Elsevier

Seminars in Oncology

Volume 43, Issue 5, October 2016, Pages 554-559
Seminars in Oncology

Genetic predisposition to gastric cancer

https://doi.org/10.1053/j.seminoncol.2016.08.006Get rights and content

Abstract

Gastric cancer ranks as the third leading cause of cancer mortality worldwide and confers a 5-year survival of 20%. While most gastric cancers are sporadic, ~1%–3% can be attributed to inherited cancer predisposition syndromes. Germline E-cadherin/CDH1 mutations have been identified in families with an autosomal dominant inherited predisposition to diffuse gastric cancer. The cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is reportedly 70% for men and 56% for women. Female mutation carriers also have an estimated 42% risk for developing lobular breast cancer by age 80 years. However, most individuals meeting clinical criteria for hereditary diffuse gastric cancer syndrome (HDGC) do not have a germline CDH1 mutation, and germline CDH1 mutation carriers do not all exhibit similar clinical outcomes in terms of age of diagnosis or cancer types. E-cadherin (CDH1) as the one known causative gene for HDGC accounts for only 40% of cases, leaving 60% with an unknown genetic diagnosis. In addition to HDGC, we will review other genetic syndromes with elevated gastric cancer risk, as well as newly implicated alterations in other genes (CTNNA1, DOT1L, FBXO24, PRSS1, MAP3K6, MSR1, and INSR) that may affect gastric cancer susceptibility and age-specific penetrance.

Section snippets

Background

Gastric cancer is a heterogeneous disease, caused by a variety of genetic and environmental factors, and comprised of several pathologic subtypes with different molecular features and clinical outcomes [1]. The incidence and prevalence of gastric cancer varies widely, but China, Korea, Japan and Portugal bear the highest rates of disease [2]. In the west, although the overall rate of has decreased substantially over the past century, the incidence of adenocarcinomas of the gastroesophageal

Histological characterization

Gastric cancer can be subtyped pathologically according to Lauren’s classification published in 1965 and revised by Carneiro in 1995 [6], [7]. The four histological categories include (1) glandular/intestinal, (2) mixed intestinal/diffuse, (3) border foveal hyperplasia, and (4) solid/undifferentiated.

The worldwide relative proportions of gastric cancer subtypes are 74% intestinal, 16% diffuse, and 10% other [8]. Intestinal type gastric tumors often present as solid masses with atrophic

Etiological characterization

A host of etiological factors are implicated as causes of gastric cancer. Correlations have been shown with chronic ingestion of pickled vegetables, salted fish, excessive salt intake, smoked meat, and smoking. Epstein-Barr virus has been implicated in about 10% of worldwide gastric carcinoma, and Helicobacter pylori has been consistently implicated as a major risk factor, primarily in intestinal type.

About 5%–10% of gastric cancers are associated with strong familial clustering and can be

Hereditary diffuse gastric cancer

To date, the major gene implicated in hereditary diffuse gastric cancer syndrome (HDGC) is CDH1, located on chromosome 16q22.1. Inherited germline mutations in this gene are associated with 1%–3% of all gastric cancers and account for approximately one third of familial associated gastric cancers of the diffuse or signet ring type [9]. The International Gastric Cancer Linkage Consortium (IGCLC) developed diagnostic criteria for HDGC that includes at least two cases of diffuse gastric cancer in

HDGC screening and management

Early-stage diffuse gastric cancer is diagnostically elusive: symptoms are generally nonspecific and do not appear until the disease is advanced. While endoscopy is considered to be the best screening method, it regularly fails to identify diffuse gastric carcinoma as these lesions spread submucosally as single cells or clustered islands of cells. Unfortunately, to date no tests (procedures or biomarkers) have been shown to be clinically useful for screening and/or early detection in

Other hereditary cancer susceptibility syndromes associated with gastric cancer risk

Peutz-Jeghers syndrome (PJS) is a rare disorder with an estimated 1/25,000 to 1/250,000 incidence rate. PJS is characterized by both hamartomatous and adenomatous polyposis throughout the gastrointestinal tract, and confers a high predisposition to gastrointestinal malignancies (Table 1). It may be clinically diagnosed based on histologically confirmed hamartomatous polyps and two of the following: positive family history, hyperpigmentation of the digits and mucosa of the external genitalia,

Challenges in stratifying risk and concluding remarks

With the inclusion of CDH1 on many multi-gene cancer panels due to its high-penetrance breast cancer risk, we are now identifying unexpected CDH1 pathogenic mutations in individuals without a personal or family history of HDGC-related cancers. Currently, there are no defined guidelines for how to interpret a CDH1 mutation in the midst of personal and family history lacking diffuse gastric cancer or lobular breast cancer. Given the poor diagnostic yield of screening endoscopy, it is a major

Conflicts of interest

None.

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