Mitochondrial DNA Mutation at the D310 (Displacement Loop) Mononucleotide Sequence in the Pathogenesis of Gallbladder Carcinoma

Purpose: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot s...

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Published in:Clinical cancer research 2004-02, Vol.10 (3), p.1041-1046
Main Authors: MOYING TANG, BAEZ, Sergio, PRUYAS, Martha, DIAZ, Alfonso, CALVO, Alfonso, RIQUELME, Erick, WISTUBA, Ignacio I
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Antineoplastic agents
Biological and medical sciences
Carcinoma - genetics
Cholecystitis - genetics
DNA - metabolism
DNA, Mitochondrial - genetics
Female
Gallbladder Neoplasms - genetics
Gene Deletion
Genotype
Humans
Male
Medical sciences
Middle Aged
Mutation
Neoplasms - metabolism
Pharmacology. Drug treatments
Polymerase Chain Reaction
Repetitive Sequences, Nucleic Acid
Tumors
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Summary:Purpose: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC). Experimental Design: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases. Results: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions. Conclusions: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normal-appearing epithelium from chronic cholecystitis. Our findings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-0701-3