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

Abstract

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 normalappearing 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.

Mitochondrial DNA Mutations in Pancreatic Cancer

“…This is not entirely unexpected, as nuclear gene alterations (e.g., KRAS2 gene mutations) can be observed in nonneoplastic settings (e.g., chronic pancreatitis) [23], and analogous "field defects" in nonneoplastic tissues are well established in the setting of other solid cancers [19,20]. We and others have previously identified mtDNA mutations in preneoplastic lesions [7,[24][25][26], and the compendium of these findings suggests that mtDNA alterations are an early genetic event in the multistep progression of human cancers. Whether these mutations represent an "innocent bystander" effect of high cell turnover and ROS generation or actively contribute to the process of carcinogenesis remains a contentious issue [4,27,28].…”

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

“…1).The D310 area has been recently identified as a frequent hot spot of deletion/insertion mutation in some disorders such as tumors [42,43]. This polymorphic cstretch (CCCCCCCTCCCCC) is involved in the formation of the persistent RNA-DNA hybrid which is essential for the mtDNA heavy strand replication [44].…”

Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis

“…Several molecular abnormalities, including allelic losses at TSG loci (7) and mitochondrial DNA mutations (49), have been demonstrated in a subset (up to 25%) of CC specimens, suggesting that they harbor clones of epithelial cells with malignant potential. Recently, House et al (13) detected gene promoter methylation in three (P16 INK4A , 10%; hMLH1, 10%; MGMT, 15%) of six genes examined in formalin-fixed, paraffin-embedded CC specimens.…”