Review

Hereditary Gastric Cancer – Diagnosis and Clinical Implications

¹ 1Banasiewicz Tomasz ^{2 3}, Stojcev Zoran, ⁴ , 4Pławski Andrzej

• ¹1 Department of General Surgery, Oncologic Gastroenterological and Plastic Surgery, Poznań University of Medical Sciences, Poland
• ²2 Regional Hospital, Słupsk, Department of General, Vascular and Oncologic Surgery, Słupsk, Poland
• ³3 Department of Oncologic Surgery, Gdańsk Medical University, Gdańsk, Poland
• ⁴4 Institute of Human Genetics, Polish Academy of Sciences Poznan, Poland

• Friday, June 14, 2013
• Tuesday, August 06, 2013
• Sunday, January 26, 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ((http://creativecommons.org/licenses/by/3.0)which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Abstract

Gastric cancer is still one of the world's leading causes of cancer mortality. Approximately 10% of gastric cancers appear to have a familial predisposition. In this this group, 1-3% are considered as hereditary syndromes, with a clear genetic pathway, associated with the most important mechanisms of the CDH1 germline mutations. This mutation leads to the hereditary diffuse gastric cancer syndrome (HDGC). Other syndromes of familial prevalence of the gastric cancer, correlated with genetic mutations, are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Familial Adenomatous Polyposis, Cowden disease. Families HDGC can be identified and tested for causative mutations in CDH1; in other syndromes screening gastroduodenoscopy is indicated.

Key words

gastric cancer; CDH1 mutations; gastrectomy, HDGC

Hereditary Gastric Cancer

Gastric cancer is one of the world's leading causes of cancer mortality [1].with an average 700,000 deaths a year [2,3].diffuse and intestinal. Intestinal type usually follows multifocal atrophic gastritis and accompanied by intestinal metaplasia is more frequently observed in older patients. Diffuse cancer, observed more frequently on young patients, can be multifocal and can be hereditary [4].

Approximately 10% of gastric cancers appear to have a familial predisposition, and only 10% shows a familial cluster. In this this group, 1-3% are considered as hereditary syndromes, with a clear genetic pathway, associated with the most important mechanisms of the CDH1 germline mutations leaded to the hereditary diffuse gastric cancer syndrome (HDGC). Other syndromes, correlated with genetic mutations are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Familial Adenomatous Polyposis, Cowden disease, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and others [5].

Gastric carcinoma involves numerous genetic and epigenetic alterations. The most common, sporadic gastric cancer is developed through multistep processes, including the infectious cases as Helicobacter pylori or Epstein-Barr virus. Those types of the two infection-associated gastric cancers are characterized by global CpG island methylation in the promoter region of cancer-related genes [6]. A significantly smaller part of gastric cancers can be caused by a specific germ-line mutation of the E-cadherin gene (CDH1).

Germline mutations in the E-cadherin/CDH1 gene

The existence of a familial form of gastric cancer was described in the Napoleon Bonaparte family, with multiple cases of the gastric cancers in this family [7].During long years individuals from these families lived with the uncertainty of developing lethal gastric cancer, but now families with this type of gastric cancer can be identified and tested for causative mutations in CDH1 [8].The cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is up to 80%. Women from these families have an increased risk for developing lobular breast cancer [9].

Approximately 1–3% of gastric cancer can be caused by a germline mutation in the CDH1 gene, encoding E-cadherin. The data from these families suggest that the penetrance of CDH1 gene mutations is high, ranging between 70 and 80% [10]. In families with HDGC CDH1 germline mutation is observed in 30-40%, the remaining 60–70% are genetically unexplained and may be caused by alterations in other genes [11]Those mutations were initially identified in 1998 in New Zeeland, in Maori families that were predisposed to diffuse gastric cancer [12].

E-cadherin plays an import role in the processes of development, cell differentiation, and maintenance of epithelial architecture [13].Analysis of genetic abnormalities in CDH1found in HDGC shows that the most common are inactivating mutations (splice site, frameshift, and nonsense) rather than missense mutations. Furthermore, CDH1 germline mutations are evenly distributed along the E-cadherin gene. In families with HDGC recently frequent deletions of CDH1 have been recognized [14].The clustering in exons 7–9 is observed in sporadic diffuse gastric cancer C [15].Loss of heterozygosity as the “second hit” does not appear to be frequent in HDGC. As well as E-cadherin dysregulation, overexpression of epidermal growth factor receptor (EGFR) is among the most frequent genetic alterations associated with diffuse-type gastric carcinoma. There are some evidence suggests a functional relationship between E-cadherin and EGFR that regulates both proteins [16].

Germline alleles of E-cadherin (CDH1) can explain approximately 30-40% of HDGC. The factors driving susceptibility for the remaining families remain unknown. Some of them can be explain for example by the germline truncating allele of alpha-E-catenin (CTNNA1). It can call attention to the broader signaling network surrounding these proteins in HDGC, because alpha-E-catenin functions in the same complex as E-cadherin [17].

