Facile Detection of Mitochondrial DNA Mutations in Tumors and Bodily Fluids

Abstract

Examination of human bladder, head and neck, and lung primary tumors revealed a high frequency of mitochondrial DNA (mtDNA) mutations. The majority of these somatic mutations were homoplasmic in nature, indicating that the mutant mtDNA became dominant in tumor cells. The mutated mtDNA was readily detectable in paired bodily fluids from each type of cancer and was 19 to 220 times as abundant as mutated nuclear p53 DNA. By virtue of their clonal nature and high copy number, mitochondrial mutations may provide a powerful molecular marker for noninvasive detection of cancer.

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

“…In the present study, which is the largest series of HNSCC analysed for mtDNA mutations in the literature, we report a 21% frequency of D-Loop somatic mutations. This frequency is similar to that obtained by Fliss et al (2000) who performed a sequence analysis of 80% of the mitochondrial genome and found a D-Loop mutation in three of 13 (23%) HNSCC patients. However, other studies on small series of patients reported more frequent D-Loop mutations, ranging from 37 to 61% Ha et al, 2002;Poetsch et al, 2004) of the cases.…”

“…We showed that tumours located in the hypopharynx (24.8% of all tumours) were significantly more mutated than tumours in other sites. Proportion of hypopharynx tumours is not known in the other studies (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Poetsch et al, 2004). So, we can speculate that a higher proportion of tumours located in the hypopharynx would be associated with a higher frequency of mtDNA mutation.…”

“…It is also composed of a 1.2 kb noncoding region, the Displacement-Loop (D-Loop), which contains essential transcription and replication elements. Owing to a particular susceptibility to oxidative damage due to high levels of reactive oxygen species (ROS) generation in mitochondria, inefficient DNA repair system and a lack of protective histones in this organelle, mutation rate has been reported to be 10 -17-fold higher in the mtDNA than in the nDNA (Fliss et al, 2000). Mitochondria has long been suspected to be involved in carcinogenesis (Warburg, 1956).…”

“…Its role in apoptosis supports this hypothesis (Zamzami and Kroemer, 2001) and it was shown that mtDNA mutations may lead to a dysregulation of oxidative phosphorylation that can enhance production of the carcinogenic ROS. Over last years, somatic mtDNA mutations have been reported in many human tumours (Polyak et al, 1998;Maximo et al, 2000;Richard et al, 2000;Yeh et al, 2000;Hibi et al, 2001b;Sanchez-Cespedes et al, 2001;Kirches et al, 2001;Liu et al, 2001;Lievre et al, 2005), including head and neck squamous cell carcinoma (HNSCC) that were found mutated in small series in 37 -77% of the cases (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004). Although mutations may occur throughout the mitochondrial genome, the vast majority of them have been described in the noncoding region of the D-Loop and particularly in a mononucleotide repeat named D310 (C-tract, nucleotide position: 303 -315) that has emerged as a mutational hotspot in HNSCC (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004).…”

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma

“…Recently, somatic mutations in the mitochondrial DNA (mtDNA) have been identified in various human cancers such as colon cancer, gastric cancer and HCC (Polyak et al, 1998;Fliss et al, 2000;Nishikawa et al, 2001;Sanchez-Cespedes et al, 2001). Human mtDNA is a 16.5-kb circular double-stranded DNA molecule, which contains genes coding for 13 polypeptides involved in respiration and oxidative phosphorylation, two rRNAs and a set of 22 tRNAs that are essential for protein synthesis in mitochondria (Anderson et al, 1981).…”