Hereditary gastric cancer caused by germline CDH1 gene mutations in the Netherlands.

Abstract

4080 Background: Germline mutations in the CDH1 gene lead to the hereditary diffuse gastric cancer syndrome (HDGC), with strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). We report on the geno-/phenotypical data of all Dutch families with germline mutations in the CDH1 gene. Methods: Index patients of families suspect for HDGC were tested for CDH1 mutations in a central molecular genetics laboratory. Of families with CDH1 mutations all cancer data were retrieved. Surgical data of prophylactic gastrectomies were collected. Pathologic investigation was performed according to the Swiss roll technique by expert pathologists. Results: In 6 families 6 different CDH1 mutations were found. Symptomatic GC was diagnosed in 26 individuals. Mean age at diagnosis was 40 years (range 23-65 years), with 3 GCs < 30 years. Of 18 confirmed GCs, 17 were diffuse cancers, one intestinal type. Symptomatic LBC was diagnosed in 1 carrier. Forty out of 79 tested family members carried a CDH1 mutation. Twenty-four of these carriers, aged 18-61 years, underwent prophylactic gastrectomy, in 2/24 combined with prophylactic mastectomy. In 1 patient a small focus of invasive diffuse gastric cancer and an in situ carcinoma were found. Multiple foci of intramucosal cancer and one GIST were diagnosed in 13 other patients. In 8 patients no cancer cells were found. Foci of invasive LBC and multifocal LCIS were found in all mastectomy specimens. Two out of 40 carriers were diagnosed with GC or precursor lesions at gastroscopy before planned gastrectomies. Re-laparotomy was necessary in 3 subjects because of abdominal infection, anastomotic leakage or residual gastric mucosa. Clefts of lip and/or palate were reported in 6 individuals from 3 families (3 proven mutation carriers). Conclusions: The age at onset of GC in our families is highly variably, which has to be included in the counselling on planning prophylactic gastrectomies. A multidisciplinary approach is obligatory in the care for HDGC patients in order to maximize the quality and to minimize the physical impact of prophylactic procedures. Taking a family history should include clefts in gastric cancer families. No significant financial relationships to disclose.