CDH1/E-cadherin germline mutations in early-onset gastric cancer

Background

Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E‐cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear.

Aims

To examine the frequency of CDH1 germline mutations in a population‐based series of early‐onset gastric cancer (EOGC <50 years old).

Methods

211 cases of EOGC were identified in Central‐East Ontario region from 1989 to 1993, with archival material and histological confirmation of non‐intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single‐strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E‐cadherin (HECD‐1) using immunohistochemistry.

Results

1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30‐year‐old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early‐onset isolated cell gastric cancer.

Conclusion

This is the first population‐based study, in a low‐incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2–3% of EOCG cases in North Americans may be owing to high‐risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.Gastric cancer is the second most common cause of cancer deaths worldwide.¹ Despite an overall decline in the incidence of gastric cancer in older people, the incidence of early‐onset (⩽50 years old) gastric cancer (EOGC) and familial clustering of gastric cancer remains stable in frequency.² Genetic predisposition to gastric cancer caused by known genes such as CDH1 and the mismatch repair genes may have an important role in the development of gastric cancer in these cases.³ Autosomal dominant gastric cancer is estimated to account for about 1–3% of all cases.⁴ We have previously reported two new germline mutations (2 of 139 cases) in the hMLH1 gene in our population‐based series of EOGC.⁵In 1998, Guildford et al⁶ first described inactivating germline mutations in E‐cadherin (CDH1 gene) responsible for the development of diffuse‐type gastric cancer (DGC) in three families of Maori origin. Additional family studies have shown that E‐cadherin is responsible for some families presenting with DGC, according to the Lauren classification.⁷ In 1999, the International Gastric Cancer Linkage Consortium (IGCLC) provided the first clinical management guidelines for this autosomal dominant hereditary predisposition syndrome, hereditary diffuse gastric cancer (HDGC, MIM#137215), as defined by Guildford et al earlier that year.^8,9 HDGC is caused by germline inactivating mutations in E‐cadherin (CDH1, MIM# 192090). However, other genes are likely to cause HDGC, as only 30% of families with HDGC meeting the primary criteria for HDGC have been found to have CDH1 germline mutations. To date, 57 distinct functional CDH1 germline mutations have been reported. Of these, 50 are listed in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/gene.php?gene = CDH1), an additional five functional mutations were reported by Suriano et al,¹⁰ and a further two splice mutations associated with cleft lip/palate and HDGC were more recently reported by Frebourg et al.¹¹ Most of these mutations result in a truncated, non‐functional protein. Although primary criteria are fairly well established for screening of CDH1 germline mutations in kindreds with gastric cancer, the IGCLC recognise the need for large population‐based studies of genetic predisposition to gastric cancer to determine the role of germline mutations in sporadic EOGC. Here, we report the first population‐based study of EOGC to determine the frequency of CDH1 germline mutations in a population at a low risk for gastric cancer.

Keypoints

• This is the first and largest population‐based study of genetic predisposition to gastric cancer in a low‐incidence region reporting a new germline CDH1 mutation.
• 2–3% of cases of early‐onset gastric cancer (EOGC) in North America may be owing to high‐risk genetic mutations.
• Informs geneticists on the use of searching for genetic mutations in EOGC.