CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling.
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.
Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands. i.kluijt@nki.nl
Irma
I
Kluijt
Ester J M
EJ
Siemerink
Margreet G E M
MG
Ausems
Theo A M
TA
van Os
Daphne
D
de Jong
Joana
J
Simões-Correia
J Han
JH
van Krieken
Marjolijn J
MJ
Ligtenberg
Joana
J
Figueiredo
Els
E
van Riel
Rolf H
RH
Sijmons
John T M
JT
Plukker
Richard
R
van Hillegersberg
Evelien
E
Dekker
Carla
C
Oliveira
Annemieke
A
Cats
Nicoline
N
Hoogerbrugge
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics; D002972:Cleft Palate / Q000235:genetics; D005260:Female; D005743:Gastrectomy; D005817:Genetic Counseling; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008408:Mastectomy; D008875:Middle Aged; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins