Hereditary diffuse gastric cancer

HDGC

• An inherited form of diffuse-type gastric cancer

Genetics

• Autosomal dominant
• High penetrance
• Germline variant in either of two genes
  • CDH1 (codes for cadherin 1 or e-cadherin/epithelial cadherin)
    • Located 16q22.1
    • Wide range of pathogenic variants (about 2800 found so far)
    • E-cadherin is a tumour suppressor gene because it normally helps with cell adhesion - when lost, cells move around and metastasise more freely - somatic second hit is required
  • CTNNA1
    • Codes for alpha catenin which assists with E-cadherin-mediated cell-cell adhesion

Diagnosis

• Presence of a pathologic germline variant in either CDH1 or CTNNA1
• Either an isolated individual or in a family with one or more cases
• Criteria for genetic testing - consensus guidelines from the International Gastric Cancer Linkage Consortium (IGCLC)
  • Family criteria - any of
    • Two or more gastric cancer cases in a family regardless of age, at least one confirmed DGC
    • One or more cases of DGC at any age, and one or more cases of lobular breast cancer at age <70 years, in different family members
    • Two or more cases of lobular breast cancer in family members <50yo
  • Individual criteria (any of)
    • DGC <50yo
    • DGC at any age in Maori people
    • DGC at any age in an individual with a personal or family history (first-degree relative) of cleft lip/palate
    • Personal history of DGC and lobular breast cancer, both diagnosed <70yo
    • Bilateral lobular breast cancer diagnosed at age <70yo
    • Gastric in situ signet ring cells or pagetoid spread of signet ring cells on a gastric biopsy in individuals <50yo
  • Testing can occur 16-18yo, but taking into account the age of earliest cancer in the family

Risks

• Gastric cancer
  • Risk 37-42% in men and 25-33% in women by age 80
  • Varies depending on exact variant
  • Average age of onset 38 years (range 14-82)
  • Tumours are often multifocal and located beneath an intact mucosal surface
  • Typically results in abundant intracellular mucin, pushing the nucleus aside in a typical signet ring phenotype
• Breast cancer
  • Lobular type
  • 42% lifelong risk for women
  • Risk starting around age 30
• Some other cancers described, but no evidence of particularly increased risk

Screening (until prophylactic surgery)

• Annual gastroscopy at a minimum (counsel as to inadequacy of gastroscopy/biopsies for surveillance)
  • PET scan not useful for screening
• Annual breast surveillance - MRI starting age 30

Surgery

• Prophylactic gastrectomy
  • Prophylactic total gastrectomy by a surgeon experienced with HDGC, from age 20-30
    • Distal margin 1cm beyond pylorus with frozen section to confirm squamous mucosa
    • Conservative harvest of peri-gastric nodal tissue along greater and lesser curvatures, but preserve omentum
    • D2 not necessary
    • Reconstruction is not standardised - often Roux-en-Y
  • Recommended for any person with confirmed disease
  • Appropriate age 20yo, or five years younger than earliest cancer in the family
  • May choose to delay for various personal reasons, in which case counsel the patient and continue screening
• Prophylactic mastectomy