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www.thelancet.com/oncology Vol 16 February 2015 e60 Review Lancet Oncol 2015; 16: e60–70 *These authors contributed equally Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, (C Oliveira PhD, H Pinheiro PhD, J Figueiredo PhD, R Seruca MD, Prof F Carneiro MD), and Department of Pathology and Oncology, Faculty of Medicine (C Oliveira, R Seruca, F Carneiro), University of Porto, Porto, Portugal; and Centro Hospitalar S João, Porto, Portugal (F Carneiro) Correspondence to: Prof Fátima Carneiro, Institute of Molecular Pathology and Immunology, University of Porto, Rua Dr Roberto Frias s/n, 4200-465, Porto, Portugal [email protected] Familial gastric cancer: genetic susceptibility, pathology, and implications for management Carla Oliveira*, Hugo Pinheiro*, Joana Figueiredo, Raquel Seruca, Fátima Carneiro Familial gastric cancer comprises at least three major syndromes: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families affected b-y these syndromes, but only hereditary diffuse gastric cancer is genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li- Fraumeni, Peutz-Jeghers, hereditary breast–ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies. Introduction Gastric cancer affects nearly 1 million individuals every year, 70–85% of whom die within 5 years of diagnosis, making it the third most lethal cancer worldwide. 1 The high mortality associated with gastric cancer (nearly 800 000 deaths per year) is mainly a result of late diagnosis, and limited therapeutic options. The two major subtypes—diffuse and intestinal 2 —are characterised by distinct epidemiological, morphological, and molecular features. Although most gastric cancers are sporadic, aggregation within families occurs in roughly 10% of cases. In regions where the incidence of gastric cancer is low, most familial cases are probably due to heritable pathogenic mutations that increase risk from birth. 3,4 Truly hereditary cases are thought to account for 1–3% of the global burden of gastric cancer and comprise at least three main syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC). A genetic basis has been found in only around 40% of families affected by HDGC. The identification of inherited factors among individuals with family histories of gastric cancer is therefore a crucial step for early diagnosis and disease management. In this Review, we discuss the available knowledge on hereditary gastric cancer and cancer-associated syndromes from which gastric cancer can arise, with the aim of clarifying questions relevant for the translation of basic research into clinical practice. Hereditary gastric cancer syndromes The recognition of familial aggregation (eg, high occurrence in siblings or offspring) is the first step towards the identification of a disease with a genetic component and is clinically useful. Family history, histological classification, and age at onset of disease (<45 years) are used to guide genetic testing and clinical surveillance in the context of a particular gastric cancer hereditary syndrome. The advent of new, fast, and inexpensive massive parallel sequencing technologies is expected to improve the identification of novel causative genetic events, which will affect genetic testing and the management of families with a high frequency of gastric cancers. HDGC was the first of the hereditary gastric cancer syndromes to be recognised, initiated by inherited causative mutations in the E-cadherin gene (CDH1). 5 Mutations in the alpha-E-catenin gene (CTNNA1) have been identified as an additional genetic cause of HDGC (table 1). 6 Several patients with early-onset diffuse-type gastric cancers with no apparent family history have been found to be carriers of CDH1 germline mutations, which supports the role of CDH1 germline deficiency in disease initiation and helped to identify de-novo HDGC families. 7,8 In HDGC families, lobular breast cancer is the second most frequent type of neoplasia. 9 Although colorectal cancer also arises as part of the tumour spectrum, whether the risk in HDGC families is higher than that in the general population remains unclear. 9 Congenital malformations, such as cleft lip or cleft palate, occur in some CDH1-mutation-driven HDGC families, 10 but are not a defining clinical characteristic because of their rarity. However, clinicians should collect infor- mation about them when counselling at-risk families. 11 According to published data, the penetrance of diffuse gastric cancer in mutation carriers reaches more than 80% in both men and women by 80 years of age, and the probability of women developing lobular breast cancer is 60%. 9 The combined risk of gastric cancer and breast cancer in women has been calculated to be 90% at 80 years. 12 Efforts are being made to calculate the penetrance of gastric cancer in a larger number of HDGC CDH1 mutant families. GAPPS was identified in 2012, and is characterised by the autosomal dominant transmission of fundic gland polyposis (including dysplastic lesions or intestinal-type gastric adenocarcinoma, or both) that are restricted to the proximal stomach with no evidence of colorectal or duodenal polyposis or other hereditary gastrointestinal cancer syndromes (table 1). 13 It is characterised by incom- plete penetrance, and some elderly obligate carriers have
Transcript
Page 1: Familial gastric cancer: genetic susceptibility, pathology ... · Familial gastric cancer comprises at least three major syndromes: hereditary diff use gastric cancer, gastric adenocarcinoma

www.thelancet.com/oncology Vol 16 February 2015 e60

Review

Lancet Oncol 2015; 16: e60–70

*These authors contributed equally

Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, (C Oliveira PhD, H Pinheiro PhD, J Figueiredo PhD, R Seruca MD, Prof F Carneiro MD), and Department of Pathology and Oncology, Faculty of Medicine (C Oliveira, R Seruca, F Carneiro), University of Porto, Porto, Portugal; and Centro Hospitalar S João, Porto, Portugal (F Carneiro)

Correspondence to:Prof Fátima Carneiro, Institute of Molecular Pathology and Immunology, University of Porto, Rua Dr Roberto Frias s/n, 4200-465, Porto, [email protected]

Familial gastric cancer: genetic susceptibility, pathology, and implications for managementCarla Oliveira*, Hugo Pinheiro*, Joana Figueiredo, Raquel Seruca, Fátima Carneiro

Familial gastric cancer comprises at least three major syndromes: hereditary diff use gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families aff ected b-y these syndromes, but only hereditary diff use gastric cancer is genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li-Fraumeni, Peutz-Jeghers, hereditary breast–ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies.