Microsatellite Instability

Genetic instability at the level of microsatellite instability (MSI) occurs in many sporadic human cancers. The levels of MSI found in gastric carcinomas from both Western and Eastern populations are probably in the region of up to 15–20% [18,19].In some studies frameshift mutations in the Wnt pathway genes AXIN2 and TCF7L2 have been found in GCs with high microsatellite instability [20].frequently occurs in mismatch repair system-deficient gastric carcinoma [21].Several authors demonstrated that the subset of sporadic GC with high-frequency MSI (MSI-H) is characterized by the distinct clinicopathologic and genetic profile, when compare with those with a low frequency (MSI-L) or microsatellite stable (MSS) genotype [22,23 and 24].However, whereas the role of microsatellite instability and DNA mismatch repair gene defects in HNPCC is unquestionable and well established, the relevance of this phenomenon in GC has limited clinical value and is currently still don’t recognized [25].

Others Hereditary Syndromes

There are multiple syndromes with elevated risk of the gastric cancer, as: Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability, in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations, in familial adenomatous polyposis caused by germline APC mutations, in Li-Fraumeni syndrome due to germline p53 mutations, in Peutz-Jeghers syndrome associated with germline STK11 mutations, in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes and in Cowden disease associated with mutations in PTEN gene [26].FAP: The incidence of gastric cancer in Western FAP patients is not significantly different from the general population.Asian patients, on the other hand, have increased prevalence of gastric cancer in FAP patients (2, 1 - 4.2%) [27].In most cases gastric cancer arises from adenomatous polyps via the adenomacarcinoma sequence, but several reports have shown that gastric adenocarcinoma can be developed from fundic gland polyp in FAP patients [28,29,30].Fundic gland polyps are the most prevalent gastric lesions, followed by adenomatous polyps. Those polyps occurred in about 50% of FAP patients and are in this group the most common type of the gastric polyps. In some recent study the prevalence of fundic gland polyp was about 60%, with the prevalence of gastric adenoma as 6-14% [31].Fundic gland polyps are common in familial adenomatous polyposis and attenuated familial adenomatous polyposis and, if voluminous, may interfere with effective endoscopic gastric cancer surveillance. This family is believed to be the first of its type reported with focus upon education and genetic counseling in the setting of a family information service [32].

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is the new, recent describe autosomal dominant gastric polyposis syndrome. GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes. This syndrome was recognized in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centers [33].

In a nationwide epidemiologic study in Sweden Hemminki and Jiang [34].found that the population-attributable proportion of familial gastric carcinoma was much lower than that cited in the literature. Patterns of multiple carcinomas suggested that immunologic factors modulate susceptibility to gastric carcinoma. The authors concluded that environmental factors, perhaps H. pylori infections, were the main reason for familial clustering of gastric carcinoma.

Gastric cancer arises also from the accumulation of genetic and epigenetic alterations. Genetic variants of the genes IL-10, IL-17, MUC1, MUC6, DNMT3B, SMAD4, and SERPINE1 have been reported to modify the risk of developing GC. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (GSK3β, CD133, DSC2, P-Cadherin, CDH17, CD168, CD44, metalloproteinases MMP7 and MMP11, and a subset of miRNAs) and through tumor suppressor gene inactivation mechanisms (TFF1, PDX1, BCL2L10, XRCC, psiTPTE-HERV, HAI-2, GRIK2, and RUNX3). The another potential mechanism involved in the gastric carcinogenesis is the inflammatory mediator cyclooxygenase-2 (COX-2), discussed also as a potential molecular target for therapy [35].

Lynch syndrome: The patients with colorectal cancer and MMR gene mutations are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast, prostate and gastric cancer. The risk for stomach cancer is in this patients elevated compared with the general population (SIR = 5.65, 95% CI = 2.32 to 9.69) for both sexes [36].In patients with Lynch syndromes the MLH1 methylation may lead to the increased risk colorectal cancer as well as stomach cancer and possibly ovarian and liver cancer [37].Somatic mutations of mismatch repair (MMR) genes such as hMLH1 or hMSH2 are extremely rare in sporadic GCs, with only one mutation found, in hMSH2 and two cases of a germline frameshift mutation in hMLH1 [36].More recently, 29 sporadic GCs with high level of MSI were screened for somatic mutations in MLH1, MSH2, MSH6, MLH3, and MBD4, and only five truncating mutations (3 in MSH6, 1 in MLH3, and 1 in MBD4) and one missense mutation (MLH1) were identified. All truncating mutations were found in the coding poly-A tracts, thus suggesting that they result from the MSI phenotype rather than causing it [38]. However, MSI positive tumours can still lack hMLH1 protein expression and many studies suggest that hypermethylation of the hMLH1 promoter region may be the principal mechanism of gene inactivation in sporadic gastric carcinomas with a high frequency of MSI [39,40].There is well-known fact that MSI may be found in sporadic carcinomas that are characteristic of hereditary nonpolyposis colorectal cancer (HNPCC) [41],a syndrome where germline mutations of the mismatch repair genes are present. Genome-wide expression profiles of sporadic GCs with and without microsatellite instability reveal that the immune and apoptotic gene networks efficiently discriminated these two cancer types [42]. Li-Fraumeni syndrome: hereditary, as well as sporadic, gastric cancer can also be caused by germline mutations of the TP53tumour suppressor gene. This mutation occurs in the Li–Fraumeni syndrome [43] and new germ line mutations in this gene continue to be discovered [44].Mutations of tumor protein p53 (TP53) and β-catenin (CTNNB1) genes are detected early in the development of GC. Furthermore, significant numbers of GCs show loss of Runx3 due to hemizygous deletion and hypermethylation of the promoter region. Aberrant Cdx2 expression has been shown in precancerous lesions as well as GC. However, it remains unclear whether Cdx2 plays an oncogenic role in gastric carcinogenesis [45]. BRCA1 and BRCA2 gene mutations: Those mutations increased the risk of the breast cancer, but the risk of gastric, ovarian, pancreatic, and prostate cancers is also higher than in normal population [46].

