Mitochondrial genomic instability in colorectal cancer: No correlation to nuclear microsatellite instability and allelic deletion of hMSH2, hMLH1, and p53 Genes, but prediction of better survival for dukes' stage C disease
Journal
Annals of Surgical Oncology
Journal Volume
16
Journal Issue
10
Pages
2918-2925
Date Issued
2009
Author(s)
Abstract
Purpose. Malfunction of mismatch repair (MMR) system and p53 produces nuclear genomic instability and is involved in colorectal tumorigenesis. In addition to a nuclear genome, eukaryotic cells have cytoplasmic genomes that are compartmentalized in the mitochondria. The aims of this study were to detect the mitochondrial genomic instability (mtGI) in colorectal carcinomas, and to explore its relationship with nuclear genetic alterations and its prognostic meaning. Methods. Eighty-three colorectal carcinomas with corresponding normal mucosa were analyzed for mtGI, nuclear microsatellite instability (nMSI), and loss of heterozygosity (LOH) of hMSH2, hMLH1, and p53 genes. Mitochondrial and nuclear alterations were examined for mutual correlation and for associations with clinicopathological features and clinical outcomes. Results. Out of 83 cases, mtGI was identified in 23 carcinomas (27.7%), whereas nMSI was detected in 11 (13.3%). Of the 23 cases with mtGI, only two showed nMSI simultaneously. The frequencies of LOH of hMSH2, hMLH1, and p53 were 16.1%, 11.6%, and 65.3%, respectively. There was no significant association between mtGI and these allelic losses. Notably, Dukes' C patients with mtGI had better disease-free and overall survival than those lacking this feature (p = 0.0516 and 0.0313, respectively). Conclusions. Mitochondrial genomic instability occurs with a high frequency in colorectal carcinomas but is independent of nMSI and allelic deletion of hMSH2, hMLH1, and p53 genes. The results suggest that, instead of nuclear MMR system, there might be different mechanisms involving mitochondrial genomic integrity, and mtGI confers a better prognosis in Dukes' C colorectal cancer. ? 2009 Society of Surgical Oncology.
SDGs
Other Subjects
protein MLH1; protein MSH2; protein p53; mitochondrial DNA; MLH1 protein, human; MSH2 protein, human; nuclear protein; protein MSH2; protein p53; signal transducing adaptor protein; TP53 protein, human; tumor marker; adult; aged; allele; article; cancer survival; colorectal carcinoma; controlled study; disease association; disease free survival; disease severity; female; gene deletion; gene frequency; genomic instability; heterozygosity loss; human; human tissue; major clinical study; male; microsatellite instability; mitochondrial genome; overall survival; prognosis; cancer staging; cell nucleus; colorectal tumor; follow up; gene deletion; genetics; middle aged; mitochondrion; pathology; survival rate; Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Cell Nucleus; Colorectal Neoplasms; DNA, Mitochondrial; Female; Follow-Up Studies; Humans; Loss of Heterozygosity; Male; Microsatellite Instability; Middle Aged; Mitochondria; MutS Homolog 2 Protein; Neoplasm Staging; Nuclear Proteins; Prognosis; Sequence Deletion; Survival Rate; Tumor Markers, Biological; Tumor Suppressor Protein p53
Type
journal article