IntroductionGastric cancer aff ects nearly 1 million individuals every year, 70–85% of whom die within 5 years of diagnosis, making it the third most lethal cancer worldwide.1 The high mortality associated with gastric cancer (nearly 800 000 deaths per year) is mainly a result of late diagnosis, and limited therapeutic options. The two major subtypes—diff use and intestinal2—are characterised by distinct epidemiological, morphological, and molecular features. Although most gastric cancers are sporadic, aggregation within families occurs in roughly 10% of cases. In regions where the incidence of gastric cancer is low, most familial cases are probably due to heritable pathogenic mutations that increase risk from birth.3,4 Truly hereditary cases are thought to account for 1–3% of the global burden of gastric cancer and comprise at least three main syndromes: hereditary diff use gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC). A genetic basis has been found in only around 40% of families aff ected by HDGC. The identifi cation of inherited factors among individuals with family histories of gastric cancer is therefore a crucial step for early diagnosis and disease management.

In this Review, we discuss the available knowledge on hereditary gastric cancer and cancer-associated syndromes from which gastric cancer can arise, with the aim of clarifying questions relevant for the translation of basic research into clinical practice.

Hereditary gastric cancer syndromesThe recognition of familial aggregation (eg, high occurrence in siblings or off spring) is the fi rst step towards the identifi cation of a disease with a genetic component and is clinically useful. Family history, histological classifi cation, and age at onset of disease (<45 years) are used to guide genetic testing and clinical surveillance in the context of a particular gastric cancer hereditary syndrome. The advent of new, fast, and inexpensive massive parallel sequencing technologies is

expected to improve the identifi cation of novel causative genetic events, which will aff ect genetic testing and the management of families with a high frequency of gastric cancers.

HDGC was the fi rst of the hereditary gastric cancer syndromes to be recognised, initiated by inherited causative mutations in the E-cadherin gene (CDH1).5 Mutations in the alpha-E-catenin gene (CTNNA1) have been identifi ed as an additional genetic cause of HDGC (table 1).6 Several patients with early-onset diff use-type gastric cancers with no apparent family history have been found to be carriers of CDH1 germline mutations, which supports the role of CDH1 germline defi ciency in disease initiation and helped to identify de-novo HDGC families.7,8 In HDGC families, lobular breast cancer is the second most frequent type of neoplasia.9 Although colorectal cancer also arises as part of the tumour spectrum, whether the risk in HDGC families is higher than that in the general population remains unclear.9 Congenital malformations, such as cleft lip or cleft palate, occur in some CDH1-mutation-driven HDGC families,10 but are not a defi ning clinical characteristic because of their rarity. However, clinicians should collect infor-mation about them when counselling at-risk families.11

According to published data, the penetrance of diff use gastric cancer in mutation carriers reaches more than 80% in both men and women by 80 years of age, and the probability of women developing lobular breast cancer is 60%.9 The combined risk of gastric cancer and breast cancer in women has been calculated to be 90% at 80 years.12 Eff orts are being made to calculate the penetrance of gastric cancer in a larger number of HDGC CDH1 mutant families.

GAPPS was identifi ed in 2012, and is characterised by the autosomal dominant transmission of fundic gland polyposis (including dysplastic lesions or intestinal-type gastric adenocarcinoma, or both) that are restricted to the proximal stomach with no evidence of colorectal or duodenal polyposis or other hereditary gastrointestinal cancer syndromes (table 1).13 It is characterised by incom-plete penetrance, and some elderly obligate carriers have

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normal endoscopies. The genetic cause has yet to be identifi ed.13,14

FIGC is characterised mainly by intestinal gastric cancer (table 1). An autosomal dominant inheritance pattern has been noted in many families with intestinal-type gastric cancer.15 In practical terms, FIGC should be thought of as a potential diagnosis when histopathological reports refer to intestinal-type adenocarcinoma segregating within families without gastric polyposis. The genetic cause is unknown, and only a few recommendations have been advanced for the clinical management of patients at risk of FIGC.16

Associations with other hereditary cancer syndromesGastric cancer has been identifi ed as part of the tumour spectrum in several other hereditary cancer syndromes, and thus the risk of it should be taken into account in patients with these syndromes. Lynch syndrome is a highly penetrant colorectal cancer syndrome bearing a molecular phenotype of microsatellite instability that is caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, PMS1, PMS2, or EPCAM.17 The frequency of gastric cancer in carriers of Lynch syndrome mutations has been estimated at 1·6%, and intestinal-type disease is the main histotype.18 The risk of development of gastric cancer was 4·8% in patients with germline defects of MLH1 and 9% in those with germline defects of MSH2. Surveillance with oesophago-gastro duodenoscopy is necessary in patients with Lynch syndrome who carry mutations in mismatch repair genes.18

Li-Fraumeni syndrome encompasses several tumour types that develop generally before 45 years of age because of inherited TP53 mutations,19,20 including early-onset gastric cancer. The frequency of gastric cancer in families carrying TP53 mutations ranges from 1·8% to 4·9%.21,22 40% of families with TP53 mutations present with at least one gastric cancer (mean age 43 years, median age 36; age range 24–74 years), with an excess of early onset gastric cancers.22 These data support periodic screening with oesophagogastroduodenoscopy in young carriers of TP53 germline mutations, and particularly in Li-Fraumeni syndrome families in which at least one case of gastric cancer has been reported.22 Data for the histological type of gastric cancer are insuffi cient to associate a particular histotype with Li-Fraumeni syndrome. Importantly, gastric cancer can occur in Li-Fraumeni syndrome families without TP53 mutations (two of 73 families studied), suggesting that incidence could be independent from the presence of germline TP53 mutation.21

