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.

Abstract

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. 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. 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). 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.