LBC, INCLUDED
GASTRIC CANCER, FAMILIAL DIFFUSE, AND CLEFT LIP WITH OR WITHOUT CLEFT PALATE, INCLUDED
GASTRIC CANCER, FAMILIAL DIFFUSE BREAST CANCER, LOBULAR, INCLUDED
GASTRIC CANCER, HEREDITARY DIFFUSE
HDGC
Familial stomach cancer
Hereditary diffuse gastric cancer is an autosomal dominant cancer predisposition syndrome. Heterozygous CDH1 mutation carriers have a 70 to 80% lifetime risk of developing diffuse gastric cancer. In addition to gastric cancer, up to 60% of female mutation ... Hereditary diffuse gastric cancer is an autosomal dominant cancer predisposition syndrome. Heterozygous CDH1 mutation carriers have a 70 to 80% lifetime risk of developing diffuse gastric cancer. In addition to gastric cancer, up to 60% of female mutation carriers develop lobular carcinoma of the breast, and some carriers may develop colorectal cancer. Identification of mutation carriers is important, because the characteristic microscopic foci of signet ring cell adenocarcinoma in HDGC usually involves the submucosa and is often not readily detectable by routine upper endoscopy screening (summary by Fitzgerald et al., 2010). HDGC is considered to be a distinct disease entity from the more common sporadic occurrence of gastric cancer (613659), which can be associated with environmental factors, such as Helicobacter pylori infection, high-fat diet, or smoking, and is often associated with somatic mutations in disease tissue.
Caldas et al. (1999) reported the proceedings of the First Workshop of the International Gastric Cancer Linkage Consortium convened to produce consensus statements and guidelines for familial gastric cancer. Caldas et al. (1999) noted that review of pathologic ... Caldas et al. (1999) reported the proceedings of the First Workshop of the International Gastric Cancer Linkage Consortium convened to produce consensus statements and guidelines for familial gastric cancer. Caldas et al. (1999) noted that review of pathologic samples from 8 families with inactivating germline mutations in the E-cadherin gene showed that all of the gastric cancers in these families were of diffuse type, and 2 of these had a glandular/intestinal component. Hereditary diffuse gastric cancer was defined as existing in any family in which there were (1) 2 or more documented cases of diffuse gastric cancer in first- or second-degree relatives with at least one cancer diagnosed before the age of 50; or (2) 3 or more cases of diffuse gastric cancer in first- or second-degree relatives independent of age of onset. Caldas et al. (1999) also noted that since 5 individuals below the age of 18 had developed diffuse gastric carcinoma, testing of minors might be justified. Fitzgerald et al. (2010) presented updated consensus guidelines for HDGC, which included broadening of CDH1 testing criteria: histologic confirmation of diffuse gastric criteria is only required for 1 family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Large genomic rearrangements of CDH1 should be sought in addition to direct sequencing. Benusiglio et al. (2013) suggested that the criteria for CDH1 testing put forth by Fitzgerald et al. (2010) may be too strict, and proposed that a personal or family history of 2 histologically proven lobular breast cancers before age 50, after exclusion of a germline mutation in BRCA1 and BRCA2, should be added to the criteria for CDH1 testing.
Jones (1964) described 3 multigenerational Maori families from New Zealand segregating early-onset familial gastric cancer. These families were later studied in detail by Guilford et al. (1998). In 1 family, 25 members ranging in age from 14 years ... Jones (1964) described 3 multigenerational Maori families from New Zealand segregating early-onset familial gastric cancer. These families were later studied in detail by Guilford et al. (1998). In 1 family, 25 members ranging in age from 14 years upwards had died over 30 years. The majority of cases occurred before age 40 years, which was in marked contrast to the general experience in New Zealand, where about 80% of gastric cancers occur in people older than 60 years. There was no evidence of an increased cancer rate of other organs in this family. Pathology showed histologically poorly differentiated, high-grade, diffuse gastric cancer. Kakiuchi et al. (1999) studied the clinical features of the probands of 16 Japanese gastric cancer families, which was defined as the existence of 3 or more family members with gastric cancer in at least 2 successive generations. These patients developed cancers more frequently in the cardiac region of the stomach. In addition, the cancers were more often of the undifferentiated type, and were more frequently associated with disseminated peritoneal and liver metastases compared to sporadic cases. Richards et al. (1999) reported a family from the U.K. in which 6 individuals developed diffuse gastric cancer. In addition to the 6 members with gastric cancer, 1 member of the family developed adenocarcinoma of the rectum at the age of 30 years. Genetic analysis identified a heterozygous mutation in the CDH1 gene (192090.0008). Huntsman et al. (2001) described genetic screening, surgical management, and pathologic findings in young persons with truncating CDH1 mutations (192090.0012; 192090.0013) in 2 unrelated families with hereditary diffuse gastric cancer reported by Gayther et al. (1998). Total gastrectomy was performed prophylactically in 5 carriers of mutations who were between 22 and 40 years of age. In each case, superficial infiltrates of malignant signet ring cells were identified in surgical samples. Chun et al. (2001) reported a family with a strong history of HDGC. Five family members, including a sister and brother and 3 first cousins, underwent endoscopic evaluations, which were negative for malignancy, and elected to undergo a prophylactic total gastrectomy with Roux-en-Y esophagojejunostomy. Intramucosal signet ring cell adenocarcinoma was found in various regions of the stomach in all 5 patients, and all 5 demonstrated diminished or absent E-cadherin reactivity in the cancerous mucosa. The age of the 5 patients at the time of surgery varied from 40 to 63 years. Brooks-Wilson et al. (2004) reported 10 different families with hereditary gastric cancer who had germline mutations in the CDH1 gene. There