Familial adenomatous polyposis is caused by APC germline mutations and is characterised by the development of more than 100 colonic and rectal adenomas and early development of colorectal cancer.23,24 Roughly 8% of patients have attenuated disease, in which fewer adenomas are present and disease onset is later.24 Adenomas also develop in the upper gastrointestinal tract, especially in the duodenum, and, if untreated, can progress to malignant disease in roughly 5% of cases.24 A grading system was developed for duodenal polyps in familial adenomatous polyposis for assessment of disease severity.25 In the stomach, gastric fundic gland polyps and adenomas in the antrum

Clinical criteria Genetic screening Alterations described

Hereditary diff use gastric cancer

Two or more cases of gastric cancer, one confi rmed case of diff use gastric cancer in someone younger than 50 years;Three or more confi rmed diff use gastric cancer cases in fi rst-degree or second-degree relatives, independent of age of onset;Diff use gastric cancer before age 40 years without a family history;Personal or family history of diff use gastric cancer and lobular breast cancer, one of which must be diagnosed before age 50 years

Sequencing of CDH1 coding sequences;Multiplex ligation-dependent probe amplifi cation (large CDH1 rearrangements);Sequencing of CTNNA1 coding sequences

Mutations throughout the CDH1 gene and deletions mainly implicating fl anking untranslated regions;

One germline truncating mutation in CTNNA1

Gastric adenocarcinoma and proximal polyposis of the stomach

Gastric polyps restricted to the body and fundus with no evidence of colorectal or duodenal polyposis;More than 100 polyps carpeting the proximal stomach in the index case or more than 30 polyps in a fi rst-degree relative of another case;Mainly fundic gastric polyps, some with regions of dysplasia (or a family member with either dysplastic fundic gastric polyps or gastric adenocarcinoma);Autosomal dominant pattern of inheritance;Exclusions include other heritable gastric polyposis syndromes and use of proton-pump inhibitors*

No screening available No inherited inherited mutations so far

Familial intestinal gastric cancer

Two or more cases of gastric cancer in fi rst-degree or second-degree relatives, with at least one confi rmed case of intestinal histology in someone younger than 50 years;Three or more confi rmed cases of intestinal gastric cancer in fi rst-degree or second-degree relatives, independent of age

No screening available No inherited inherited mutations so far

*Proton-pump inhibitors can induce a phenotype similar to that of gastric adenocarcinoma and proximal polyposis of the stomach. Patients taking these drugs should undergo a repeat endoscopy off -therapy to confi rm diagnosis of gastric adenocarcinoma and proximal polyposis of the stomach.

Table 1: Clinical criteria, recommended screening, and inherited alterations of familial gastric cancer syndromes

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can also occur.24,26 Fundic gland polyps are reported in around 88% of people in familial adenomatous polyposis families,27 and occur more frequently in those with attenuated disease.28 Gastric adenocarcinomas in familial adenomatous polyposis are generally thought to arise from the adenomas, and evidence suggests that fundic gland polyps can transform into adenocarcinomas.26,28 Despite these concerns about fundic gland polyps, in western countries, the risk of gastric adenocarcinoma does not seem appreciably higher in patients with familial adenomatous polyposis than in patients with sporadic fundic gland polyps.26,27 Carriers of APC mutations undergo prophylactic colectomies because the probability of malignant transformation of colorectal polyps is 100% with this mutation. In patients who have undergone this operation, the main cause of death is upper gastrointestinal malignancy, justifying surveillance with oesophagogastroduodenoscopy.29 Prophylactic gastrec tomy has been discussed for patients with familial adenomatous polyposis (including those with attenuated disease) displaying diff use fundic gland polyps, and high-grade dysplasia or large polyps.30

Peutz-Jeghers syndrome is caused by mutations in STK11, and is characterised by the association of hamartomatous gastrointestinal polyps with muco-cutaneous pigmentation and increased cancer risk, particularly for gastrointestinal and breast cancers, which develop at younger ages than in the general population.31,32 The frequency of gastric cancer in Peutz-Jeghers syndrome families has been reported in two cohorts—it was 2·1% in one32 (mean age 40 years) and 3·0% in the other33 (mean age 41·5 years). Age at diagnosis ranged from 20 years to 61 years.32,33 A meta-analysis32 suggested a cumulative risk of gastric cancer of 29% by age 65 years. Based on the increased cancer risk, surveillance recommendations for patients with Peutz-Jeghers syndrome include oesophagogastroduodenoscopy from age 20 years (repeated every 2–5 years depending on endoscopic and histological fi ndings).32

Juvenile polyposis syndrome is a hereditary cancer syndrome characterised by numerous juvenile polyps developing in the colon or stomach, or both, and is caused by SMAD4 or BMPR1A mutations (at similar frequencies).34,35 Gastric cancer has been noted in 21% of patients with juvenile polyposis syndrome who are aff ected by gastric polyps.35 Surveillance recommendations encompass monitoring of gastrointestinal symptoms from infancy and upper endoscopy at age 15 years or when symptoms are present, in addition to surveillance for colorectal cancer. Endoscopy should be repeated every 1–3 years, depending on the load of gastric polyps.35

Hereditary breast or ovarian cancer syndrome is caused by germline BRCA1 and BRCA2 mutations, which increase the risk of gastric cancer development. Gastric tumours are included in the tumour spectrum of this syndrome.36 A meta-analysis37 of more than 30 studies showed that the relative risk of gastric cancer

in BRCA1 or BRCA2 carriers is 1·69 (95% CI 1·21–2·38), which is higher than the relative risk for pancreatic, prostate, and colorectal cancer. No details of pathological changes were provided in the studies included in the meta-analysis, and whether a histological subtype of gastric cancer predominates in BRCA-associated families is unknown.38

