Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) is a highly penetrant, yet rare, autosomal dominant condition that predisposes to diffuse gastric cancer and lobular breast cancer.  It accounts for <1% of all gastric cancers and is caused by mutations in the CDH1 gene.

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Hereditary diffuse gastric cancer (HDGC) is a highly penetrant, yet rare, autosomal dominant condition that predisposes to diffuse gastric cancer and lobular breast cancer.  It accounts for <1% of all gastric cancers and is caused by mutations in the CDH1 gene.

Disease Name 
Hereditary diffuse gastric cancer
Gastric cancer
Disease Information 

Gastric cancer is the fifth most common cancer in the world, with approximately 952,000 new cases diagnosed and >700,000 related deaths in 2012.1 A genetic predisposition has been observed 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.2 People with HDGC typically present with diffuse-type, signet ring cell gastric cancer and, at late stage, linitis plastica. Individuals with HDGC also have an increased risk to develop lobular breast cancer (LBC) and some studies have shown that some families with CDH1 mutations may present with breast cancer.3-5 Some individuals with CDH1 mutations may also have cleft lip/palate in combination with DGC.6

According to the International Gastric Cancer Linkage Consortium (IGCLC), an individual has a clinical diagnosis of HDGC if any of the following criteria are met:7

  1. 2 or more cases of gastric cancer in first- or second-degree relatives, with 1 or more confirmed cases of diffuse gastric cancer (DGC) diagnosed before age 50
  2. 3 or more cases of DGC in first- or second-degree relatives, diagnosed at any age 
  3. An individual with DGC, diagnosed before age 40
  4. A personal or family history of DGC LBC, with at least one case diagnosed before age 50

The penetrance of CDH1 mutations is incomplete, yet relatively high. A study estimated the cumulative risk of DGC for CDH1 mutation carriers by age 80 years to be 70% for men and 56% for women.7 The average age of onset of HDGC is 38 years. Those with HDGC typically present with diffuse-type, signet ring cell gastric cancer, a poorly differentiated adenocarcinoma that infiltrates the stomach lining and causes thickening called linitis plastica. Women carrying CDH1 mutations are also estimated to have a 42% lifetime risk of developing lobular breast cancer.8

Testing Benefits & Indication 

Genetic testing is useful to confirm a diagnosis of HDGC in symptomatic individuals, and for testing of at-risk asymptomatic family members.  Since the diffuse type of gastric cancer associated with HDGC is difficult to detect by traditional screening measures (such as upper endoscopy), many cases of diffuse gastric cancer are not diagnosed until late stages (III or IV). Genetic testing may help to identify those at risk and offer early intervention measures for these individuals to significantly reduce their risk, such as upper endoscopy with biopsy, prophylactic gastrectomy, and high-risk breast cancer screening.

Indications for CDH1 testing include the above clinical diagnostic criteria. As well, clinical practice guidelines recommend the following criteria for consideration of genetic testing:9

  1. Bilateral LBC, or a family history of 2 or more cases of LBC diagnosed before 50
  2. A personal or family history of cleft lip/palate in a patient with DGC  
  3. In situ signet ring cells and/or pagetoid spread of signet ring cells on pathology
Test Description 

CDH1 coding exons 1-16 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-16. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.10  Gross deletion/duplication analysis of CDH1 using multiplex ligation-dependent probe amplification (MLPA) is also performed.

Mutation Detection Rate 

Ambry’s CDH1 testing is capable of detecting greater than 99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
4726 CDH1 Gene sequence and deletion/duplication analyses     10-21 
4722 CDH1 Specific site analysis 7-14 

 

Specialty 
Genes 
CDH1
References 
  1. International Agency for Research on Cancer (World Health Organization). GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. “Stomach Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012” fact sheet. Available from: http://globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp (Accessed July 15, 2015)
  2. Oliveira C, et al. Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC). Eur J Hum Genet. 2013; 21(8).
  3. Schrader KA, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008; 7:73-82.
  4. Masciari S, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007; 44:726-731.
  5. Xie ZM, et al. Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer. 2011; 117(14):3112-7.
  6. Frebourg T, et al. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet. 2006. 43:138–42.
  7. Fitzgerald RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010; 47:436-444.
  8. Hansford, S. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015; 1:23-32.
  9. van der Post RS, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015; 52:361-374.
  10. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.