CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling.
ABSTRACT CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20-72 years) and one LBC case. Twenty-nine/37 carriers alive, aged 18-61 years, underwent prophylactic gastrectomy. Invasive GC-foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long-standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.
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ABSTRACT: Hereditary diffuse gastric cancer can be caused by epithelial cadherin mutations for which genetic testing is available. Inherited cancer predisposition syndromes including Lynch, Li-Fraumeni, and Peutz-Jeghers syndromes, can be associated with gastric cancer. Chromosomal and microsatellite instability occur in gastric cancers. Several consistent genetic and molecular alterations including chromosomal instability, microsatellite instability, and epigenetic alterations have been identified in gastric cancers. Biomarkers and molecular profiles are being discovered with potential for diagnostic, prognostic, and treatment guidance implications.Gastroenterology clinics of North America 06/2013; 42(2):241-60. · 2.56 Impact Factor
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ABSTRACT: Prophylactic total gastrectomy is performed in hereditary diffuse gastric cancer (HDGC) patients carrying the CDH1 mutation because endoscopic surveillance often fails to detect microscopic disease. The aim of this study was to determine the natural history and outcomes of patients with HDGC undergoing endoscopy. Prospective, cohort observational study. Tertiary referral center. Patients fulfilling criteria for HDGC who opted to undergo endoscopy. Research surveillance program using high-resolution white-light endoscopy with autofluorescence and narrow-band imaging combined with targeted and multiple random biopsies assessed by an expert histopathologist for the presence of signet ring cell carcinoma. The primary endpoint was the endoscopic yield of microscopic signet ring cell carcinoma according to patient mutation status and subsequent decision to undergo surgery. The secondary endpoint was the additional yield of targeted biopsies compared with random biopsies. Between September 2007 and March 2013, 29 patients from 17 families underwent 70 surveillance endoscopies. Signet ring cell carcinoma foci were identified in 14 of 22 (63.6%) patients with confirmed CDH1 germline mutations and 2 of 7 (28.6%) with no pathogenic mutation identified. Eleven of 16 (9 CDH1-positive) patients proceeded to gastrectomy in a median 5.7 months. Five patients delayed surgery. In 1 patient, advanced gastric cancer developed 40.2 months after the first endoscopic findings. No control group. Careful white-light examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and help to inform decision making with regard to gastrectomy. Autofluorescence and narrow-band imaging are of limited utility. Delaying gastrectomy in individuals with signet ring cell carcinoma foci carries a high risk and has to be weighed carefully.Gastrointestinal endoscopy 01/2014; · 6.71 Impact Factor
- European journal of human genetics: EJHG 02/2013; · 3.56 Impact Factor