The unsolved enigma of CDH1 down-regulation in hereditary diffuse gastric cancer.
BACKGROUND
Hereditary diffuse gastric cancer (HDGC) is a disease mediated by down-regulation of the tumor suppressor E-cadherin (CDH1). This disease is particularly dangerous because of the youth of the patients, and for clinical management, hampered by the submucosal spread of tumor invisible at endoscopy. Two mechanisms of CDH1 down-regulation have been described in HDGC: missense mutations in the CDH1 gene and gene silencing through promoter methylation.


METHODS
Seven patients affected by HDGC were enrolled. Tumor tissues were checked for CDH1 expression by immunohistochemistry (IHC). CDH1 DNA sequencing was performed for all its 16 exons from tumor and normal tissues of the same patients to detect somatic and germ-line mutations. Methylation promoter study was performed using specific primers and PCR.


RESULTS
IHC analysis confirmed CDH1 down-regulation in all patients. DNA sequencing revealed the presence of six missense mutations in five patients. Four mutations were at the EC-3 domain of CDH1, whereas the other two were found in the cytoplasmic region interacting with catenins. All six mutations were absent in normal tissue, thereby excluding its presence in germ-line cells. Four patients exhibited both DNA missense mutations and gene silencing through promoter methylation. In two patients we did not notice either DNA missense mutations or promoter methylation.


CONCLUSIONS
CDH1 somatic mutations and promoter methylation synergistically induce CDH1 down-regulation in HDGC patients, whereas germ-line mutations are relatively rare. However, other unknown mechanisms of CDH1 suppression are involved to explain CDH1 down-regulation in HDGC patients without CDH1 mutations and promoter methylation.
Laboratory of Antineoplastic Pharmacology, Università Cattolica Sacro Cuore, Rome, Italy.
Paola
P
Concolino
Valerio
V
Papa
Simona
S
Mozzetti
Cristiano
C
Ferlini
Fabio
F
Pacelli
Enrica
E
Martinelli
Riccardo
R
Ricci
Flavia
F
Filippetti
Giovanni
G
Scambia
Giovanni Battista
GB
Doglietto
D015820:Cadherins / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D020125:Mutation, Missense; D010375:Pedigree; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics*
D015820:Cadherins