were multiple cases of breast cancers, including pathologically confirmed lobular breast cancer, in these families. In a retrospective study of French patients who underwent genetic testing for germline mutations in the CDH1 gene, Benusiglio et al. (2013) found that 18 (11%) of 165 index cases carried pathogenic mutations. Eleven of these patients had a personal or family history that fulfilled diagnostic criteria delineated by Fitzgerald et al. (2010) (see DIAGNOSIS). However, 7 remaining cases did not meet the HDGC criteria: 3 women had sporadic bilateral lobular breast cancer before age 50; 3 came from families with 2 cases of DGC after age 50; and 1 had sporadic diffuse gastric cancer after age 40. Of the 3 woman with LBC before age 50, 2 were only tested for CDH1 after subsequently developing symptomatic DGC and thus meeting the criteria. The remaining woman had CDH1 testing and prophylactic gastrectomy that revealed DGC despite a negative screening endoscopy. These findings suggested that early-onset LBC might be the first manifestation of HDGC, and that a personal or family history of multiple LBCs at a young age, even in the absence of DGC, should prompt cancer geneticists to test for CDH1 germline mutations. - Hereditary Diffuse Gastric Cancer With or Without Cleft Palate Frebourg et al. (2006) reported 2 unrelated families segregating diffuse gastric cancer and cleft palate. Genetic analysis confirmed that affected individuals with gastric cancer with or without cleft palate had heterozygous mutations in the CDH1 gene (192090.0019 and 192090.0020, respectively). In 1 family, 4 mutation carriers had diffuse gastric cancer and cleft lip/palate and 2 mutation carriers had gastric cancer without clefting. In the second family, a man and his 2 daughters had gastric cancer, a daughter with the mutation had cleft lip but no gastric cancer at age 25, and a 16-year-old son with the mutation had congenital aplasia cutis of the scalp and partial acrania (107600) but no known gastric cancer. Both mutations were splicing mutations generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant-negative effects. Expression of CDH1 in human embryos during critical stages of lip and palate development suggested that alteration of the E-cadherin pathway may contribute to human clefting.
In affected members of 3 New Zealand families with HDGC, Guilford et al. (1998) identified heterozygous germline mutations in the CDH1 gene (192090.0005-192090.0007).
Grady et al. (2000) noted that patients with heterozygous germline mutations in the ... In affected members of 3 New Zealand families with HDGC, Guilford et al. (1998) identified heterozygous germline mutations in the CDH1 gene (192090.0005-192090.0007). Grady et al. (2000) noted that patients with heterozygous germline mutations in the CDH1 gene develop gastric cancer, but their cancers consistently demonstrate no loss of heterozygosity (LOH) at the CDH1 locus. They hypothesized that methylation of the CDH1 promoter might represent the 'second genetic hit' in the genesis of these tumors. The CDH1 promoter was found to be consistently unmethylated in normal stomach mucosa, whereas 3 of 6 HDGC tumors with negative CDH1 staining had aberrant CDH1 promoter methylation. Two tumors that had retained unmethylated CDH1 promoters harbored somatic CDH1 mutations. No somatic mutations were found in 2 HDGC tumors showing CDH1 promoter methylation, but sequence polymorphisms confirmed that they retained a second wildtype allele. These findings indicated that the formation of HDGC tumors requires biallelic CDH1 inactivation, which in one-half of cases is accomplished by promoter methylation of a retained wildtype allele. In a family with a strong history of diffuse gastric carcinoma, Chun et al. (2001) found a 1558insC germline mutation in the CDH1 gene (192090.0014). Oliveira et al. (2002) performed germline CDH1 mutation screening in 39 kindreds with familial aggregation of gastric cancer, a subset of which fulfilled the criteria defined by the International Gastric Cancer Linkage Consortium (IGCLC) for hereditary diffuse gastric cancer. CDH1 germline mutations were detected in 4 of 11 (36.4%) HDGC families. No mutations were identified in 63.6% of HDGC families or in kindreds with familial aggregation of gastric cancer not fulfilling criteria for HDGC. These results added support to the evidence that only HDGC families harbor germline mutations in CDH1 and that genes other than CDH1 remained to be identified. Among 43 apparent cases of hereditary gastric cancer, Brooks-Wilson et al. (2004) identified heterozygous mutations in the CDH1 gene in 10 different families. There were 10 loss-of-function mutations, including 2 insertions, 5 deletions, 2 splice site substitutions, and 1 complex deletion/insertion involving a splice site. They also found 3 heterozygous missense mutations that were predicted to affect conserved residues and to have deleterious effects on protein function. Oliveira et al. (2009) reported 6 (6.5%) of 93 previously described mutation-negative hereditary diffuse gastric cancer probands who carried genomic deletions of the CDH1 gene (see, e.g., 192090.0022 and 192090.0023). The statistically significant overrepresentation of Alu repeats around breakpoints indicated nonhomologous allelic recombination of Alu repeats as a likely mechanism for these deletions. When all mutations and deletions were considered, the overall frequency of CDH1 alterations in HDGC was approximately 46% (73 of 160), and large CDH1 deletions occurred in 3.8% of HDGC families. Among 18 index patients with germline CDH1 mutations identified retrospectively, Benusiglio et al. (2013) found 16 different mutations, including 14 point mutations and 2 large deletions. Most of the mutations were truncating; 9 of the 16 mutations had not previously been reported.
Criteria for consideration of CDH1 molecular genetic testing in individuals with diffuse gastric cancer (DGC) were revised in 2005 when a new cohort of families with hereditary DGC was tested [Suriano et al 2005]. These current criteria are applicable to North America, northern Europe, and other regions of low gastric cancer incidence but are likely too broad for use in regions of high gastric cancer incidence such as Japan and Korea. ...
