Hereditary gastric cancer caused by germline CDH1 gene mutations in the Netherlands.
Irma KluijtEster SiemerinkM.G.E.M. AusemsM. J. L. LigtenbergDebora de JongRolf H. SijmonsJohn Theodorus PlukkerRichard van HillegersbergAnnemieke CatsNicoline Hoogerbrugge
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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.Keywords:
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The International Gastric Cancer Linkage Consortium (IGCLC) predicted that up to 25% of families fulfilling the criteria for hereditary diffuse gastric cancer (HDGC) would harbor CDH1 germline mutations. This was based on observations from the low number of diffuse gastric cancer families described at the time, and its validation would require analysis of larger numbers. Here we report the results of germline CDH1 mutation screening in 39 kindred with familial aggregation of gastric cancer, a subset of which fulfills the criteria defined by the IGCLC for HDGC. CDH1 germline mutations were detected in four of 11 (36.4%) HDGC families. No mutations were identified in 63.6% of HDGC families or in kindred with familial aggregation of gastric cancer not fulfilling criteria for HDGC. These results add support to the evidence that only HDGC families harbor germline mutations in CDH1 and that genes other than CDH1 remain to be identified. Hum Mutat 19:510–517, 2002. © 2002 Wiley-Liss, Inc.
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Hereditary diffuse gastric cancer (HDGC) is an autosomal dominate cancer syndrome that leads to an increased risk of developing invasive diffuse type (signet ring cell) gastric carcinoma. Approximately 30% of HDGC cases are caused by a germline mutation involving the E-cadherin (CDH1) gene. Those with the CDH1 mutation have an 80% and 60% cumulative lifetime risk of developing diffuse type gastric carcinoma and lobular breast carcinoma respectively. Due to the focal nature of early diffuse type gastric carcinoma, identifying early lesions with surveillance endoscopy is limited. As a result, elective risk-reducing total gastrectomy is currently recommended. In this report, the clinical, intraoperative, and pathologic work-up is reviewed regarding a patient with known CDH1 germline mutation.
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