A Frameshift Mutation of the Pro-Apoptotic VDAC1 Gene in Cancers with Microsatellite Instability

Dear editor, Apoptosis is a fundamental biochemical cell-death pathway that plays important roles in various physiological and pathological processes during fetal development and in adult tissues. In the intrinsic pathway, a number of death stimuli engage the apoptotic machinery by causing release of cytochrome c from mitochondria, which in turn induces recruitment of caspase-9 into an apoptosome. Activated caspase-9 initiates a proteolytic cascade by activating effector caspases that cleave key molecules to induce apoptosis. As inactivation of pro-apoptotic genes through genetic alterations have been reported in many cancers, they are considered tumor suppressor genes. Voltage-dependent anion channel 1 (VDAC1) is located in the outer mitochondrial membrane (OMM), and is involved in controlling metabolic cross-talk between mitochondria and the cytosol. In addition, VDAC1 plays a key role during intrinsic apoptosis. VDAC1 constitutes an OMM channel that mediates the release of a number of apoptogenic molecules, including cytochrome c, second mitochondria-derived activator of caspase (Smac), HTRA serine peptidase 2 (HTRA2), apoptosis-inducing factor (AIF), and endonuclease G (EndoG) from mitochondria to the cytosol by OMM permeabilization. VDAC1-deficient mitochondria from a mutant cell did not exhibit a Bax/Bak-induced loss in membrane potential of OMM and in cytochrome c release. Since VDAC1 plays an important role in apoptosis signaling, it could be hypothesized that VDAC1 gene is inactivated through somatic mutation in human cancers. To date, however, the data on the mutation status of VDAC1 in human cancers is lacking. By analyzing the public database (http://genome.cse.ucsc. edu/), we found an A8 repeat in exon 6 of VDAC1 gene (nucleotides 325-332) that had not been analyzed for mutations in cancers. Microsatellite instability (MSI) is defined by