DiagnosisClinical DiagnosisCriteria for consideration of CDH1 molecular genetic testing in individuals with diffuse gastric cancer (DGC) were revised in 2005 when a new cohort of families with hereditary DGC was tested [Suriano et al 2005]. These current criteria are applicable to North America, northern Europe, and other regions of low gastric cancer incidence but are likely too broad for use in regions of high gastric cancer incidence such as Japan and Korea. Modified testing criteriaFamily with two or more cases of gastric cancer (GC), with at least one DGC diagnosed before age 50 years. (>30%)Family with multiple lobular breast cancer (LBC) with or without DGC in first- or second-degree relatives (unknown)Single individual from a low-incidence population (<10%) diagnosed with DGC before age 35 yearsAn individual with both DGC and LBC (unknown)Potential additional criteriaFamily with three or more cases of GC diagnosed at any age, one or more of which is documented to be DGC; no other criteria met (such families are extremely rare)Family with one or more cases of both DGC and signet ring colon cancer (this association is unproven)The International Gastric Cancer Linkage Consortium (IGCLC) recently redefined the clinical criteria in consensus guidelines [Fitzgerald et al 2010; see for full text] as follows:Two gastric cancer (GC) cases in family, one individual under age 50 years with confirmed diffuse gastric cancer (DGC) Three confirmed DGC cases in first- or second-degree relatives independent of ageSimplex case (i.e., a single occurrence in a family) of DGC occurring before age 40 yearsPersonal or family history of DGC and lobular breast cancer, one diagnosed before age 50 yearsMolecular Genetic TestingGene. CDH1, encoding the protein E-cadherin, is the only gene in which mutations are known to be associated with HDGC [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Yoon et al 1999, Dussaulx-Garin et al 2001, Humar et al 2002, Oliveira et al 2002, Jonsson et al 2002, Brooks-Wilson et al 2004, Keller et al 2004, Suriano et al 2005, Frebourg et al 2006, Rodriguez-Sanjuan et al 2006, Kaurah et al 2007, Masciari et al 2007, More et al 2007, Roviello et al 2007, Van Domselaar et al 2007, Oliveira et al 2009, Ghaffari et al 2010, Mayrbaeurl et al 2010]. Evidence for possible locus heterogeneity. Mutations in CDH1 account for approximately 30%-50% of HDGC in North American families with HDGC [Kaurah et al 2007].Since between 50%-70% of families with HDGC reported to date have no identifiable CDH1 germline mutation, it is likely that some of these families may have mutations in other unidentified HDGC-susceptibility genes. Although the candidate genes have been analyzed, no mutations have been found to date in any of them. Candidate genes considered and excluded include:TP53. TP53 mutations are common in many cancers (see Li-Fraumeni Syndrome); however, mutations in TP53 tend to occur in intestinal GC rather than in diffuse GC. In two studies that included a total of 66 families that had an excess of individuals with GC, two families had a TP53 germline mutation [Keller et al 2004, Oliveira et al 2004]. In a study of 29 families with HDGC in which no CDH1 mutation had been identified, none had a TP53 mutation [Huntsman, unpublished data]. SMAD4. SMAD4 is a tumor suppressor gene that has been described in hereditary juvenile polyposis (JPS). A study of 32 families with gastric cancer did not reveal a SMAD4 germline mutation in affected individuals [Oliveira et al 2004]. No germline mutations in SMAD4 were found in the 29 families studied by Huntsman [Huntsman, unpublished data].CASP10. A study on families with gastric cancer did not reveal a CASP10 germline mutation in affected individuals [Oliveira et al 2004].β-catenin (CTNNB1) and α-catenin (CTNNA1). CTNNB1 mutations have been described in IGC.Twenty-nine families with DHGC, in which no CDH1 mutation had been identified, were analyzed for mutations in both CTNNA1 and CTNNB1 but none were found [Huntsman, unpublished data]. MET. Further investigations are needed to clarify the association of MET germline mutations and diffuse gastric cancer.Lee et al [2000] identified a missense MET germline mutation in a proband with intestinal gastric cancer; however, family history was not reported. In the first study to associate a MET germline mutation with diffuse gastric cancer, Kim et al [2003] identified a germline pathologic missense MET mutation in one of 21 Korean families with gastric cancer. No MET germline mutations were identified in the 18 Indian and European probands studied by Chen et al [2001]. RUNX3. Keller et al [2004] did not identify a germline mutation in 34 families with GC.HPP1. Keller et al [2004] did not identify a germline mutation in 34 families with GC.Clinical testing Sequence analysis. Bidirectional sequence analysis of all coding portions and intron-exon boundaries of CDH1 detects mutations in about 30%-50% of individuals with a clinical diagnosis of HDGC [Oliveira et al 2006, Kaurah et al 2007]. This technique detects mutations that include single base substitutions as well as small deletions and insertions. Deletion/duplication analysis. Deletion/duplication analysis identifies exonic or whole-gene deletions in:6.5% of individuals with HDGC who do not have a mutation identified on sequence analysis [Oliveira et al 2009]; 4% of all families with clinically defined HDGC. Table 1. Summary of Molecular Genetic Testing Used in Hereditary Diffuse Gastric Cancer View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCDH1Sequence analysisSequence variants 230%-50%ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions4% 4 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 4. All persons with HDGCInterpretation of test results Truncating mutations are assumed to be pathogenic. For issues to consider in interpretation of sequence analysis results, click here.Note: Clinical management in individuals with missense mutations remains problematic because both extensive family data and functional data are needed in order to predict the pathogenicity of a missense mutation. In the absence of such data, it may not be appropriate to use CDH1 missense mutation to define risks. Testing StrategyTo confirm/establish the diagnosis in a proband suspected of having gastric cancer, the following consensus guidelines have been developed by the IGCLC [Fitzgerald et al 2010, Figure 1; see for full text].A complete personal medical history A three-generation family history to determine if diffuse gastric cancer, lobular breast, and/or signet ring cell colon cancer is present in the family Endoscopic biopsy to confirm the diagnosis of diffuse gastric cancer or precursor lesions in one family member Sequence analysis of CDH1, followed by deletion/duplication analysis if a mutation is not identified, to determine if a germline CDH1 mutation is present in a family member with diffuse gastric cancer and/or lobular breast cancerPredictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe loss of E-cadherin protein expression in sporadic diffuse gastric and lobular breast tumors is associated with somatic CDH1 point mutations, loss of heterozygosity, and promoter hypermethylation in the tumors [Becker et al 1994, Oda et al 1994, Day et al 1999, Anastasiadis & Reynolds 2000, Tamura et al 2000, Kallakury et al 2001, Machado et al 2001].
