Genetic Susceptibility, Pathology, and Implications for Management

Review 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 diff use gastric cancer, gastric Lancet Oncol 2015; 16: e60–70 adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development *These authors contributed of gastric cancer is high in families aff ected b-y these syndromes, but only hereditary diff use gastric cancer is equally genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also Ipatimub-Institute of associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li- Molecular Pathology and Immunology & Instituto Fraumeni, Peutz-Jeghers, hereditary breast–ovarian cancer syndromes, familial adenomatous polyposis, and juvenile Instituto de Investigação e polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric Inovação em Saúde, cancer, and discuss research and technological developments, which together are expected to open avenues for new (C Oliveira PhD, H Pinheiro PhD, genetic testing approaches and novel therapeutic strategies. J Figueiredo PhD, R Seruca MD, Prof F Carneiro MD), and Department of Pathology and Introduction expected to improve the identifi cation of novel causative Oncology, Faculty of Medicine Gastric cancer aff ects nearly 1 million individuals every genetic events, which will aff ect genetic testing and the (C Oliveira, R Seruca, F Carneiro), year, 70–85% of whom die within 5 years of diagnosis, management of families with a high frequency of gastric University of Porto, Porto, Portugal; and Centro 1 making it the third most lethal cancer worldwide. The cancers. Hospitalar S João, Porto, high mortality associated with gastric cancer (nearly HDGC was the fi rst of the hereditary gastric cancer Portugal (F Carneiro) 800 000 deaths per year) is mainly a result of late syndromes to be recognised, initiated by inherited Correspondence to: diagnosis, and limited therapeutic options. The two causative mutations in the E-cadherin gene (CDH1).5 Prof Fátima Carneiro, Institute of major subtypes—diff use and intestinal2—are Mutations in the alpha-E-catenin gene (CTNNA1) have Molecular Pathology and Immunology, University of characterised by distinct epidemiological, morphological, been identifi ed as an additional genetic cause of HDGC Porto, Rua Dr Roberto Frias s/n, 6 and molecular features. Although most gastric cancers (table 1). Several patients with early-onset diff use-type 4200-465, Porto, Portugal are sporadic, aggregation within families occurs in gastric cancers with no apparent family history have [email protected] roughly 10% of cases. In regions where the incidence of been found to be carriers of CDH1 germline mutations, gastric cancer is low, most familial cases are probably which supports the role of CDH1 germline defi ciency in due to heritable pathogenic mutations that increase risk disease initiation and helped to identify de-novo HDGC from birth.3,4 Truly hereditary cases are thought to families.7,8 In HDGC families, lobular breast cancer is the account for 1–3% of the global burden of gastric cancer second most frequent type of neoplasia.9 Although and comprise at least three main syndromes: hereditary colorectal cancer also arises as part of the tumour diff use gastric cancer (HDGC), gastric adenocarcinoma spectrum, whether the risk in HDGC families is higher and proximal polyposis of the stomach (GAPPS), and than that in the general population remains unclear.9 familial intestinal gastric cancer (FIGC). A genetic basis Congenital malformations, such as cleft lip or cleft palate, has been found in only around 40% of families aff ected occur in some CDH1-mutation-driven HDGC families,10 by HDGC. The identifi cation of inherited factors among but are not a defi ning clinical characteristic because of individuals with family histories of gastric cancer is their rarity. However, clinicians should collect infor- therefore a crucial step for early diagnosis and disease mation about them when counselling at-risk families.11 management. According to published data, the penetrance of diff use In this Review, we discuss the available knowledge on gastric cancer in mutation carriers reaches more than hereditary gastric cancer and cancer-associated 80% in both men and women by 80 years of age, and the syndromes from which gastric cancer can arise, with the probability of women developing lobular breast cancer is aim of clarifying questions relevant for the translation of 60%.9 The combined risk of gastric cancer and breast basic research into clinical practice. cancer in women has been calculated to be 90% at 80 years.12 Eff orts are being made to calculate the Hereditary gastric cancer syndromes penetrance of gastric cancer in a larger number of HDGC The recognition of familial aggregation (eg, high CDH1 mutant families. occurrence in siblings or off spring) is the fi rst step GAPPS was identifi ed in 2012, and is characterised by towards the identifi cation of a disease with a genetic the autosomal dominant transmission of fundic gland component and is clinically useful. Family history, polyposis (including dysplastic lesions or intestinal-type histological classifi cation, and age at onset of disease gastric adenocarcinoma, or both) that are restricted to the (<45 years) are used to guide genetic testing and clinical proximal stomach with no evidence of colorectal or surveillance in the context of a particular gastric cancer duodenal polyposis or other hereditary gastrointestinal hereditary syndrome. The advent of new, fast, and cancer syndromes (table 1).13 It is characterised by incom- inexpensive massive parallel sequencing technologies is plete penetrance, and some elderly obligate carriers have www.thelancet.com/oncology Vol 16 February 2015 e60 Review Clinical criteria Genetic screening Alterations described Hereditary diff use Two or more cases of gastric cancer, one confi rmed case of diff use gastric Sequencing of CDH1 coding Mutations throughout the gastric cancer cancer in someone younger than 50 years; sequences; CDH1 gene and deletions Three or more confi rmed diff use gastric cancer cases in fi rst-degree or Multiplex ligation-dependent mainly implicating fl anking second-degree relatives, independent of age of onset; probe amplifi cation (large CDH1 untranslated regions; Diff use gastric cancer before age 40 years without a family history; rearrangements); Personal or family history of diff use gastric cancer and lobular breast Sequencing of CTNNA1 coding One germline truncating cancer, one of which must be diagnosed before age 50 years sequences mutation in CTNNA1 Gastric Gastric polyps restricted to the body and fundus with no evidence of No screening available No inherited inherited adenocarcinoma and colorectal or duodenal polyposis; mutations so far proximal polyposis More than 100 polyps carpeting the proximal stomach in the index case or of the stomach 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* Familial intestinal Two or more cases of gastric cancer in fi rst-degree or second-degree No screening available No inherited inherited gastric cancer relatives, with at least one confi rmed case of intestinal histology in mutations so far 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 *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 normal endoscopies. The genetic cause has yet to be Li-Fraumeni syndrome encompasses several tumour identifi ed.13,14 types that develop generally before 45 years of age because FIGC is characterised mainly by intestinal gastric of inherited TP53 mutations,19,20 including early-onset cancer (table 1). An autosomal dominant inheritance gastric cancer. The frequency of gastric cancer in families pattern has been noted in many families with intestinal- carrying TP53 mutations ranges from 1·8% to 4·9%.21,22 type gastric cancer.15 In practical terms, FIGC should be 40% of families with TP53 mutations present with at least thought of as a potential diagnosis when histopathological one gastric cancer (mean age 43 years, median age 36; age reports refer to intestinal-type adenocarcinoma range 24–74 years), with an excess of early onset gastric segregating within families without gastric polyposis. cancers.22 These data support periodic screening with The genetic cause is unknown, and only a few oesophagogastroduodenoscopy in young carriers of TP53 recommendations have been advanced for the clinical germline mutations, and particularly in Li-Fraumeni management of patients at risk of FIGC.16 syndrome families in which

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