TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma.
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.


OBJECTIVE
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.
Moreno
Mauricio
M
Department of Gastroenterology, Pontificia Universidad Católica de Chile, P.O.Box 114-D Santiago, Chile.
Pimentel
Fernando
F
Gazdar
Adi F
AF
Wistuba
Ignacio I
II
Miquel
Juan F
JF
D000368:Aged; D000483:Alleles; D002764:Cholecystitis / Q000235:genetics* / Q000473:pathology; D005260:Female; D005704:Gallbladder / Q000473:pathology / Q000502:physiology; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology; D042882:Gallstones / Q000235:genetics / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53