Associated disorders

The CDH1 gene is associated with autosomal dominant hereditary diffuse gastric cancer (HDGC) syndrome (MedGen UID: 310839) and lobular breast cancer.

The CHD1 gene encodes the protein E-cadherin, a protein embedded in the cell membrane that contributes to cell-cell adhesion, primarily in epithelial cells. Loss of E-cadherin function due to pathogenic variants in CDH1 impairs the ability of epithelial cells to adhere to each other and predisposes them to become metastatic and invade other tissues during cancer progression. The lack of cell-cell adhesion contributes to the diffuse nature of the resulting adenocarcinoma.

CDH1 heterozygote
MedGen UID: 310839

Clinical condition
Hereditary diffuse gastric cancer (HDGC) syndrome is an adult-onset hereditary cancer predisposition syndrome characterized by an increased risk of gastric cancer and lobular breast cancer.

Diffuse gastric cancer is a type of adenocarcinoma that infiltrates and thickens the stomach wall without forming a distinct tumor mass. Signet ring cells are often observed throughout the stomach wall. Symptoms typically present in advanced disease and can include stomach pain, nausea, vomiting, difficulty swallowing, decreased appetite, and weight loss. The risk of gastric cancer is 56–83% for women and 67–80% for men (PMID: 11729114 20591882 25979631 ). Women with HDGC have a 39–52% chance of developing lobular breast cancer, with the average age at diagnosis of 53 years (PMID: 17545690 11729114 25979631 ). Evidence suggests that orofacial clefts may also be a feature of HDGC (PMID: 23124477 ). Additionally, there are data suggesting an increased risk of colorectal cancer associated with HDGC, though these data are limited and emerging (PMID: 26182300 10072428 25979631 ). An individual with a CDH1 pathogenic variant will not necessarily develop cancer in his/her lifetime, but the risk for cancer is increased over the general population risk.

Gene information
CDH1 is a tumor-suppressor gene that provides instructions for making epithelial cadherin, or E-cadherin. This protein is found within the membranes surrounding epithelial cells. E-cadherin belongs to a family of proteins called cadherins that play a role in cell adhesion, signal transduction, controlling cell maturation and movement, and regulating the activity of certain genes ( Genetics Home Reference. CDH1. Accessed October 2015 UniProt consortium, UniprotKB – P12830 ).

Hereditary diffuse gastric cancer (HDGC) syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant in CDH1 has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in CDH1 has a 50% risk of passing that variant on to offspring.

Management guidelines for individuals with HDGC have been developed (PMID: 20591882 20301318 National Comprehensive Cancer Network. Genetic/Familial High Risk Assessment: Breast and Ovarian. Version 2.2015. National Comprehensive Cancer Network. Gastric Cancer. Version 3.2015 ). Those who have HDGC due to a pathogenic variant in CDH1 are advised to pursue total gastrectomy due to the high mortality rate of gastric cancer and the low rate of detection by endoscopic screening. Careful pathologic examination and sampling should occur (PMID: 25979631 ). Baseline endoscopy is recommended prior to gastrectomy to assess for the presence of macroscopic tumor foci or other factors that may lead to a more complex surgery.

Multidisciplinary care should be incorporated pre- and post-surgery and should include the gastroenterologist, surgeon, pathologists, and nutritionists. The individual’s physical and psychological fitness, as well as age, nutrition, lifestyle, and family support, must be considered along with an assessment of the emotional effects a total gastrectomy will have.

Annual endoscopy is proposed for those with HDGC who do not opt for prophylactic gastrectomy or for whom gastrectomy has been deferred. Endoscopic screening including a detailed, 30-minute endoscopic examination of the gastric mucosa with multiple random biopsies and biopsies of subtle lesions is recommended at six- to twelve-month intervals (PMID: 10593993 ). Screening should begin five to ten years earlier than the earliest age of diagnosis in the family. Also, it is recommended that this procedure be performed at a center that has experience with HDGC. Microscopic tumor foci have been detected on most prophylactic gastrectomy pathology in those with HDGC who have recently undergone endoscopic screening, highlighting the limitations of endoscopic screening in these high-risk individuals (PMID: 17522512 20301318 ). Affected individuals should be counseled of the high risks of mortality from delaying prophylactic gastrectomy (PMID: 24472763 ).

Because lobular breast cancer is often difficult to diagnose on clinical examination and mammography, MRI should be considered because it appears to be more sensitive than mammography. The National Comprehensive Cancer Network recommends annual breast MRI screening for women with a pathogenic variant in CDH1. It has been suggested that breast MRI screening begin either by age 35 years or by five to ten years prior to the youngest age of breast cancer diagnosis in the family (PMID: 20591882 20301318). Discussion of risk-reducing mastectomy is also recommended (PMID: 20301318 NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian. Version 2.2015 ).

Although there is currently no conclusive evidence that risk for colon cancer is elevated in those with HDGC, it has been suggested that colonoscopy screening be considered every 3 to 5 years, starting either at age 40 years or 10 years prior to the earliest age of diagnosis of colon cancer in the family (PMID: 20591882 ).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic CDH1 variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding CDH1 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Reference date: October 2015

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CDH1 NM_004360.3