Genetic Testing for Linitis Plastica
Yes, patients with linitis plastica (diffuse gastric cancer) should be offered germline genetic testing starting with CDH1 analysis, and if negative, broader hereditary cancer panel testing should be considered based on updated clinical criteria.
Primary Recommendation: CDH1 Testing
Linitis plastica represents the diffuse histologic subtype of gastric cancer, which is the hallmark presentation of Hereditary Diffuse Gastric Cancer (HDGC) syndrome. All patients diagnosed with linitis plastica under age 50 should undergo CDH1 genetic testing, as the 2020 International Gastric Cancer Linkage Consortium guidelines expanded testing criteria from the previous age cutoff of 40 years 1. This relaxation of age restrictions aims to identify more at-risk individuals while balancing healthcare costs and psychological burden 1.
Key Testing Indications for Linitis Plastica Patients:
- Isolated diffuse gastric cancer diagnosed before age 50 warrants CDH1 testing 1
- Any age with family history of diffuse gastric cancer or lobular breast cancer in first- or second-degree relatives 1
- Multiple signet ring cell carcinoma lesions identified endoscopically or in surgical specimens 1
- Specific ethnic populations: All New Zealand Māori patients with diffuse gastric cancer should undergo CDH1 testing, as approximately 13% carry pathogenic germline variants 1
Technical Requirements for CDH1 Testing
Genetic testing must be performed in certified molecular diagnostic laboratories (CLIA-approved, ISO 15189 accredited, or equivalent) 1. The analysis should include complete sequencing of the entire open reading frame, intron-exon boundaries, AND copy number analysis to detect deletions or duplications, as large deletions account for less than 5% of pathogenic variants 1.
Critical Interpretation Caveat:
Missense variants in CDH1 require extreme caution in interpretation 1. Currently published in vitro or in silico functional assays cannot reliably predict pathogenicity of CDH1 missense variants and should not be used for clinical variant classification 1, 2. To date, the only missense variants classified as pathogenic or likely pathogenic are those proven to affect splicing 2.
Broader Panel Testing After Negative CDH1
If CDH1 testing is negative, CTNNA1 analysis should be considered next, as pathogenic variants in this gene occur in a minority of HDGC families 1.
Additional Genes to Consider:
Beyond CDH1 and CTNNA1, broader hereditary cancer panel testing may identify other relevant variants 1, 3:
- PALB2: Emerging evidence suggests germline pathogenic variants may explain gastric cancer risk in some families, though not confined to diffuse subtype 1, 3
- Other moderate-penetrance genes: ATM, BRCA2, Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2), APC, TP53, STK11, and SDHB have been identified in families meeting HDGC clinical criteria but lacking CDH1 mutations 1, 3
In one study of 144 HDGC probands without CDH1 mutations, candidate mutations were identified in 11% of cases across these broader cancer susceptibility genes 3.
Clinical Implications of Positive Results
For CDH1 Pathogenic Variant Carriers:
- Cumulative gastric cancer risk by age 80: 70% for males, 56% for females 3
- Prophylactic total gastrectomy is strongly recommended starting at age 20 years for any pathogenic or likely pathogenic CDH1 variant carrier 1, 4, 5
- For women: 42% cumulative breast cancer risk (specifically lobular breast cancer) by age 80, requiring annual breast MRI surveillance starting at age 30-35 years 3, 5
For Those Declining Prophylactic Surgery:
Endoscopic surveillance with systematic biopsies can be offered in expert centers for patients who wish to postpone surgery, though prophylactic total gastrectomy remains the gold standard recommendation 1, 4, 6.
Important Pitfalls to Avoid
Do not order CDH1 testing for ductal/invasive breast carcinoma of no special type (IC-NST) – CDH1 pathogenic variants are only associated with lobular breast cancer, not ductal or other rare breast cancer types 1. This distinction is critical to avoid unnecessary testing and misinterpretation.
Variants of uncertain significance (VUS) or likely benign variants do not warrant presymptomatic testing in family members 1. Only confirmed pathogenic or likely pathogenic variants (which have 90% likelihood of pathogenicity) should trigger cascade testing 1.
Genetic Counseling Requirements
All patients meeting testing criteria should receive comprehensive genetic counseling that includes 1:
- Three-generation family pedigree evaluation
- Histopathological confirmation of cancer diagnoses
- Discussion of prophylactic surgery risks/benefits and long-term sequelae
- Psychosocial assessment and family communication planning
- Reproductive options including preimplantation genetic testing for variant carriers
Testing should be offered from the legal age of consent (generally 16-18 years) for at-risk family members 1.