Diagnostic issuesThe search for a specifi c inherited germline mutation in clinically selected families with aggregation of gastric cancer or early onset gastric cancer, or both, relies on information from pathology reports from at least the proband in the family. Studying pathological changes establishes whether a family is classifi ed as HDGC, GAPPS, or FIGC, and determines which diagnostic genetic test—if any—should be done. In most molecular diagnostic laboratories, conventional genetic testing is generally off ered on the basis of one gene for one syndrome (or, infrequently, several genes for one syndrome—eg, MLH1, MSH2, MSH6, PMS1, PMS2, EPCAM for Lynch syndrome). In hereditary gastric cancer, only families fulfi lling the criteria for HDGC proposed by the International Gastric Cancer Linkage Consortium9 are tested for CDH1. Endoscopic surveillance is off ered periodically to individuals at risk in non-HDGC families, because no germline causative mutations have been described to guide genetic testing.9

Dependence on clinical and pathological data to guide appropriate genetic testing can delay or prevent the fi nding of causative genetic mutations in individuals at risk. To circumvent some of these shortcomings, genetic diagnosis with multigene sequencing panels, which has proved eff ective in several hereditary disorders, could be used. Genes causing both hereditary gastric cancer syndromes and cancer-associated syndromes in which gastric cancers are implicated are obvious candidates for such panels. The identifi cation of more susceptibility genes will improve informed genetic testing, prevention, early detection, and management of individuals at high risk of gastric cancer. An increased attentiveness for these issues amongst medical doctor and genetic counsellor communities is therefore required.

HDGCGenetic susceptibilityThe genetic susceptibility to, and the molecular basis for, HDGC were fi rst identifi ed in Maori families in work published in 1998,5 which was shortly followed by studies39–41 reinforcing the role of CDH1 in susceptibility to HDGC in other populations.39–41 Since then, several hundred probands (aff ected individuals through whom a family with a genetic disorder is ascertained) meeting the 2010 International Gastric Cancer Linkage Consortium criteria for HDGC have been tested for CDH1 mutations, roughly 40% of whom carry CDH1 germline alterations. So far 104 diff erent CDH1 deleterious structural changes

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causing germline fi rst-hit inactivation mechanisms have been reported in HDGC probands (table 2). A third of these changes have been detected in two or more families. Notably, germline CDH1 changes aff ect the entire coding sequence and all the protein’s functional domains. 90 of the 104 known mutations are predicted to lead to premature protein truncation or lack of mRNA expression, and enclose small frameshifts, splice-site and nonsense mutations, and large rearrangements (table 2). The identifi cation of large deletions (from 357 bp to 275 kb in length) led to the addition of multiplex ligation-dependent probe amplifi cation to the screening strategy in HDGC families who test negative for CDH1 point mutations.9,42

The genotype–phenotype correlation is straightforward for truncating mutations, but the same is not true for so-called pure missense mutations. 14 pure missense mutations and four missense mutations that activate cryptic splicing have been reported and classifi ed as potentially pathogenic, accounting for 18 (17%) of the mutations described so far (table 2). Seven of these 18 missense mutations recur in unrelated HDGC families.

Many other missense alterations have been described, although their pathogenicity remains to be fully established, raising a substantial problem for genetic counselling and clinical management. Clinical and genetic assessments of the pathogenicity of missense variants should take into account their allelic frequency in healthy controls, cosegregation within families and recurrence in unrelated HDGC families.43,44 This analytical pipeline has clear limitations because of the low number of aff ected individuals and small pedigrees that prevent segregation analysis.44 Furthermore, the absence of mutation hotspots precludes the establishment of a correlation between the mutation site and its functional consequence.43–45

In-silico and in-vitro approaches have been developed to predict the pathogenicity of CDH1 missense

mutations.45,47 In-silico methods allow the prediction of the eff ect of missense variants in E-cadherin native-state stability and in cryptic splicing.45,46 However, they cannot be used to establish the clinical implications of missense mutations or to derive informed reports for clinicians and patients. In vitro functional and biochemical analysis of cell lines expressing wild-type CDH1 and pathogenic missense mutants were implemented to address these issues.44,47 When compared with wild-type-expressing cells, CDH1 missense mutants are thought to be deleterious because of the following eff ects: disruption of cell adhesion, incorrect binding of E-cadherin to fundamental adhesion-complex regulators, impairment of E-cadherin stability at the plasma membrane, and induction of cell migration or invasion.43,45–47 CDH1 missense mutations should be functionally analysed in reference laboratories. Novel bioimaging technologies that are based on immunofl uorescence and detect changes in E-cadherin protein expression and abnormal localisation are expected to improve further the interpretation of functional consequences of CDH1 missense mutations.48,49

Once a germline missense CDH1 mutation has been classifi ed as deleterious, clinicians and genetic counsellors might suggest that mutant carriers enter a surveillance programme similar to that off ered to carriers of truncating CDH1 mutations. Microscopic foci of invasive cancer have been detected in carriers of missense mutations carriers who were submitted to prophylactic gastrectomy, showing the relevance of this type of mutation in the clinical setting.50

Roughly 60% of HDGC families do not have mutations in CDH1 coding regions, but present with a germline phenotype of monoallelic CDH1 downregulation which can be detected with allele-specifi c expression analysis.51,52 More than 90% of patients with such a phenotype show loss or low expression of E-cadherin in tumours.53,54 Three families who have germline monoallelic CDH1 downregulation with deleterious large deletions encompassing CDH1 non-coding regulatory regions have been described, supporting allele-specifi c expression analysis as a promising prescreening strategy.51

The only gene other than CDH1 that has been implicated in HDGC is CTNNA1. So far, only one CTNNA1 germline truncating mutation has been detected, in a large HDGC pedigree.6 In this family, the onset of HDGC occurred relatively late in life (after age 50 years), which could be a feature of CTNNA1-driven disease. Furthermore, penetrance was incomplete, similar to what happens in CDH1-driven HDGC. Importantly, reduced expression of E-cadherin was noted in addition to complete loss of CTNNA1 expression in the tumours.6 The defi nitive proof of CTNNA1 mutations as drivers of HDGC depends on the identifi cation of additional families harbouring inactivated alleles.

