FaCD Online Syndrome Fact Sheet

Last updated: 18 Jun 2013

Name: Hereditary Diffuse Gastric Cancer

Synonym: HDGC

Mode of Inheritance: AD

OMIM number: 137215

Genes

CDH1, mapped to 16q22.1
CTNNA1, mapped to 5q31.2

Tumor features

breast cancer, lobular
gastric cancer, diffuse type
gastric cancer, mixed intestinal & diffuse type

Tumor features (possible)

colorectal cancer
melanoma, cutaneous
prostate cancer

Non-tumor features (possible)

cleft lip
cleft palate

Comment

Guilford et al.[1] detected germline mutations in the E-cadherin (CDH1) gene in 3 Maori families from New Zealand with (autosomal dominant) early-onset, high-grade, diffuse (isolated and mixed types) gastric cancer. Their findings were subsequently confirmed in non-Maori families[2-6]. Although the proportion of germline E-cadherin mutations in gastric cancer patients in general may not be more than 3%[7], this percentage may be as high as 30% in families which meet the criteria for hereditary diffuse gastric cancer listed below. These germline mutations also confer an increased risk to develop lobular type breast cancer(LBC). Germline CDH1 mutations have been observed in familial LBC cases in the absence of a family history of diffuse gastric cancer[11,22]. Risk for colorectal cancer and prostate cancer may be increased as well, however, data are presently too limited to reach any firm conclusions[4;6;8-10]. An association of germline CDH1 mutations with cleft lip/palate has been suggested[21]. Multiple relatives with melanoma have been observed in CDH1 gastric cancer and gastric cancer/lobular breast cancer families[11].

Pharoah et al. calculated a cumulative risk of gastric cancer by age 80 years of 67% for men (95% confidence interval [95% CI, 39-99) and 83% for women (95% CI, 58-99). For women, the cumulative risk of breast cancer was 39% (95% CI, 12-84).[15]. In four families from Newfoundland, Kaurah et al. calculated a cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% CI, 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%)[16]. Occult gastric cancer has been observed in most of the preventive gastrectomy specimens[17-20]

Criteria[10]: criteria 1(a+b) or 2 fulfilled
(1a) at least 2 documented cases of diffuse gastric cancer (isolated or mixed; as opposed to glandular/intestinal and solid types) in first or second-degree relatives +
(1b) at least one relative diagnosed before the age of 50
OR
(2) at least 3 cases of documented diffuse gastric cancer in first or second-degree relatives (diagnosed at any age).

Families with aggregation of gastric cancer and an index case with diffuse gastric cancer, but not fulfilling the IGCLC criteria for HDGC, are classified as familial diffuse gastric cancer (FDGC).
Suriano et al proposed that the cut-off age for screening CDH1 germline mutations in single cases of early-onset diffuse gastric cancer should be decreased to 35 years[13]. Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age[14].

Recently, in a large family with diffuse gastric cancer, a germline truncating mutation in the alpha-E-Catenin gene was identified, suggesting that more genes in the E-cadherin pathway can cause this syndrome [23].

References