Gene test interpretation: Cadherin 1 gene (CDH1)

INTRODUCTION — This monograph summarizes the interpretation of germline testing of the CDH1 gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately [1].

OVERVIEW

How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).

Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).

●Determining the genotype – Identifies variants. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, or comparable accreditation body in other jurisdictions, if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected hereditary diffuse gastric cancer [HDGC] syndrome).

●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of uncertain significance (VUS).

The table provides a glossary of genetic testing terms (table 2).

Disease associations — Pathogenic variants in CDH1 can lead to a number of cancers and congenital abnormalities, collectively referred to as HDGC syndrome, an autosomal dominant disorder. Lobular breast cancer and nonsyndromic cleft lip/palate are also part of the HDGC syndrome. The term hereditary lobular breast cancer (HLBC) has been proposed as the presence of a pathogenic germline CDH1 variant in either an isolated individual with LBC, or a family with one or more LBC cases in first-degree or second-degree relatives, but no known DGC in either situation.

The CDH1 gene encodes E-cadherin, a protein on the cell surface that promotes cell-cell adhesion. CDH1 is a tumor suppressor gene, and therefore a somatic second hit is required in addition to the germline pathogenic variant for initiation of tumor formation. The trigger and molecular mechanisms by which the second allele of CDH1 is inactivated appear to be diverse, and include promoter hypermethylation, mutation, and loss of heterozygosity. The end result is biallelic inactivation and loss of expression of E-cadherin. Of note, another gene associated with HDGC is CTNNA1.

Gastric cancer — HDGC is an inherited form of diffuse-type gastric cancer, a highly invasive tumor that is characterized by young age at diagnosis, late stage at presentation, and a poor prognosis. The lifetime risk of gastric cancer in individuals from affected families is variable, and likely high for families that meet traditional testing criteria for HDGC (cumulative risk of gastric cancer by age 80 years is as high as 70 percent for men and 56 percent for women). More contemporary estimates of the cumulative risk of gastric cancer in carriers of a pathogenic or likely pathogenic variant by age 80 years are 37 to 42 percent for men, and 25 to 33 percent for women [2,3]. These estimates are derived from CDH1 pathogenic and likely pathogenic variant-positive kindreds identified through commercial testing for hereditary cancer risk using multigene panel testing that is unselected for HDGC clinical criteria. Affected patients may develop DGC in their teens or early 20s [4,5]. (See "Hereditary diffuse gastric cancer", section on 'Risk of cancer in carriers of a pathogenic or likely pathogenic CDH1 variant'.)

Breast cancer — Individuals with HDGC syndrome have an increased risk for invasive lobular breast cancer (ILBC), an estrogen and progesterone receptor (ER and PR) positive breast cancer type that is challenging to diagnose because these tumors often do not form a discrete mass nor do they have a classical malignant appearance on mammography. These breast cancers generally have a good prognosis. The cumulative risk by age 80 is approximately 42 to 55 percent [2,3]. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CDH1 (Hereditary diffuse gastric cancer syndrome)' and "Hereditary diffuse gastric cancer", section on 'Breast cancer'.)

Nonsyndromic cleft lip/palate — There are reports of an association between cleft lip/palate and CDH1 pathogenic or likely pathogenic variants in families with HDGC.

Blepharocheilodontic syndrome — Blepharocheilodontic syndrome is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. Rarely, patients may have imperforate anus.

Other associations

●Colon cancer – Although cases of colorectal and appendiceal signet ring cell carcinomas have been reported in carriers of a CDH1 pathogenic or likely pathogenic variant, there is no evidence for a significantly increased risk of colorectal cancer or other cancer types in such individuals [6,7].

IMPLICATIONS OF A PATHOGENIC OR LIKELY PATHOGENIC VARIANT — We consider all individuals with a pathogenic or likely pathogenic variant in CDH1 to be at risk for hereditary diffuse gastric cancer (HDGC) syndrome, regardless of the initial reason for testing.

Discussion should include the range of associated risks, possible interventions for cancer surveillance or risk reduction, and implications for family members. (See 'At-risk relatives' below and "Gene test interpretation: CTNNA1", section on 'At-risk relatives'.)

Counseling may require additional visits or referrals. Acting upon genetic testing results is rarely an emergency; the individual can be reassured that management decisions can be deferred until questions are answered.

We adhere to guidelines by the International Gastric Cancer Linkage Consortium (IGCLC) for cancer surveillance and risk reduction [8]. Findings in family members (type of cancers, age of onset) may also inform surveillance (for example, starting at an earlier age if a family member has an earlier age of onset).

Several evaluations and interventions are recommended to reduce the risk of cancers associated with HDGC syndrome (algorithm 1).

●Gastric cancer

•Risk-reducing (prophylactic) total gastrectomy is recommended in individuals with a germline CDH1 pathogenic or likely pathogenic variant from families with confirmed HDGC syndrome. Prophylactic gastrectomy is generally advised as early as age 20 years or at an age of five years younger than the youngest family member who developed gastric cancer, whichever is earlier. However, the timing of the operation may vary according to the preferences, age, and physical as well as psychological well-being of the individual.