Data published in 2014 point to other possible susceptibility genes for hereditary gastric cancer. In one

Frequency of mutation Recurrence

CDH1

Frameshift 39/104 (38%) 10/39 (26%)

Splice site 24*/104 (23%) 10/24 (42%)

Missense† 18‡/104 (17%) 7/18 (39%)

Nonsense 18/104 (17%) 7/18 (39%)

Large rearrangements 9/104 (9%) 4/9 (44%)

CTNNA1

Frameshift 1/1 NA

Data are n/N (%), where N=total number of diff erent pathogenic mutations reported to date. NA=not applicable. *Includes four mutations that activate cryptic splicing because of a missense mutation. †Only missense mutations with proven pathogenicity based on recurrence, segregation, or in vitro functional analysis (or any combination thereof), and that have been reported as such, are shown. ‡Includes four missense mutations that activate cryptic splicing.

Table 2: Type, frequency, and recurrence of pathogenic germline defects in hereditary diff use gastric cancer families

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study, MAP3K6 was suggested as a novel predisposing factor because the investigators detected fi ve germline mutations in the gene in fi ve unrelated individuals.55 The authors of another study56 claim to have identifi ed several candidate genes for early-onset and familial gastric cancer, and the full description of their results are keenly awaited. Discovery and characterisation of novel susceptibilities will broaden knowledge of clinical and pathological aspects of familial gastric cancer, generate data for penetrance analysis and tumour spectrum assessment, and improve genetic screening, risk stratifi cation, and management of patients.

Molecular somatic events in HDGC lead to inactivation of the remaining wild-type CDH1 allele through a

second-hit mechanism, causing aberrant E-cadherin expression and initiation of gastric signet ring cell carcinoma (SRCC).53,57–59 Initial reports addressing the type and frequency of CDH1 second hits in HDGC tumours suggested that promoter hypermethylation is the most common mechanism leading to CDH1 biallelic inactivation (table 3).57,59 A second mutation or deletion (loss of heterozygosity or intragenic deletions) has been described less frequently.57–59 In the most comprehensive study53 of CDH1 second-hit mechanisms in HDGC, several primary and metastatic HDGC lesions were analysed (table 3).53 This work showed for the fi rst time that diff erent neoplastic lesions from the same patient can present distinct second hits, and that the same neoplastic lesion can present diff erent second-hit mechanisms (table 3).53

Overall, studies of HDGC cases analysed for CDH1 second hits encompass 50 lesions: 38 primary tumours, and 12 lymph node metastases.53,57,59 Promoter hypermethylation was the most frequent second hit in HDGC primary tumours (occurring in 13 primary tumours); isolated loss of heterozygosity, a second

mutation, or combinations of diff erent second hits occurred only rarely. In lymph node metastases, loss of heterozygosity was the most prevalent second-hit event (fi ve occurrences), followed by combination of loss of heterozygosity with promoter hypermethylation (fi gure 1; table 3). However, second hits associated with CDH1 inactivation were not identifi ed in 16 primary tumours and four nodal metastases.

These results are especially relevant because HDGC is a disease characterised by multiple tumour foci scattered in the stomach of mutation carriers.60 The heterogeneity of second hits in neoplastic lesions from the same patient, the diff erence between type of second hit in primary and metastatic lesions, and the plasticity of hypermethylated promoters during tumour development, suggest that drugs targeting only epigenetic changes might be less eff ective than was initially anticipated, particularly in patients with metastatic HDGC.

C-Src, fi bronectin, P-Fak, and P-Stat3, all of which have roles in the c-Src kinase pathway are strongly expressed in large intramucosal HDGC lesions with poorly diff erentiated cells and in cells invading the muscularis mucosae, by contrast with small intramucosal cancer foci, in which the expression is low or absent.61 These fi ndings start to shed light into the pathways implicated in cancers in which E-cadherin function is lost, and warrant further study.

In CDH1-driven HDGC, no somatic mutations have been searched for in tumours, apart from those in CDH1. By contrast, in the single CTNNA1-associated HDGC family reported, several genes have been identifi ed to be somatically mutated in a single tumour sample analysed, including LMTK3, MCTP2, MED12, PIK3CA, ARID1A, and other genes recently shown to be mutated in sporadic gastric cancer exomes.6

Lesions Primary tumours (n=38) Lymph node metastases (n=12)

Promoter hyper-methylation

Loss of hetero-zygosity

Mutation Promoter hyper-methylation and loss of heterozygosity

Promoter hyper-methylation and mutation

Loss of hetero-zygosity and mutation

No alteration

Promoter hyper-methylation

Loss of hetero-zygosity

Promoter hyper-methylation and loss of hetero zygosity

No alteration

Grady et al,57 2000

Six lesions from six people in two families

3/6 0/6 2/4 0/6 0/4 0/4 1/6 NA NA NA NA

Barber et al,59

200816 lesions from 16 people in nine families

2/16 0/5 0/16 0/5 2/16 0/5 12/16 NA NA NA NA

Oliveira et al,53 2009

28 lesions from 17 people in 15 families

8/16 2/16 0/16 3/16 0/16 0/16 3/16 1/12 5/12 2/12 4/12

Combined frequency of second hits*

·· 13/38 2/27 2/36 3/27 2/36 0/25 16/38 1/12 5/12 2/12 4/12

The numbers in this table are descriptive and represent the summary of mechanisms reported in three published works. *In some lesions there was a combination of diff erent second hits.