Age of onset. The average age of onset of hereditary diffuse gastric cancer (HDGC) is 38 years, with a range of 14 to 69 years. The majority of the gastric cancers occur before age 40 years. The age of onset is also variable between and within families [Gayther et al 1998, Guilford et al 1998]. The lifetime risk for diffuse gastric cancer in males and females heterozygous for a CDH1 germline mutation is 80% [Paul Pharoah, unpublished data]....
Natural HistoryAge of onset. The average age of onset of hereditary diffuse gastric cancer (HDGC) is 38 years, with a range of 14 to 69 years. The majority of the gastric cancers occur before age 40 years. The age of onset is also variable between and within families [Gayther et al 1998, Guilford et al 1998]. The lifetime risk for diffuse gastric cancer in males and females heterozygous for a CDH1 germline mutation is 80% [Paul Pharoah, unpublished data].Symptoms. Symptoms are nonspecific in the early stages of the disease. Consequently, when present, nonspecific symptoms tend to be dismissed both by affected individuals and by physicians. By the time symptoms appear, affected individuals are in an advanced stage of the disease [Wanebo et al 1993]. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of stomach cancer, a palpable mass may be present. Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Other cancers. Other cancers reported in family members include: Lobular breast cancer (LBC). Females with a CDH1 germline mutation have an increased lifetime risk (39%-52%) of LBC [Keller et al 1999, Pharoah et al 2001, Oliveira et al 2002, Brooks-Wilson et al 2004, Kaurah et al 2007]. The average age of onset for breast cancer is 53 years [Pharoah et al 2001]. In a study of 318 women who had a personal and family history of LBC but no family history of DGC, Schrader et al [2011] found that 1.3% had a CDH1 germline mutation. Colorectal cancer [Richards et al 1999, Oliveira et al 2002, Brooks-Wilson et al 2004]. In the study by Brooks-Wilson et al [2004], an individual with a histologically defined signet ring cell cancer (SRCC) of the colon was found to harbor a pathologic CDH1 missense mutation. The same group had previously seen a missense mutation in another family with DGC and SRCC of the colon. Survival. When sporadic (i.e., non-hereditary) diffuse gastric cancer is detected early, i.e., before it has invaded the wall of the stomach, the five-year survival rate can be greater than 90%. The five-year survival rate drops to lower than 20% when the diagnosis is made at a late stage [Karpeh et al 2001]. Because early detection of DGC is difficult, survival of individuals with CDH1 mutations is believed to be the same as in individuals with sporadic DGC. Pathology. In DGC, loss of the E-cadherin protein causes the individual tumor cells to grow and invade neighboring structures. The individual malignant cells infiltrate and spread under histologically normal-looking mucosa causing widespread thickening and rigidity of the gastric wall, a phenomenon known as linitis plastica [McColl 2006]. No tumor mass is formed, unlike that of the intestinal type. The malignant cells have a distinctive signet ring appearance which is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. There is no known premalignant lesion for DGC.
About 5%-10% of all gastric cancer is thought to be familial [Zanghieri et al 1990, La Vecchia et al 1992]. Familial gastric cancer is both clinically and genetically heterogenous. ...
