HEREDITARY DIFFUSE GASTRIC CANCER

Hereditary Diffuse Gastric Cancer — CDH1 loss-of-function carrying up to 70% lifetime gastric cancer risk, where the cancer develops beneath the gastric mucosa and is invisible to endoscopy until it is surgically unresectable.

Whole genome sequencing identifies all CDH1 variants — including large deletions and mosaic mutations — to establish the diagnosis that triggers the prophylactic total gastrectomy recommendation before an endoscopically invisible cancer advances.

CDH1

About this condition

Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer predisposition syndrome caused by pathogenic variants in CDH1 (E-cadherin) on chromosome 16q22.1. CDH1 encodes a cell-cell adhesion protein critical for epithelial integrity; its loss-of-function leads to the poorly cohesive, infiltrating growth pattern characteristic of diffuse gastric cancer (signet ring cell carcinoma). HDGC was first defined in 1998 in a large Maori kindred from New Zealand, and remains one of the most lethal hereditary cancer syndromes — lifetime gastric cancer risk in CDH1 pathogenic variant carriers is estimated at 40-70% in males and 45-70% in females. The median age of onset in familial cases is 38 years, but cases have been documented in patients in their 20s.

The clinical challenge of HDGC is that diffuse gastric cancer grows as individual signet ring cells infiltrating the submucosa — a growth pattern that does not form a visible mass and cannot be reliably detected by standard endoscopy. Endoscopic surveillance, even with systematic biopsy protocols, misses the majority of early HDGC lesions. Every total gastrectomy performed prophylactically in CDH1 pathogenic variant carriers reveals occult signet ring cell foci on pathology — meaning that even 'normal' appearing stomachs harbor microscopic cancer in virtually all carriers. This single biological fact drives the recommendation for prophylactic total gastrectomy for CDH1 carriers between ages 18-40, rather than surveillance.

Female CDH1 carriers also face substantially elevated lobular breast cancer risk — estimated at 42-56% lifetime. Lobular breast cancer, like diffuse gastric cancer, grows in an infiltrating single-file pattern that standard mammography may not detect, making breast MRI an essential component of surveillance. CDH1 is included in the ACMG SF v3.2 secondary findings list, reflecting consensus that identifying CDH1 carriers before cancer develops is both clinically actionable and life-saving. Approximately 40% of families meeting clinical HDGC criteria are CDH1-negative; some of these families have variants in CTNNA1 (alpha-E-catenin) or other genes, and a comprehensive genomic approach is indicated.

Gene locus: CDH1 (16q22.1)

Standard hereditary cancer panels miss large CDH1 deletions and mosaic variants. In a syndrome where prophylactic surgery depends on molecular confirmation, an incomplete genetic result has direct surgical consequences.

Large CDH1 deletions account for 10-15% of HDGC and are missed by exon-sequencing panels

Approximately 10-15% of CDH1 pathogenic variants in HDGC families are large genomic deletions spanning one or more exons. Exon-sequencing panels that do not include deletion/duplication analysis by MLPA or copy number variant calling will miss these variants. Additionally, somatic mosaicism — where the CDH1 variant is present in only a fraction of the patient's cells — has been documented in some families and may be missed by standard sequencing depths. Whole genome sequencing provides simultaneous point mutation detection and copy number variant analysis across the entire CDH1 gene, resolving both common intragenic variants and structural rearrangements in a single test.

Prophylactic gastrectomy requires molecular confirmation — a negative panel result is not the same as a true negative

Total gastrectomy is a major surgical procedure with significant long-term quality of life implications. It is recommended in CDH1 carriers because early-stage diffuse gastric cancer is endoscopically invisible and surveillance has failed to prevent deaths in known carrier families. This recommendation is only appropriate when molecular confirmation of a CDH1 pathogenic variant is established. An incomplete panel that did not evaluate large deletions or perform comprehensive CDH1 analysis provides false reassurance to a family where the pathogenic variant may still exist but was simply not detectable by limited testing. Whole genome sequencing removes this ambiguity.

Hereditary Diffuse Gastric Cancer — CDH1 loss-of-function carrying up to 70% lifetime gastric cancer risk, where the cancer develops beneath the gastric mucosa and is invisible to endoscopy until it is surgically unresectable.

Hereditary Diffuse Gastric Cancer

Standard hereditary cancer panels miss large CDH1 deletions and mosaic variants. In a syndrome where prophylactic surgery depends on molecular confirmation, an incomplete genetic result has direct surgical consequences.

Large CDH1 deletions account for 10-15% of HDGC and are missed by exon-sequencing panels

Prophylactic gastrectomy requires molecular confirmation — a negative panel result is not the same as a true negative

Others in Hereditary Cancer

One test. A lifetime of answers.