We searched PubMed with the terms “hereditary diffuse 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 files, particularly for papers about gastric-cancer-associated syndromes and the pathology of HDGC. We generated the final reference list on the basis of
ReviewFamilial gastric cancer: genetic susceptibility, pathology, and implications for management
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 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 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.
Section snippets
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
Associations with other hereditary cancer syndromes
Gastric cancer has been identified 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
Diagnostic issues
The search for a specific 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 classified 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
Genetic susceptibility
The genetic susceptibility to, and the molecular basis for, HDGC were first identified in Maori families in work published in 1998,5 which was shortly followed by studies39, 40, 41 reinforcing the role of CDH1 in susceptibility to HDGC in other populations.39, 40, 41 Since then, several hundred probands (affected 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
Genetic susceptibility
Other heritable polyposis syndromes should be excluded before considering GAPPS as a diagnosis. Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis (which has autosomal recessive inheritance) are defined by their colorectal phenotype. Patients with Peutz-Jeghers syndrome might also have fundic gastric polyps and intestinal gastric cancer, but the polyp distribution differs from that in GAPPS. After the initial description of a GAPPS family,
Genetic susceptibility
The 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 features
The 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 management
Few 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 compounds 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.
Animal models of HDGC
Three mouse models of E-cadherin inactivation exist.80, 81, 82 CDH1 heterozygous knockout animals, derived from a previous homozygous knockout model,83 were used to establish the first murine model of diffuse gastric cancer.80 Wild-type and heterozygous knockout mice were treated with N-methyl-N-nitrosourea to promote gastric carcinogenesis. Heterozygous knockout mice developed intramucosal SRCC that closely mimicked human disease with an 11-times higher frequency than did wild-type mice. All
Conclusions
The genetic and pathogenic determinants of hereditary gastric cancer syndromes are not yet fully recognised. For GAPPS and FIGC, efforts 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.
Search strategy and selection criteria
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These authors contributed equally