Clinical implications in families with hereditary gastric cancerThe recent advances in the molecular genetics lead to the recognition of the hereditary diffuse gastric cancer that inherited in a dominant autosomal manner with incomplete penetrance. About 25-30% of families fulfilling the criteria have germline mutation of the CDH1 gene coding the calcium-dependent E-cadherin protein. In the families with the occurrence of the HDGC testing for CDH1 mutation is recommended [47,48].HDGC families can be identified, tested for causative mutations in CDH1, and for those families where a pathogenic mutation can be identified, prophylactic total gastrectomy can be implemented in asymptomatic mutation carriers who elect to virtually eliminate their risk of developing this lethal disease [49].Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers, because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance [50].The total gastrectomy is suggested in the early adolescent age [51].In families with HDGC there is also an increased frequency of cancers occurring at other sites such as the breast, colorectum, and prostate in these mutation carriers [52].However, inclusion of associated cancers into the definition of HDGC is not yet recommended [53].

There is a lack of recommendation in the other genetic syndromes with the increased risk of the gastric cancer. In families with polyposis syndromes esophagogastroduodenoscopy by age 25 years or prior to colon surgery is recommended [54].Endoscopy should be repeated every 1-2 years. The screening esophagogastroduodenoscopy should be the most accepted procedure in families with the aggregation of the gastric cancers.

Prevention and Treatment in Hereditary Gastric Cancer

The prevence of the gastric cancer, both sporadic as the hereditary foms, is possible mainly throught the elimination of the life style and environmental risk factors. The cigarette smoking and H. pylori infection are classically associated with gastric cancer [55].and diet is a known etiological factor, especially for intestinal-type adenocarcinoma whereby an adequate intake of fruit and vegetables appears to lower the risk with ascorbic acid, carotenoids, folates and tocopherols acting as antioxidants [56].There are some data suggested, that cereal fibre intake may reduce the risk of adenocarcinoma, particularly diffuse type [57].The interplay of diet on genomic stability has been recognized, by showing that substances such as green tea can affect methylation status of genes [58].

Different study confirm the role of selenium in carcinogenesis. The development and progression of gastric carcinoma can be associated with decreasing levels of serum Se. This concept is greatly supported by the antioxidant action of Se [59].Supplementation of the selenium may protect against the development of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cardia adenocarcinoma (GCA) [60].

The number of genetic therapies in gastric cancer is still very limited. Targeted therapy against GC with ERBB2 amplification recently improved the prognosis of patients with advanced GC. In addition, epigenetic changes in GC could be attractive targets for cancer treatment with modulators. A genome-wide search has been undertaken to identify novel methylation-silenced genes in GC, which will help us understand the overall molecular features of GC and further provide novel opportunities in the treatment of GC [61].

The interesting data analysed the influence of the selenium on the chromosome breakage in BRCA1 carriers sugest that this treatment may be effective also in other genetic syndromes correlated with the hereditary gastric cancer [62].

Conclusions

Identification of the mutation and test for causative mutation in CDH1 is indicated in hereditary diffuse gastric cancer syndrome. For families, where a pathogenic mutation can be identified, prophylactic total gastrectomy can be implemented in asymptomatic mutation carriers who elect to eliminate their risk of developing this lethal disease. Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers, because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance. In families with HDGC there is also an increased frequency of cancers occurring at other sites such as the breast, colorectum, and prostate in these mutation carriers.

In others hereditary syndromes with familial prevalence of the gastric cancer, as HNPCC, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Familial Adenomatous Polyposis, Cowden disease the screening esophagogastroduodenoscopy should be the most accepted procedure

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

TB conceived of the study, and participated in its design and coordination and helped to draft the manuscript.

ZS participated in the design of the publication, review of the literature and data analysis, final review and draft preparation

PK participated in the design of the publication, review of the literature and data analysis

AP participated in the design of the publication, review of the literature and data analysis

All authors read and approved the final manuscript.

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