•Individuals with a CDH1 pathogenic or likely pathogenic variant with no significant personal or family history of cancer associated with HDGC syndrome should be referred to specialist centers for consultation about screening and preventive surgery. The magnitude of the cancer risk for patients with CDH1 variants who lack a family history of multiple gastric cancers remains uncertain. At the very least, any individual identified with a CDH1 pathogenic variant who chooses to defer total prophylactic gastrectomy should follow the endoscopy screening protocol.

•Upper endoscopy with biopsies (Cambridge protocol) to screen for gastric cancer may be considered in selected patients. Potential candidates for upper endoscopy include:

-Individuals with a pathogenic or likely pathogenic variant who are identified prior to age 20 years may undergo annual surveillance endoscopy with surgery deferred until after age 20.

-Patients over age 20 years who receive a recommendation for prophylactic gastrectomy, but who decide to postpone (or refuse) the procedure.

•Patients who chose to undergo upper endoscopy to screen for gastric cancer should be informed that there is no reliable endoscopic screening test for the early diagnosis of diffuse gastric cancer. Gastric cancers that arise in patients with HDGC are signet ring cancers that are located beneath an intact surface epithelium and only become visible on direct mucosal evaluation later in the disease process.

•Individuals who carry a pathologic CDH1 mutation who refuse or delay prophylactic gastrectomy should be screened for infection with Helicobacter pylori (H. pylori) and treated if positive.

•Total gastrectomy is indicated in patients with signet ring cell carcinoma on gastric biopsy. Patients with a positive biopsy finding (signet ring cell carcinoma) who still wish to forego total gastrectomy should have endoscopy repeated at six-month intervals.

●Breast cancer – Women are managed similarly to other high-risk breast cancer conditions with annual breast magnetic resonance imaging (MRI; this test can be combined with mammography) starting at age 30. The option of risk-reducing mastectomy should be discussed. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CDH1 (Hereditary diffuse gastric cancer syndrome)'.)

●Additional details and supporting evidence are discussed separately. (See "Hereditary diffuse gastric cancer" and "Surgical management of hereditary diffuse gastric cancer" and "Overview of hereditary breast and ovarian cancer syndromes".)

IMPLICATIONS OF A NEGATIVE TEST — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes (eg, alpha-1-catenin [CTNNA1] gene).

●If a familial CDH1 variant is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for hereditary diffuse gastric cancer (HDGC) syndrome, with caveats outlined above (see 'How to read the report' above and "Gene test interpretation: CTNNA1", section on 'How to read the report'). However, it is important to provide an individualized risk assessment based on family history and other risk factors.

●If a familial CDH1 variant is not known and results of genetic testing are negative, the extent of additional testing depends on the personal and family history. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to guide additional genetic testing based on the personal and family history. Intensive endoscopic screening may be considered in patients who meet HDGC criteria. (See 'Locating an expert' below and "Gene test interpretation: CTNNA1", section on 'Locating an expert'.)

IMPLICATIONS OF A VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history. Annual endoscopic surveillance for gastric cancer is suggested in patients with a CDH1 VUS for at least two years; it should ideally be done as a part of a research study [8]. Women with a CDH1 VUS should receive individualized breast cancer risk assessment and surveillance recommendations (algorithm 1).

New information may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually). (See "Hereditary diffuse gastric cancer", section on 'Surveillance for breast cancer'.)

The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary cancer syndromes may be appropriate.

CONSIDERATIONS FOR FAMILY MEMBERS

Reproductive counseling — Reproductive counseling is appropriate for individuals with a pathogenic or likely pathogenic CDH1 variant who are considering childbearing.

Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)

At-risk relatives — Individuals with a pathogenic variant or likely pathogenic variant in CDH1 should inform their at-risk relatives about the importance of genetic counseling and possible testing.

●The risk of having inherited the variant is 50 percent for first-degree relatives, including siblings and parents; if one parent carries the variant, then the risk to siblings is also 50 percent. Others at risk may include aunts, uncles, nieces, nephews, and cousins.

●Usually, the variant segregates on the side of the family with a history of gastric or breast cancer; however, if possible, it is recommended to test a parent or other relative with cancer.

●Genetic testing for at-risk relatives may be considered as early as 16 to 18 years. Age of cancer onset for relatives may help guide the timing. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications of a pathogenic or likely pathogenic variant' above and "Gene test interpretation: CTNNA1", section on 'Implications of a pathogenic or likely pathogenic variant'.)

RESOURCES

UpToDate topics

●Hereditary diffuse gastric cancer (HDGC) syndrome – (See "Hereditary diffuse gastric cancer" and "Surgical management of hereditary diffuse gastric cancer" and "Overview of hereditary breast and ovarian cancer syndromes", section on 'CDH1 (Hereditary diffuse gastric cancer syndrome)'.)

●Cleft lip/palate – (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate" and "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx" and "Overview of craniofacial clefts and holoprosencephaly".)

●Genetics:

•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)

•Terminology – (See "Genetics: Glossary of terms".)

•Genetic testing – (See "Genetic testing".)

•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

Locating an expert

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●National Institutes of Health (NIH) Cancer Genetics Services Directory