Table 3: CDH1 somatic mechanisms acting as second hits in tumours of patients with hereditary diff use gastric cancer in multi-family studies

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Macroscopic and microscopic featuresMacroscopic features in the stomachs of asymptomatic CDH1 mutation carriers submitted to prophylactic gastrectomy diff er from those in index cases with HDGC. Stomachs of asymptomatic carriers nearly always seem normal to the naked eye because of the absence of mass lesion, and slicing shows normal mucosal thickness.62,63 However, in some normal-seeming stomachs, subtle

pale areas are visible on standard white light endoscopy,64 which, after formalin fi xation, show up as white patches under close inspection, suggesting intramucosal diff use carcinoma or SRCC. Most index cases with HDGC present with advanced cancers that are indistinguishable from sporadic diff use gastric cancer. They often have features of linitis plastica, which can implicate all topographical regions in the stomach.

Microscopic features of HDGC were initially assessed in the stomachs of CDH1 mutation carriers who underwent total gastrectomies. Multiple foci of intramucosal (T1a) SRCC were noted in most cases.59,60,62,63,65 The individual foci are small, ranging from 0·1 mm to 10 mm (fi gure 2). The neoplastic cells are small at the neck-zone level and usually enlarge towards the surface of the gastric mucosa, displaying the distinctive SRCC phenotype (fi gure 2).

In North American and European families, microscopic foci of intramucosal carcinoma are not restricted to any topographical region in the stomach: foci were identifi ed from cardia to the prepyloric region, without antral clustering.60,65 In New Zealand Maori families, most early invasive carcinomas developed in the distal stomach and the body-antral transitional zone.62 Background genetics and environmental factors are putative contributing factors to the diff erent anatomical localisations of the cancer foci.

Two distinct types of intraepithelial lesions have been identifi ed as precursors of invasive cancers in CDH1 mutation carriers:60 in-situ SRCC corresponds to the

Figure 2: Macroscopic appearance of a prophylactic gastrectomy displaying lesions identifi ed by histology

Pagetoid spread of signet ring cells

Intramucosal signet ring cell carcinoma

In-situ carcinoma

Nodal metastases

Loss of heterozygosity and promoter hypermethylation

Loss of heterozygosityLoss of heterozygosity and promoter hypermethylationPromoter hypermethylation

Somatic mutation

Promoter hypermethylation

Loss of heterozygosity

Primary tumour

Somatic mutation and promoter hypermethylation

Figure 1: Schematic of advanced hereditary diff use gastric cancer displaying features of linitis plastica, and summary of CDH1 second-hit inactivating mechanisms identifi ed in primary tumours and nodal metastases

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presence of signet ring cells, generally with hyper-chromatic and depolarised nuclei, within the basal membrane (fi gure 2), and pagetoid spread of signet ring cells below the preserved epithelium of glands or foveolae (fi gure 2).

Confi rmation of carcinoma in situ and pagetoid spread of signet ring cells by an independent pathologist with experience in this area is strongly recommended. Strict adherence to the criteria below for the identifi cation of these precursor lesions will diminish the risk of over-diagnosis of non-specifi c changes, and will help pathologists to distinguish legitimate precursor lesions and tiny foci of early intramucosal carcinoma from mimics of signet ring cells (eg, telescoped normal glands, globoid cells in hyperplastic lesions, xanthomatous cells, neuroendocrine cell nests, and clear or glassy cell change of mucous glands).7 E-cadherin is aberrantly expressed (dotted in membrane and cytoplasm), reduced, or absent in precursor lesions and early invasive gastric carcinomas (T1a); expression should be normal in adjacent non-neoplastic mucosal membranes.7

Advanced HDGC presents as a poorly diff erentiated diff use carcinoma, sometimes with a few signet ring cells, that invades widely the whole thickness of the gastric wall, which becomes rigid (linitis plastica). It also presents as undiff erentiated or mixed subtypes with mucinous and occasionally tubular components. These advanced gastric carcinomas of CDH1 mutation carriers do not have any characteristics that can be used to diff erentiate them from sporadic gastric cancers. Mild chronic gastritis has been identifi ed as a background change in the gastric mucosa of patients with HDGC; but intestinal metaplasia and infection with Helicobacter pylori have been rarely reported in the HDGC setting in families from North America and Europe.60

Clinical managementClinically accepted approaches in HDGC include prophylactic total gastrectomy and endoscopic screening. Prophylactic gastrectomy is the only therapeutic option for carriers of CDH1 pathogenic mutations, and is off ered even when carriers are asymptomatic in view of the high penetrance of HDGC, the limitations of endoscopic surveillance (which often does not detect microscopic disease), and the dismal prognosis of HDGC at advanced stages.9,66,67 Patients considering prophylactic gastrectomy should take into account the mortality of the procedure (<1%) and the short-term and long-term adverse events associated with it, which have eff ects on quality of life.66 A multidisciplinary approach to preoperative counselling is essential, and should include input from a gastro-enterologist, surgeon, dietitian, genetic counsellor, and specialist nurse.9,67,68 For patients with symptomatic invasive HDGC, non-surgical treatment regimens used in sporadic diff use gastric cancer are often the only therapeutic option.

