AA. Gastric C I 06. ppt - Università degli studi di Pavia

Model for development of
hereditary diffuse gastric cancer
* gastric mucosa in CDH1 (E - cadherin
gene) germline mutation carriers is
normal until second CDH1 allele is
inactivated or repressed (second hit) by
transcriptional downregulation;
[- promoter hypermethylation is one
mechanism for downregulation
(transcription factor mediated events
also play a role, including environmental
and physiological factors such as diet,
carcinogen exposure, ulceration and
gastritis)];
- since downregulation may occur in
multiple cells, multifocal tumors develop;
- tumor expands slowly until additional genetic events, possibly combined with
an altered microenvironment → clonal expansion and disease progression;
[- because second hit does not involve somatic, irreversible, mutation of second
CDH1 allele, it is possible that early stage lesions is reversible]