Molecular alterations in mitochondrial DNA of hepatocellular carcinomas: is there a correlation with clinicopathological profile?

Molecular defects in the mitochondrial genome responsible for a broad clinical spectrum of maternally inherited neuromuscular mitochondrial disorders have been documented extensively.1,2 Mitochondrial dysfunction causes cellular degeneration, particularly in nerve and muscle cells that have a high demand for energy. The role of the mitochondria in apoptotic pathways, and the identification of tumour suppressing functions of several genes involved in metabolism, suggests that mutant mitochondria are at the crossroads of tumorigenesis and programmed cell death. In recent years, numerous reports on somatic mtDNA mutations in cancers have supported the concept that somatic mtDNA alterations are an integral part of tumorigenesis.3–12 Extensive analysis of the mitochondrial genome with direct sequencing has shown that about 30–70% of all types of tumours harbour alterations in mtDNA.3–13 The laborious effort involved in sequencing the entire mitochondrial genome means that mutational analyses usually have been performed on small numbers of specimens and were limited to only part of the mitochondrial genome. Most of these studies focused on the hypervariable, non-coding Dloop region only.3,8–10,13,14 The only comprehensive mutational analysis that covered the entire mitochondrial genome with overlapping primers was achieved recently with the use of the effective temperature gradient gel electrophoresis method.15–17 Previous reports showed that most of the somatic mtDNA mutations found in patients with cancer were in the homoplasmic form.7,11 This observation led to the conclusion that mutant mitochondria gained a replicative advantage during tumorigenesis and became homoplasmic within a few generations.7 Our recent comprehensive investigation of somatic mtDNA mutations in breast tumours and medulloblastomas showed that mutations in the coding region did occur, as did a significant number of heteroplasmic alterations.4,16 Results from others’ and our own studies of various types of cancers suggest that …