CDH1-related hereditary diffuse gastric cancer syndrome: Clinical variations and implications for counseling

• Published in: International journal of cancer Vol. 131; no. 2; pp. 367 - 376
• Main Authors: Kluijt, Irma, Siemerink, Ester J.M., Ausems, Margreet G.E.M., van Os, Theo A.M., de Jong, Daphne, Simões-Correia, Joana, van Krieken, J. Han, Ligtenberg, Marjolijn J., Figueiredo, Joana, van Riel, Els, Sijmons, Rolf H., Plukker, John T.M., van Hillegersberg, Richard, Dekker, Evelien, Oliveira, Carla, Cats, Annemieke, Hoogerbrugge, Nicoline
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.07.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Cadherins - genetics; Cancer; CDH1; Cleft Lip - genetics; Cleft Palate - genetics; clefts; Female; Gastrectomy; Gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Counseling; Genetic Variation; hereditary diffuse gastric cancer; Heterozygote; Humans; lobular breast cancer; Male; Mastectomy; Medical research; Medical sciences; Middle Aged; Mutation; Mutation, Missense; Neoplastic Syndromes, Hereditary - genetics; prophylactic gastrectomy; Stomach Neoplasms - diagnosis; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Young Adult; prophylactic gastrectomy; hereditary diffuse gastric cancer; Stomatology; Congenital cleft; lobular breast cancer; Malignant tumor; Clinical counseling; Gastrectomy; Hereditary; Congenital disease; Stomach cancer; Breast lobular carcinoma; Prevention; Mammary gland diseases; Cancerology; Treatment; Malformation; CDH1; Surgery; clefts; Digestive diseases; E Cadherin; Cancer; Gastric disease
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26398

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.