Differential DiagnosisIntestinal-Type Gastric Cancer (IGC) vs Diffuse Gastric Cancer (DGC)About 5%-10% of all gastric cancer is thought to be familial [Zanghieri et al 1990, La Vecchia et al 1992]. Familial gastric cancer is both clinically and genetically heterogenous. The characteristic morphologic difference between the two variants results from either the presence or lack of a key intercellular adhesion molecule, E-cadherin. There is loss of expression of the E-cadherin protein in the diffuse type, whereas it tends to be well preserved in the intestinal type. Consequently, IGC, the more common of the two variants [Crew & Neugut 2006] is composed of tubular or glandular formations of variable differentiation that resemble adenocarcinomas of the intestinal tract [Lynch et al 2005]. IGC arises from a precursor lesion, intestinal metaplasia; it forms a large protruded, ulcerated, or infiltrative lesion in the stomach. IGC:Is the more common of the two [Crew & Neugut 2006]; Tends to occur more frequently in men than in women;Increases significantly with age;Shows marked geographic variation with the highest rates found in China, South Korea, Japan, Eastern Europe, and South America and the lowest rates occurring in North America, Northern and Western Europe, Northern and Western Africa, and Southeast Asia; Incidence does appear to be declining [Hamilton & Aaltonen 2000, Parkin et al 2001, Crew & Neugut 2006, Ajani et al 2010];Appears to be sporadic and is related to environmental factors. The most well-recognized environmental risk factor for GC is chronic gastric mucosal infection with Helicobacter pylori leading to a chronic atrophic gastritis [Uemura et al 2001, Suerbaum & Michetti 2002]. This led to the bacterium being declared as a class one carcinogen by the International Agency for Research on Cancer and the World Health Organization in 1994. Although approximately two thirds of the world’s population (primarily in developing countries) is infected with the H. pylori, only a small proportion develop GC. The risk to an infected individual of developing IGC depends on the following three factors: Genetic features of the bacterial strain. Tiwari et al [2008] showed that young individuals infected with H. pylori with the genotype cagT+ve/hrgA+ve/cagA+ve/cagE+ve/vacAs1+ve have an increased risk for cancer. In a follow-up study, Tiwari et al [2010] revealed a closer relationship between the genotypes of the H. pylori, plasma malondialdehyde levels, and nitric oxide levels and gastric histopathology. Other studies have shown that cagA is associated with a 20-fold greater risk of GC than controls [Malfertheiner et al 2005]. Genetic features of the host. Certain sequence variants in the genes that constitute the interleukin-1 gene cluster − TNF (the gene encoding tumor necrosis-α) and IFNGR1 (the gene encoding interferon gamma receptor 1) − significantly increase the risk for gastric cancer, particularly in those infected with virulent strains of the bacterium [El-Omar et al 2001, El-Omar et al 2003, Rad et al 2003, Canedo et al 2008]. The bacterial and host genetic factors contribute to the progression of gastritis to chronic atrophic gastritis, to intestinal metaplasia, and finally to GC. Environment. In Colombia, intervention studies with antioxidant supplements have shown that vitamin C and β-carotene, as well as H. pylori eradication therapy, produced significant regression of gastric precancerous lesions, atrophy, and intestinal metaplasia in the stomach. This study concluded that continual supplements are required to maintain protection, as the benefits of antioxidants were no longer evident after six years [Correa et al 2000]. The improving hygiene in developed countries has also contributed to the decline of infection and therefore H. pylori-associated cancer [Roosendaal et al 1997]. Additional environmental factors including smoking and diets high in nitrites, salt, and smoked or pickled foods and low in fruit and vegetables are believed to increase the risk of GC [Forman & Burley 2006, van den Brandt & Goldbohm 2006, Liu & Russell 2008, González & López-Carrillo 2010]. Diffuse-type gastric cancer does not appear to be declining in incidence nor does it show marked geographic variation. Although the underlying causes are unknown, it may actually be increasing in incidence in North America [Borch et al 2000].H. pylori infection poses a similar risk for DGC as for IGC [Lynch et al 2005, Kamangar et al 2006], although DGC is not linked to a precursor lesion. Genetic features of the bacterial strain. There is evidence to support epigenetic effects of H. pylori infection where promoter hypermethylation of CDH1 in normal infected gastric mucosa was reversible with antibiotic treatment of the bacteria [Perri et al 2007]. Apart from the two of 17 prophylactic gastrectomy specimens reported by Blair et al [2006] that had previous H. pylori infection on serologic testing, there no evidence of increased rates of H. pylori infection associated with the microscopic DGCs in the prophylactic gastrectomy specimens of heterozygotes for a CDH1 disease-causing mutation.Other Cancer Predisposition SyndromesGastric cancer is seen in several other cancer predisposition syndromes, including Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) [Aarnio et al 1997], Li-Fraumeni syndrome (LFS) [Varley et al 1995], familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome [Williams et al 1982], and Cowden syndrome, one of the PTEN hamartoma tumor syndrome phenotypes [Hamby et al 1995]. Lynch syndrome. Lynch syndrome, which is associated with germline mutations in mismatch repair genes, predisposes heterozygotes to colorectal and other cancers. Gastric cancer is the third most common cancer in these individuals. IGC is the predominant subtype in Lynch syndrome [Lynch et al 2005]. Microsatellite instability (MSI) was observed in approximately 15% of gastric cancers from individuals in Florence, Italy, an area with high gastric cancer risk [D’Errico et al 2009]. Gastric cancers with high MSI tend to occur in the antrum of the stomach, be of the intestinal type, and have better survival rates [Leung et al 1999, Wu et al 2000, Falchetti et al 2008]. Familial adenomatous polyposis (FAP). FAP is caused by germline mutations in APC. Gastric cancer has been seen in 0.6% of persons with FAP [Jagelman et al 1988]. Li-Fraumeni syndrome (LFS). Cancers in LFS are caused by mutations in either TP53 or CHEK2. Both DGC and IGC are observed [Keller et al 2004, Oliveira et al 2004]. BRCA1 and BRCA2 hereditary breast and ovarian cancer. Increased risk of GC has been associated with mutations in BRCA1 [Brose et al 2002, Friedenson 2005] and BRCA2 [Breast Cancer Linkage Consortium 1999, Risch et al 2001]. Gastric cancer occurs in 5.7% of families with the BRCA2 6174delT mutation [Figer et al 2001]. Jakubowska et al [2002] found that in a subset (7%) of individuals with gastric cancer, a BRCA2 mutation may be the underlying genetic cause; however, the histopathology of the gastric cancer was not reported. Because the individuals with gastric cancer were deceased, they could not be tested for the mutations found in their families. There have been no updates regarding the latter study. Carney complex. A rare gastric lesion, gastric leiomyosarcoma, is found in individuals with Carney complex [Carney et al 1977]. Carney-Stratakis syndrome (CSS). Gastric stromal sarcomas were observed in 12 individuals with this disorder who had paraganglioma, gastric stromal sarcoma, or both [Carney & Stratakis 2002]. Germline mutations in SDHB, SDHC, and SDHD are causative [Pasini et al 2008]. Inheritance is autosomal dominant.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
The IGCLC has updated consensus guidelines for clinical management of individuals with a CDH1 mutation [Fitzgerald et al 2010; see for full text]. ...