In situations in which gastrectomy is not appropriate, yearly surveillance with endoscopy and biopsies is recommended.9,66 Surveillance is crucial to guide the clinical management of individuals from families with CDH1 mutations who refuse genetic testing or prefer to delay gastrectomy, in patients carrying CDH1 mutations of uncertain clinical signifi cance (eg, missense mutations), and in those from families without CDH1 mutations.9,66 The authors of a prospective cohort study66 of the outcomes of HDGC families undergoing endoscopic surveillance concluded that careful white light examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and help to inform decision making about gastrectomy. In this study, auto fl uorescence and narrow-band imaging were of limited use. Endoscopic biopsies should be assessed by pathologists with expertise in the disease to maximise surveillance output.9

Because of the high lifetime risk of developing lobular breast cancer, women carrying CDH1 mutations are recommended to undergo yearly mammography and breast MRI from age 35 years onwards.9 Prophylactic mastectomy might be an option for some, although data are insuffi cient to advise prophylactic breast surgery over surveillance.9,67 Detailed information about the clinical management of patients with HDGC is available in the International Gastric Cancer Linkage Consortium 2010

guidelines9 and the Clinical Utility Gene Card for HDGC.67

Analysis of pathological changes in HDGC prophylactic gastrectomy specimens includes a thorough microscopic assessment of the complete stomach with haematoxylin and eosin and a mucin stain, such as periodic acid-Schiff .9 Periodic acid-Schiff is a primary stain, and, as such, increases the detection rate of small invasive SRCC foci and reduces screening time. The Swiss roll technique, consisting of rolling up the gastrectomy specimen lengthwise, can be used to include the complete mucosa. The pathology report should mention all gastric abnormalities and localisation. Histological confi rmation of resection margins consisting of proximal oesophageal and distal duodenal mucosa is essential, because new gastric cancer can develop in remaining gastric mucosa.9,60

GAPPSGenetic susceptibilityOther heritable polyposis syndromes should be excluded before considering GAPPS as a diagnosis. Familial adeno matous polyposis, attenuated familial adeno-matous polyposis, and MUTYH-associated polyposis (which has autosomal recessive inheritance) are defi ned by their colorectal phenotype. Patients with Peutz-Jeghers syndrome might also have fundic gastric polyps and intestinal gastric cancer, but the polyp distribution diff ers from that in GAPPS. After the initial description

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of a GAPPS family, two Japanese families with similar clinicopathological features were reported.14 Recommended diagnostic criteria for GAPPS are listed in table 1.13 Mutations in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11, and PTEN have been excluded in fi ve GAPPS families by sequence analysis of exons and fl anking regions and assays for deletion or duplication of exons.13,14

Macroscopic and microscopic featuresMacroscopic features of GAPPS include fl orid gastric polyposis, mainly with gastric polyps with diameters of less than 10 mm. More than 100 polyps carpet the gastric body and fundus, with relative sparing along the lesser curve of the stomach.13,14 The oesophagus, gastric antrum, pylorus and duodenum are usually unaff ected. Microscopy shows mainly fundic gastric polyposis and regions of dysplasia (fi gure 3). Occasional hyperplastic and pure adenomatous polyps and some mixed polyps containing discrete areas of fundic-gastric-polyposis-like, adenomatous, and hyperplastic features can be detected amid the fundic gastric polyps. Gastric cancers that develop in patients with GAPPS display the features of intestinal-type gastric cancer. The earliest case reported

so far occurred in someone aged 33 years in one of the families studied.13

Clinical managementClinically accepted approaches to the management of GAPPS families include endoscopic surveillance, and, eventually, prophylactic gastrectomy. The limitations of endoscopic surveillance, the patient-specifi c risk of morbidity associated with prophylactic surgery, and the risk of gastric cancer within the specifi c family need to be balanced. All fi rst-degree relatives of aff ected patients should be advised to undergo am oesophago gastro-duodenoscopy and a colonoscopy.13

FIGCGenetic susceptibilityThe genetic cause of FIGC is currently unknown. The diagnosis is considered when there is a family history of gastric cancer, intestinal-type, in families without gastric polyposis.

Macroscopic and microscopic featuresThe stomach cancers display the common macroscopic features observed in the sporadic setting of gastric cancer. By histology, the tumours show the features of adenocarcinoma, intestinal-type.

Clinical managementFew recommendations have been suggested for the management of patients at risk of FIGC.16

Future directions in research and treatment of HDGC In readthrough therapies, which are also called nonsense suppression therapies, low-molecular-weight com-pounds are used to induce the translation machinery to recode a nonsense codon into a sense codon.69 Aminoglycosides and PTC124, for instance, partly restore expression of proteins with normal function from nonsense-mutated mRNA.69 Roughly 50% of CDH1 germline mutations are either nonsense or small insertions or deletions that cause premature truncation of E-cadherin nascent proteins. Amino glycosides and PTC124 have not been tested in the context of HDGC, mainly because of the high likelihood of generation of deleterious missense mutant proteins during correction. Nevertheless, when suppressor tRNA that replaces a specifi c premature stop codon by a cognate aminoacid was used, E-cadherin readthrough was induced and full-length wild-type proteins were generated in an HDGC cell line.70 The objective of such a strategy is to reverse the eff ect of germline CDH1-truncating mutations, thereby restoring expression of full-length normal E-cadherin molecules, although further research is needed.70

Chemical chaperones (eg, dimethyl sulfoxide) can restore E-cadherin folding, expression, and function in vitro, because they are modulators of traffi cking-related

Figure 3: Gastric adenocarcinoma and proximal polyposis of the stomach (A) Florid fundic gastric polyposis (haematoxilyn and eosin, 40× magnifi cation), (B) fundic gland polyp without dysplasia (haematoxilyn and eosin, 400× magnifi cation), (C) fundic gland polyp with high-grade dysplasia (haematoxilyn and eosin, 400× magnifi cation), and (D) invasive intestinal-type adenocarcinoma (haematoxilyn and eosin, 200× magnifi cation).

