TP53 Abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma§

Abstract

Background: Gallbladder carcinoma (GBC) is a frequent neoplasm in Hispanic and native American populations. GBC is preceded by gallstones, chronic cholecystitis and dysplastic changes of the gallbladder epithelium. The knowledge of the molecular events involved in its pathogenesis is scarce. Aims: We investigated the role of TP53 inactivation in the sequential pathogenesis of GBC. Methods: Invasive tumor-, dysplastic-and histologically normal GB epithelial-cells were obtained from archival formalin-fixed tissues from GBC and GB from gallstone patients without GBC. Normal GB epithelia from 5 non-gallstone specimens were also studied. DNA extracted was examined for loss of heterozygosity (LOH) using 2 microsatellite markers and for TP53 mutations at exons 5 to 8. Results: GBCs demonstrated a high frequency of LOH (81%) and mutation (67%), and both abnormalities indicating gene inactivation were detected in 52%. Similar frequency of TP53 abnormalities and gene inactivation (38%) were detected in their accompanying normal and dysplastic epithelia. Noteworthy, one third of normal and dysplastic epithelia obtained from GBs of gallstone patients without GBC demonstrated either TP53 allele loss or mutation, but gene inactivation was less frequent (11%). Most mutations affected exons 5 and 7, and they were more frequently missense point mutations. The same TP53 mutation was detected in only a subset (27%) of comparisons between non-malignant epithelia adjacent to GBCs, indicating that TP53 mutation occurs independently at several epithelial foci. Conclusions: These findings indicate that TP53 abnormalities are early and frequent events in the pathogenesis of GBC, starting from chronic cholecystitis.

Keywords

• Mutations
• loss of heterozygosity
• microdissection
• preneoplastic lesions
• gallbladder