CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer.
BACKGROUND
Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer.


METHODS
Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with D-2 node dissection and Roux-en-Y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically.


RESULTS
Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51-57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality.


CONCLUSIONS
CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.
Norton
Jeffrey A
JA
Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94035, USA. janorton@stanford.edu
Ham
Christine M
CM
Van Dam
Jacques
J
Jeffrey
R Brooke
RB
Longacre
Teri A
TA
Huntsman
David G
DG
Chun
Nicki
N
Kurian
Allison W
AW
Ford
James M
JM
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D000713:Anastomosis, Roux-en-Y; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics / Q000517:prevention & control; D015820:Cadherins / Q000235:genetics*; D018279:Carcinoma, Signet Ring Cell / Q000235:genetics / Q000473:pathology / Q000601:surgery; D003952:Diagnostic Imaging; D005260:Female; D005743:Gastrectomy; D005773:Gastroscopy; D006801:Humans; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009780:Occult Blood; D010375:Pedigree; D011322:Primary Prevention; D011446:Prospective Studies; D011788:Quality of Life; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D016896:Treatment Outcome
D015820:Cadherins