CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer

Abstract

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.

FIGURE 1. Family pedigree showing autosomal dominant inheritance of gastric cancer (GC). Individual mutation testing results for the codon 1003 CDH1 mutation are indicated by a + or −. Individuals affected with GC are shaded. The 6 who underwent prophylactic gastrectomy on the current study are numbered 1 to 6. Five other individuals who have had prophylactic gastrectomies are labeled a to e. Individual c had the procedure prior to the availability of genetic testing but was ultimately found not to have inherited a CDH1 mutation.

FIGURE 2. The mutation in this kindred is located in the central region of the E-cadherin gene that codes for the extracellular cadherin domains of the protein that contain calcium binding motifs important in the adhesion process. The C->T transition in exon 7 of nucleotide 1003 resulted in a premature stop codon (R335X), thereby producing truncated peptides lacking the transmembrane and cytoplasmic β-catenin binding domains essential for tight cell-cell adhesion. Black area indicates truncated portion of peptide. N, N-terminus; C, C-terminus; S, signal peptide; PRE, precursor sequence; TM, transmembrane domain; CP, cytoplasmic domain.

FIGURE 3. Invasive signet-ring cell carcinoma in prophylactic total gastrectomy specimens from 6 patients with hereditary diffuse gastric cancer and CDH1 E-cadherin gene mutations. A–F, Individual foci of signet-ring cell carcinoma in patients 1 to 6, respectively, from pedigree depicted in Figure 1. Cancers were multifocal, predominantly superficial, and confined to the submucosa in all cases (hematoxylin and eosin stain).

FIGURE 4. Invasive signet-ring cell carcinoma from patient 6 exhibits loss of E-cadherin (clone 4A2C7, Zymed, 1:320) protein expression (arrows), whereas the intact normal glands exhibit uniform expression of the adhesion protein (immunoperoxidase stain).