ManagementThe IGCLC has updated consensus guidelines for clinical management of individuals with a CDH1 mutation [Fitzgerald et al 2010; see for full text]. Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with hereditary diffuse gastric cancer, the following evaluations are recommended:Baseline endoscopy to look for macroscopic tumor [Fitzgerald et al 2010]Evaluation of CDH1 heterozygotes for H. pylori infection given its ability to induce promoter hypermethylation of CDH1 and its role in GC carcinogenesis Breast examination/mammography in females Treatment of ManifestationsCare by a multidisciplinary team comprising those with expertise in medical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended [Fitzgerald et al 2010, Figure 1; see for full text].Treatment as indicated for H. pylori infection.The primary curative treatment of gastric cancer is surgical resection. Regardless of the surgical procedure used for the treatment of gastric cancer, the effectiveness of surgical resection is poor if the ultimate goal is increased cure rate. Studies have shown that surgery alone is less than satisfactory in the management of early gastric cancer, with cure rates approaching only 40%. The role of adjuvant therapy was indefinite until three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone [MacDonald et al 2000, Cunningham et al 2006, Sakuramoto et al 2007]. Numerous randomized clinical trials have failed to show consistent survival benefits from adjuvant radiation therapy or chemotherapy alone in the treatment of gastric cancer. Prevention of Primary ManifestationsBiopsy-proven diffuse-type gastric carcinoma. Prophylactic total gastrectomy is recommended if a biopsy shows diffuse-type gastric carcinoma [Chun et al 2001, Fitzgerald et al 2010]. Heterozygotes for a germline CDH1 mutation. The importance of identifying the genetic basis of cancer susceptibility in families with HDGC has been underscored by the observation of early gastric cancers in prophylactic total gastrectomy (PTG) samples obtained from individuals with a germline CDH1 mutation [Chun et al 2001, Huntsman et al 2001, Norton et al 2007]. These findings suggest that currently prophylactic total gastrectomy, rather than endoscopic surveillance, is the best preventive measure for individuals who have a CDH1 germline mutation. Prophylactic total gastrectomy (PTG). PTG involves D-2 dissection and Roux-en-Y esophagojejunostomy and obtaining proximal margins to ensure removal of the gastric mucosa [Norton et al 2007].In a young, healthy individual, the risk of mortality with PTG in an experienced surgeon’s hands is less than 1% [Lynch et al 2005]. However, the morbidity from prophylactic gastrectomy is high. All individuals have long-term morbidity related to both immediate postsurgical complications as well as long-term complications. Long-term complications include rapid intestinal transit, dumping syndrome, diarrhea, eating habit alterations, and weight loss [Caldas et al 1999, Lewis et al 2001]. In addition, the risk for malabsorption increases after total gastrectomy; malabsorption accounts for the increased incidence of osteoporosis, osteomalacia, and malnutrition described in persons with gastric cancer [Liedman 1999]. In light of these possible complications, it is recommended that a multidisciplinary team including a surgeon, gastroenterologist, and dietician provide pre-operative and post-operative care for an individual undergoing PTG. The multidisciplinary team members can counsel candidates for PTG on the risks and benefits of the surgery. In making the decision to undergo PTG, the affected individual and his/her physicians should consider: The age-specific risks of gastric cancer. Due to nutritional implications, PTG is not generally recommended until the individual’s growth period is complete. In families in which gastric cancer is early onset, PTG should be considered on a case by case basis [Blair et al 2006]. In these individuals, regular endoscopic screening may be begun prior to the consideration of PTG. The 100% morbidity of gastrectomy and the 1% risk of mortality following the surgery The risk in individuals with a CDH1 mutation of developing extragastric cancers, such as lobular breast cancer and colorectal cancer, and the screening recommendations for these cancers Breast CancerReferral to a high risk breast clinic is recommended [Fitzgerald et al 2010].Prophylactic mastectomy may be considered in women heterozygous for a CDH1 germline mutation. The authors are aware of only a handful of women who have to date undergone prophylactic mastectomy for this reason. It is important to note that prophylactic mastectomy can have psychological effects so appropriate counseling should include the possible altered perception of the body and sexual relationships [Brandberg et al 2008, Lodder et al 2002].SurveillanceGastric CancerAlthough it has been proposed that individuals who have a CDH1 germline mutation undergo routine surveillance for gastric cancer, the optimal management of individuals at risk for a gastric cancer is controversial because of the unproven value of surveillance regimes. In most cases, the gastric cancer is not detected until it reaches an incurable, advanced stage. Samples obtained at the time of prophylactic gastrectomy of six asymptomatic individuals with a CDH1 germline mutation revealed occult disease on microscopic analysis even though each individual had had normal screening tests prior to surgery [Norton et al 2007]. Due to the highly penetrant nature of HDGC caused by a germline CDH1 mutation, it is recommended that at-risk individuals who are not ready to undergo PTG or who have declined it be screened every 6-12 months by upper endoscopy with multiple random biopsies [Norton et al 2007, Barber et al 2008, Fitzgerald et al 2010 (see for full text)]. Screening should begin 5-10 years prior to the earliest cancer diagnosis in the family. Several screening modalities have been tested: Endoscopy. The effectiveness of endoscopy (currently the only method in use) in detecting the early lesions of gastric cancer has not been proven. Endoscopy permits direct inspection