥3 cases of documented DGC in first- or second-degree relatives, independent of the age of onset.6 Figure 1 shows an example pedigree from a family with HDGC, demonstrating the syndrome's characteristic high penetrance and autosomal-dominant inheritance.7 The average age of onset of gastric cancer in affected families is 38 years; however, individuals as young as 14 years have died of the disease.6 It is estimated that cases of HDGC comprise 1% to 3% of all gastric cancers.8, 9
E-cadherin Gene Mutations in HDGC
A breakthrough in understanding HDGC occurred in 1998, when inactivating germline mutations in the E-cadherin gene CDH1 were identified in 3 Maori families with multiple cases of DGC.10 The CDH1 mutations in these families were inherited in an autosomal-dominant pattern with incomplete but high penetrance. Affected individuals developed lethal DGC at a young age.10 Since 1998, germline mutations of CDH1 have been identified in 30% to 50% of all patients with HDGC.8, 11, 12 Greater than 50 distinct mutations have been recognized7, 12 across diverse ethnic backgrounds, including European, African American, Pakistani, Japanese, Korean, and others.13–21 In addition to their high risk for DGC, patients with germline CDH1 mutations carry an increased risk of lobular carcinoma of the breast and possibly colorectal and prostate cancers.17, 19, 22, 23 To date, CDH1 is the only gene implicated in HDGC.
CDH1 is localized on chromosome 16q22.116 and encodes the calcium-dependent cell-adhesion glycoprotein E-cadherin. E-cadherin is a transmembrane protein that connects to the actin cytoskeleton through a complex with α-catenin, β-catenin, and γ-catenin. Functionally E-cadherin impacts maintenance of normal tissue morphology and cellular differentiation.10, 24 With regard to HDGC, it is believed that CDH1 acts as a tumor suppressor gene, with mutation of CDH1 leading to loss of cell adhesion, proliferation, invasion, and metastasis.14, 25–27
In patients with HDGC, the germline CDH1 mutation is typically a truncating mutation. Missense mutations may be causative in a few HDGC kindreds, but, most often, they are not clinical significant.8, 12 Figure 2 shows the specific truncating CDH1 mutation for the pedigree depicted in Figure 1. Within the gastric mucosa, a somatic event (usually CDH1 promoter methylation or an inactivating point mutation) provides the ‘second hit’ that leads to the complete loss of E-cadherin function.28, 29 It is unknown whether specific CDH1 mutations are associated with different phenotypic characteristics or rates of penetrance. Penetrance of DGC in patients who carry a CDH1 mutation is estimated at 63% to 83% for women and 40% to 67% for men.6, 12 Women with CDH1 mutations carry an additional 20% to 40% risk of lobular breast cancer.2
To date, most recognized mutations have been novel mutations distributed throughout CDH1. When recurrent mutations have been recognized, they usually have resulted from independent events.7, 30 However, there is evidence for the role of founder effects in certain kindreds.12 HDGC patients without recognizable CDH1 mutations most likely have mutations of a different gene, but they also may have alternative mechanisms for inactivation of CDH1, such as large genomic rearrangements or regulatory element mutations.
Testing for CDH1 mutations currently is recommended for 1) families with ≥2 cases of DGC and at least 1 case diagnosed before age 50 years; 2) families with ≥3 cases of DGC diagnosed at any age; 3) isolated individuals diagnosed with DGC before age 35 years; 4) isolated individuals with both DGC and lobular breast cancer; 5) families with 1 member with DGC and another with either lobular breast cancer OR signet ring cell colon cancer. Testing for CDH1 mutations also is recommended for families with multiple cases of lobular breast cancer, with or without a case of DGC, because germline CDH1 mutations have been detected in families with lobular breast cancer alone.31
Like in other familial cancer syndromes, genetic counseling should take place before testing. A team that includes a geneticist, gastroenterologist, surgeon, and oncologist should discuss the possible outcomes of testing and the management options associated with each. When possible, genetic testing should be performed first on a family member with DGC.6 If a CDH1 mutation is identified in that individual, then asymptomatic family members should proceed to testing by their early 20s.14 If no mutation is identifiable in the family member with DGC or if no affected family member is available for testing, then a negative test in asymptomatic family members will be uninformative.