A

C

B

D

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signalling pathways.47,71 About a fi fth of HDGC-causing mutations are missense, and often generate E-cadherin molecules that are incapable of proper folding, which get destabilised and degraded.71 Therefore, natural, chemical, or pharmacological chaperones have been advanced as promising drugs for use in carriers of CDH1 germline missense mutations.46,71

Drugs that induce DNA demethylation and the re-expression of specifi c target genes have been tested for use in gastric cancer. Vorinostat, a histone deacetylase inhibitor, has shown particular benefi t when combined with a taxane or capecitabine and cisplatin.72,73 Given the high frequency of hypermethylation of the CDH1 promoter, demethylating drugs are emerging as therapeutic options in early CDH1-driven HDGC stages without evidence of metastatic disease.53

E-cadherin signalling has a crucial role in cell behaviour. It modulates the expression and function of several molecules, such as growth factor receptors, signalling eff ectors, cytoskeletal regulators, catenins, integrins, and metalloproteinases.74,75 As an example, EGFR becomes activated when E-cadherin is mutated, and in the absence of E-cadherin expression.76 In-vitro analysis with E-cadherin mutant cells showed that the inhibition of EGFR prevents cell motility and invasion.76 Anti-EGFR therapy might still have a role in the treatment of patients with HDGC, although results from clinical trials are not encouraging.77 C-Src is overexpressed in large intramucosal HDGC lesions and cells invading the gastric wall, which suggests that inhibition of c-Src activation could be a therapeutic strategy for patients with early HDGC.61 MMP-targeting agents, Hedgehog (Hh) signalling inhibition, and inhibition of RhoA activity also improve E-cadherin-dependent cellular activities in vitro, and therefore could be molecules to investigate when designing targeted therapies for HDGC.78

Notch and TFF1 have been advanced as molecules specifi cally associated with the transcriptional signature of healthy gastric epithelia.79 These molecules seem to endow gastric epithelial cells with increased resistance to apoptosis in the event of E-cadherin downregulation, in a tissue-specifi c manner.79 If the hypothesis that normal gastric epithelial cells survive complete loss of E-cadherin, as opposed to other epithelial cells, is correct, it might explain why carriers of CDH1 germline mutations have a high risk of diff use gastric cancer.79 Gastric tissue-specifi c proteins, including Notch and TFF1, could then become targets for therapy in E-cadherin-defi cient gastric cancers (eg, HDGC).

HDCG is a rare cancer syndrome, and thus the planning of clinical trials to compare compounds that restrore E-cadherin functions with prophylactic surgery is quite diffi cult. Alternatively, if the safety and effi cacy of any of these compounds is proved in sporadic diff use gastric cancer, which is far more common, the compound could potentially be used in patients with HDGC—in particular, those who refuse or delay prophylactic surgery. However,

on the basis of available information, personalised management of HDGC families, specifi cally with regard to targeted therapies, is not foreseeable in the near future.

Animal models of HDGCThree mouse models of E-cadherin inactivation exist.80–82 CDH1 heterozygous knockout animals, derived from a previous homozygous knockout model,83 were used to establish the fi rst murine model of diff use gastric cancer.80 Wild-type and heterozygous knockout mice were treated with N-methyl-N-nitrosourea to promote gastric carcino-genesis. Heterozygous knockout mice developed intra-mucosal SRCC that closely mimicked human disease with an 11-times higher frequency than did wild-type mice. All lesions displayed decreased E-cadherin expression and low proliferative activity.80 Knockout of CDH1 has also been specifi cally induced in the parietal cell lineage, leading to loss of E-cadherin and disturbance of epithelial cell polarity, growth, and diff erentiation, but was not suffi cient to induce tumour development.81 The main limitation of the these two models is their inability to spontaneously develop cancer, which is probably a result of the mice’s short lifespan.

A double conditional knockout mouse line in which CDH1 and TP53 were specifi cally inactivated has been genetically engineered.82 Diff use gastric cancer developed in all mice within 12 months (100% penetrance); and cancers were mainly composed of poorly diff erentiated cells and SRCCs, as in human advanced HDGC.82 Furthermore, gene expression patterns of diff use gastric cancer in double knockout mice showed increased expression of mesenchymal markers and epithelial-mesenchymal-transition-related genes, resembling the molecular phenotype of the human disease.82 This model mimics more closely human disease but, because it depends on knockout of an additional gene, its use in the study of the natural history of CDH1-related HDGC could be limited.

Animals develop diff use gastric cancer rapidly, and could be very useful in several ways. They have the potential to clarify the mechanism underlying the formation of diff use gastric cancers and they can be used as disease models for preclinical intervention studies to test preventive measures and potential HDGC-targeted therapies.

Search strategy and selection criteria

We searched PubMed with the terms “hereditary diff use gastric cancer (HDGC)”, “early onset gastric cancer”, “familial gastric cancer”, “gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)”, and “E-cadherin germline mutations” for articles in English published between Jan 1, 1998, and 30 June, 2014. We also searched our fi les, particularly for papers about gastric-cancer-associated syndromes and the pathology of HDGC. We generated the fi nal reference list on the basis of originality and relevance to the broad scope of this Review.

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ConclusionsThe genetic and pathogenic determinants of hereditary gastric cancer syndromes are not yet fully recognised. For GAPPS and FIGC, eff orts need to be made to identify genetic causes that may guide patients’ genetic testing and clinical management. Much more is currently known about clinical aspects, genetics, and pathogenesis of HDGC; anticipated future technological developments should open avenues for new genetic testing approaches and novel therapeutic strategies.

ContributorsFC and CO contributed to the conceptual design, supervision, and

preparation of the Review. CO, HP, JF, RS, and FC analysed and

interpreted data. HP compiled all relevant references and tabulated data.

All authors drafted the paper and read, commented on, and approved the

fi nal version before submission.

Declaration of interestsWe declare that we have no competing interests.

AcknowledgmentsWe thank the Portuguese Foundation for Science and Technology (FCT),

the Programa Operacional Temático Factores de Competitividade

(COMPETE), and fundo Comunitário Europeu FEDER for funding the

grant (FCT PTDC/SAU-GMG/110785/2009), and postdoctoral

fellowships for HP (SFRH/BPD/79499/2011) and JF (SFRH/

BPD/87705/2012). We also thank Mafalda Nobre for the design of the

fi gures.

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