and biopsy of suspicious areas, but diffuse gastric cancer is difficult to detect at an early, treatable stage because the lesions tend to spread in the submucosa rather than as exophytic masses. The problems are: (1) difficulty in identifying the submucosal lesions and (2) sampling bias in a macroscopically normal-appearing gastric mucosa [Fitzgerald & Caldas 2004, Norton et al 2007]. It is recommended that individuals at risk who do not wish to have prophylactic gastrectomy undergo a detailed 30-minute endoscopic examination of the gastric mucosa with multiple random biopsies and biopsies of subtle lesions at six- to 12-month intervals [Caldas et al 1999]. Chromoendoscopy, using indigo-carmine staining, has been shown to improve the detection rate of early gastric cancer [Stepp et al 1998, Fennerty 1999]. Charlton et al [2004] studied six stomachs removed prophylactically after macroscopically normal gastric endoscopies. A pH-sensitive congo red dye followed by pentagastric stimulation revealed signet ring foci that were five times more prevalent in the transitional zone of the distal stomach, a finding in contrast with other studies [Carneiro et al 2004]. The transitional zone occupies less than 10% of the stomach and lacks gastric-secreting G cells. The authors suggest that chromoendoscopy using congo red dye and pentagastric stimulation may highlight this area during endoscopy and thus increase the chances of detecting cancer foci. Further research is needed to evaluate this possibility. The same group of investigators reported a year later on a follow-up of 99 surveillance endoscopies over five years [Shaw et al 2005]: 69 of 99 (70%) endoscopies were normal 23 lesions with signet ring cell cancer were identified in ten individuals The congo red/methylene blue dye detected foci between 4-10mm, not less than 4 mm. These findings need to be evaluated in larger group of CDH1 germline mutation heterozygotes. However, concerns over the toxicity of congo red have precluded the use of this stain in chromoendoscopy. Endoscopic ultrasound examination is important in the detection and staging of gastrointestinal cancers [Pfau & Chak 2002], but is not believed to be useful in detecting precursor lesions [Fitzgerald & Caldas 2004]. Other. Several other tools utilized include PET scan [van Kouwen et al 2004], endoscopic ultrasound, stool for guaiac, abdominal CT, and multiple random stomach biopsies [Barber et al 2008]. Unfortunately none of these reliably detects DGC, as demonstrated by the finding of multiple small cancer foci in six of six gastrectomy specimens from CDH1 mutation heterozygotes a week after a number of these screening investigations were done [Norton et al 2007].Lobular Breast Cancer (LBC)Currently the data on women with germline CDH1 mutations and development of lobular breast cancer are insufficient to determine the best cancer screening strategies. Recommendations for LBC risk management in CDH1 heterozygotes or at-risk women are based on recommendations for women with a BRCA1 or BRCA2 germline mutation (see BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. At-risk women should undergo regular breast screening as determined by their physicians, including monthly breast self-examinations and a clinical breast examination every six months.Because lobular breast cancer is often difficult to diagnose on clinical examination and mammography, it may also be prudent to refer a woman who has a CDH1 germline mutation to a high-risk breast cancer screening program and to consider use of MRI, which appears to be more sensitive than mammography in detecting tumors in such women [Schelfout et al 2004; Schelfout, personal communication]. The screening should begin by age 35 years or 5-10 years prior to the youngest age of breast cancer diagnosis in the family [Fitzgerald et al 2010]. Colon CancerAlthough evidence is insufficient to conclude that colon cancer is a manifestation of HDGC, it is prudent to recommend colonoscopy every three to five years beginning at age 40 years or ten years prior to the youngest age of colon cancer diagnosis in families in which both DGC and colon cancer have occurred [Fitzgerald et al 2010]. Evaluation of Relatives at RiskIt is appropriate to offer molecular genetic testing to at-risk relatives if the CDH1 disease-causing mutation is identified in an affected family member, so that morbidity and mortality can be reduced by early diagnosis and treatment. See Genetic Counseling, Testing of asymptomatic at-risk individuals younger than age 18 years for discussion of issues related to testing of this population.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Testing of Populations at RiskIn Japan, where the prevalence of gastric cancer is high, a mass population screening program allows for successful detection of early disease by endoscopy [Shiratori et al 1985]. In this program, all suspicious findings seen on endoscopy are biopsied and evaluated histologically. Suspicious findings include minute changes in the color of the mucosa, altered vascular pattern, roughened surface, flat lesions, and minor mucosal irregularities. Pregnancy ManagementEvidence shows that pregnancy after PTG can have healthy and normal outcomes. Kaurah et al [2010] discussed six healthy pregnancies and infants born to four women after total gastrectomy.Therapies Under Investigation Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Diffuse Gastric Cancer: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCDH116q22.1Epithelial cadherinCDH1 @ LOVDCDH1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Diffuse Gastric Cancer (View All in OMIM) View in own window 137215GASTRIC CANCER, HEREDITARY DIFFUSE; HDGC 192090CADHERIN 1; CDH1Molecular Genetic PathogenesisE-cadherin is a transmembrane protein that is predominantly expressed at the basolateral membrane of epithelial cells where it exerts cell–cell adhesion and invasion suppression functions [Nagar et al 1996]. E-cadherin is one member of the cadherin family of molecules, all of which are transmembrane glycoproteins mediating calcium-dependent cell-cell adhesion [Takeichi 1991, Berx et al 1995]. E-cadherin is