One challenge in managing a patient with a known CDH1 mutation is the inadequacy of current screening modalities. DGCs identified in patients with HDGC are characterized by multiple infiltrates of malignant signet ring cells that may underlie the normal mucosa.32–34 The wide distribution and small size of the malignant foci make them difficult to identify with random endoscopic biopsy.32 Chromoendoscopy-aided biopsies have been used, but this approach only detects lesions >4 mm and, thus, has limited utility in diagnosing early HDGC.35 It was demonstrated in 1 case report that positron emission tomography (PET) detected HDGC; however, in multiple other studies, it was negative in patients with proven cancer.12, 14, 36 The lack of a sensitive screening test for HDGC makes early diagnosis extremely challenging.8, 37, 38 By the time patients are symptomatic and present for treatment, many have diffuse involvement of the stomach, and the rates of mortality are high.13, 39, 40 In case reports, patients have presented with extensive DGC despite recent normal endoscopy with negative biopsies.33
Role of Prophylactic Gastrectomy
Because of high cancer penetrance, poor outcomes, and inadequacy of clinical screening in HDGC, currently, gene-directed prophylactic total gastrectomy is offered to carriers of germline CDH1 mutations.7, 14, 33, 41, 42 This scenario is analogous to total thyroidectomy on the basis of mutation of the rearranged during transfection gene (RET) in asymptomatic individuals from families with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC), or MEN2B.43–47 In published series of CDH1 mutation carriers who underwent prophylactic gastrectomy, nearly all specimens contained multiple foci of diffuse signet ring cell cancer.7, 14, 33, 42, 48 Figure 3 shows the pathology of the stomachs of 6 asymptomatic family members with an inherited CDH1 mutation who underwent prophylactic gastrectomy. Foci of DGC have been observed on final pathology even in patients with extensive negative preoperative screening, including high-resolution CT, PET scans, chromoendoscopy-guided biopsies, and endoscopic ultrasonography.14 DGC identified in asymptomatic CDH1 carriers typically is in an early stage and can be resected completely by prophylactic gastrectomy, and surgery can be considered curative.
A total gastrectomy is the recommended surgery for CDH1 mutation carriers, because the signet ring cell cancers in HDGC are multifocal and are distributed throughout the entire stomach. The operation should be performed by a surgeon who is experienced in the technical aspects of the procedure and is familiar with HDGC. The entire stomach must be removed, because HDGC arising in the residual stomach after subtotal gastrectomy has been reported.33 To our knowledge, there has not been a randomized study of methods of reconstruction after total gastrectomy to date. It has been our practice to perform Roux-en-Y esophagojejunostomy, with the end of the jejunal limb serving as a small pouch. The use of laparoscopic total gastrectomy in patients with germline CDH1 mutations now has been reported and may reduce pain and hasten recovery after surgery; however, total gastrectomy with anastamosis of the jejunum to the esophagus still is necessary.49, 50
The optimal timing of prophylactic gastrectomy in individuals with CDH1 mutations is unknown. We recommend initially considering the surgery when the individual with a CDH1 mutation is 5 years younger than the youngest family member who has developed HDGC. Clinical management and screening strategies remain uncertain for families that meet criteria for HDGC but are negative for CDH1 mutations or that carry missense mutations or variants of unknown significance. We do not recommend prophylactic gastrectomy in this situation, but we do suggest screening endoscopy starting at an age 10 years younger than the youngest family member presenting with gastric cancer.
Although it is a potentially lifesaving procedure, prophylactic gastrectomy for CDH1 mutation carries significant risks. The estimated overall mortality for total gastrectomy is as high as 2% to 4%.51 Patients must be aware that there is a nearly 100% risk of long-term morbidity with the procedure, including diarrhea, dumping, weight loss, and difficulty eating.2 In addition, the penetrance of CDH1 mutations is incomplete; thus, as many as 20% to 30% of patients who undergo prophylactic gastrectomy will never go on to develop clinically recognizable gastric cancer. In fact, prophylactic gastrectomy has been performed on several patients who reportedly had no evidence of gastric cancer on pathology.7, 41 In these patients, however, it is unclear whether or not serial sections and careful pathologic analysis of the removed stomach were performed. In our experience with 10 patients, each had had signet ring cell cancer in multiple locations when the entire stomach was examined systematically by a pathologist who was familiar with the diagnosis and the disease process.14
Some individuals who have CDH1 mutations will choose not to pursue prophylactic gastrectomy. These individuals should have careful surveillance, including biannual chromoendoscopy with biopsies, beginning at an age at least 10 years younger than the youngest family member diagnosed with DGC. Because of their increased risk of lobular breast cancer, women with CDH1 mutations also should be screened carefully with annual mammography and magnetic resonance imaging of the breast starting at age 25 years. There is clearly a need for the development of improved screening modalities for patients who do not undergo prophylactic gastrectomy. We have reported localization of signet ring cell cancer foci to the proximal one-third of the stomach, suggesting a role for anatomically targeted endoscopic biopsies.52 Another possible approach would be molecular imaging targeted to the downstream effects of CDH1 mutations, although a suitable target remains to be identified.
The identification of CDH1 mutations in HDGC and the emergence of gene-directed gastrectomy as a treatment strategy represent the culmination of a successful collaboration between molecular biologists, geneticists, oncologists, gastroenterologists, and surgeons. A previously lethal disease is now detected by molecular techniques, allowing curative surgery at an early stage, as in the case of MTC diagnosed by RET gene mutation. Future efforts in HDGC should be directed toward the development of improved screening modalities for patients with CDH1 mutations, the recognition of genetic and environmental factors that may interplay with CDH1 in cancer development, and the identification of causative mutations for the significant subset of patients HDGC without a recognizable CDH1 mutation.