Hereditary Diffuse Gastric Cancer
Hereditary Diffuse Gastric Cancer (HDGC), is a highly penetrant (80%) yet rare autosomal dominant predisposition to gastric cancer and constitutes ~1% of all gastric cancers.
PrintHereditary Diffuse Gastric Cancer (HDGC), is a highly penetrant (80%) yet rare autosomal dominant predisposition to gastric cancer and constitutes ~1% of all gastric cancers.
HDGC patients typically present with diffuse-type gastric cancer with signet ring cells and, at late stage, linitis plastica. HDGC has also been noted to occur in families in combination with lobular breast cancer. HDGC is caused by mutations in the CDH1 gene, which account for up to 30-48% of affected individuals.
The Ambry Test: HDGC offers concurrent gene sequence and deletion/duplication analysis of the CDH1 gene and is capable of detecting >99% of all described CDH1 mutations.
Gastric cancer (GC) is one of the leading causes of cancer death worldwide, with approximately 930,000 new cases being diagnosed per year, leading to >700,000 deaths. A genetic predisposition is obvious in some familial cases of gastric cancers, and germline mutations of the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), which constitutes ~1% of all gastric cancers. The International Gastric Cancer Linkage Consortium (IGCLC) defines HDGC as an autosomal-dominant cancer susceptibility syndrome characterized by the following criteria: (1) 2 or more documented cases of diffuse GC in first- or second-degree relatives, with 1 or more diagnosed before age 50; or (2) 3 or more cases of diffuse GC in first- or second-degree relatives, independent of age of onset.1 The penetrance of CDH1 mutations is incomplete yet relatively high. In one published study, the estimated cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is 67% for men and 83% for women.2 HDGC patients typically present with diffuse-type gastric cancer with signet ring cells diffusely infiltrating the wall of the stomach and, at late stage, linitis plastica. An elevated risk of lobular breast cancer is also associated with HDGC.3
Genetic analysis can confirm a clinical diagnosis of hereditary diffuse gastric cancer (HDGC). Since HDGC tends to infiltrate submucosally with a visually normal surface epithelium, the efficacy of endoscopic surveillance for HDGC is probably inadequate. Due to high penetrance of this disease, total prophylactic gastrectomy in CDH1 mutation carriers remains the only option to eliminate an inherited risk of gastric cancer.
The Ambry Test: Hereditary Diffuse Gastric Cancer is a laboratory-developed test that utilizes both gene sequence and deletion/duplication analyses to detect changes in the CDH1 gene. PCR-based automated sequencing in the sense and antisense directions for exons 1-16 of the CDH1 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns, is used for full gene sequence analysis. Gross deletion/duplication analysis, using the multiplex ligation-dependent probe amplification (MLPA) P083-B1 CDH1 developed by MRC Holland, is also performed. Specific mutation analysis for individual CDH1 mutations known to be in the family is also available.
Mutations in the CDH1 gene can be detected in 30-48% of individuals affected with hereditary diffuse gastric cancer.5 The Ambry Test: Hereditary Diffuse Gastric Cancer is capable of detecting about 99% of described mutations in CDH1.
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 µg in TE at 50-100 ng/µl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is not recommended. Please call an Ambry Genetic Counselor to discuss your
case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 4720 | CDH1 Gene Sequence Analysis | 83891x1, 83894x16, 83898x15, 83904x30, 83909x30, 83912x1 |
| 4724 | CDH1 Deletion/Duplication Analysis | 83891x1, 83894x1, 83900x1, 83901x15, 83909x1, 83912x1 |
| 4726 | CDH1 Gene Sequence Analysis and Deletion/Duplication | 83891x1, 83894x16, 83898x15, 83900x1, 83901x15, 83904x30, 83909x31, 83912x2 |
| Technique | Days |
|---|---|
| CDH1 Gene Sequence Analysis | 10-21 |
| CDH1 Deletion/Duplication Analysis | 7-14 |
| CDH1 Gene Sequence Analysis and Deletion/Duplication | 10-21 |
1 Brooks-Wilson AR et al. J Med Genet. 2004;41:508-17.
2 Pharoah PD et al. Gastro. 2001;121:1348-1353.
3 Guilford P et al. Gastric Cancer. 2010;13:1-10.
4 Pandalai PK et al. Surgery. 2010 Epub ahead of print.
5 Suriano G et al. Clin Cancer Res. 2005;11:5401-9.