critical for establishing and maintaining polarized and differentiated epithelia during development [Keller 2002]. It also plays important roles in signal transduction, differentiation, gene expression, cell motility, and inflammation. The activity of E-cadherin in cell adhesion is dependent upon its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [Jou et al 1995, Kallakury et al 2001]. A role for E-cadherin in tumor development is well established [Wijnhoven et al 2000] because many human carcinomas, for example, skin, lung, breast, urological, gastric, colon, pancreatic, and ovarian, exhibit reduced E-cadherin expression relative to their normal cellular counterparts [Karayiannakis et al 2001, Tsanou et al 2008, Ch’ng & Tan 2009, Kuner et al 2009, Giroldi et al 2000]. Loss of E-cadherin expression is seen in most diffuse gastric cancers and in lobular breast cancers; expression is usually maintained in intestinal gastric cancers and ductal breast cancers [Hirohashi 2000].Cells deficient in E-cadherin lose their ability to adhere to each other and consequently become invasive and metastasize [Birchmeier 1995, Perl et al 1998]. The causal effect of E-cadherin loss or dysregulation in tumorigenesis has been demonstrated using carcinoma cell lines and transgenic models [Hsu et al 2000]. This loss of E-cadherin expression has been shown to be an early event through the examination of in situ DGC lesions from a prophylactic total gastrectomy specimen. This loss of E-cadherin reveals that it is an early initialing event that leads to invasion [Humar et al 2007]. Loss of heterozygosity is a common phenomenon seen in association with loss of expression of tumor suppressor genes [Knudson 1971]. The tumor suppressor function of E-cadherin is supported through evidence of the loss of expression of the other CDH1 allele [Grady et al 2000, Barber et al 2008, Oliveira et al 2009]. Normal allelic variants. CDH1 comprises 16 exons that span 100 kb. Pathologic allelic variants. To date, over 100 germline mutations have been reported in families with HDGC [Guilford et al 1998, Gayther et al 1998, Yoon et al 1999, Richards et al 1999, Dussaulx-Garin et al 2001, Humar et al 2002, Oliveira et al 2002, Jonsson et al 2002, Brooks-Wilson et al 2004, Keller et al 2004, Suriano et al 2005, Frebourg et al 2006, Rodriguez-Sanjuan et al 2006, Kaurah et al 2007, Masciari et al 2007, More et al 2007, Roviello et al 2007, Van Domselaar et al 2007, Oliveira et al 2009, Mayrbaeurl et al 2010, Ghaffari et al 2010]. The mutations have mainly been truncating mutations, usually through frameshift mutations, exon/intron splice site mutations, or point mutations [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Oliveira et al 2002, Humar et al 2002, Brooks-Wilson et al 2004]. Missense mutations have also been identified in some families [Shinmura et al 1999, Yoon et al 1999, Oliveira et al 2002, Brooks-Wilson et al 2004]. The pathogenicity of missense mutations can be determined through in vitro analysis [Suriano et al 2003]. Large exonic deletions make up approximately 5% of these mutations [Oliveira et al 2009]. No "hot spots" have been identified; the mutations have been scattered throughout the gene. However, there are reports of the same mutation being found in several unrelated families: 1003C>T in exon 7 [Jonsson et al 2002, Suriano et al 2005, Kaurah et al 2007] 1137G>A in exon 8 [Frebourg et al 2006, Kaurah et al 2007, More et al 2007] 1901C>T in exon 12 [Suriano et al 2003, Kaurah et al 2007, More et al 2007]. A founder mutation has been seen in four families from Newfoundland, Canada [Kaurah et al 2007]. The mutation, 2398delC was confirmed by haplotype analysis in these families. Germline mutations have been identified in several ethnic groups; germline mutations appear to be rare in countries in which the rates of sporadic GC are high. The reason is not known; it may be postulated that the differences in genetic backgrounds of the various ethnicities may have different effects on the viability of embryos that already have one mutated germline CDH1 allele. Normal gene product. The 4.5-kb transcript is translated into a 135-kd precursor polypeptide of E-cadherin. This in turn is rapidly processed to the mature 120-kd form. The mature E-cadherin protein contains three domains: the extracellular domain encoded by exons 4-13, the transmembrane domain encoded by parts of exons 13 and 14, and the highly conserved cytoplasmic domain encoded by the rest of exon 14 to exon 16. The large extracellular domain (N-terminal) is made up of five tandem cadherin repeats each containing about 110 amino acid residues [Oliveira 2003, Bryant & Stow 2004]. The extracellular domain homodimerizes with E-cadherin expressed in neighboring epithelial cells in a Ca2+-dependent manner thus enabling cell-cell adhesion at the zonula adherens junctions of the homotypic neighboring cells. The cytoplasmic domain (C-terminal) interacts with the cytoskeleton actin filaments through α-, β-, and γ-catenins and p120ctn catenins in regulating the intracellular signaling pathways. β-catenin attaches to the C-terminal region of E-cadherin and then to α-catenin, which then binds to the F-actin microfilaments of the cytoskeleton. p120ctn binds to a juxtamembrane site of E-cadherin cytoplasmic tail [Bryant & Stow 2004]. p120 also provides complex stability [Weis & Nelson 2006].E-cadherin expression is controlled through a complex transcriptional regulation system. Several transcriptional repressors such as Snail, Slug, Twist, Sip-1/ZEB-2, dEF1/ZEB-1, and E12/E47 bind to the E-box motifs in the CDH1 promoter [Conacci-Sorrell et al 2003, Nelson & Nusse 2004, Gloushankova 2008]. Intron 2 of CDH1 has been implicated in the normal expression of the gene. Intron 2, which accounts for the majority of the non-coding intronic sequences of CDH1, contains conserved cis-regulatory elements. Stemmler et al [2005] performed a study in which deletion of murine genomic intron 2 led to inactivation of the gene during early embryonic development. Abnormal gene product. See Molecular Genetic Pathogenesis.
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