Mutational dynamics in human tumors confirm the neutral intrinsic instability of the mitochondrial D‐loop poly‐cytidine repeat

Abstract Somatic mutations at a mitochondrial noncoding polycytidine (C) n repeat (polyC) have been associated with tumor progression. We analyzed whether these alterations are due to the inherent mutability of repeated sequences. Insertion and deletion mutations were found in colon ( n = 114), stomach ( n = 105), endometrium ( n = 53), breast ( n = 45), lung ( n = 35), and prostate ( n = 20) tumors. The mutation frequency in colon, gastric, and endometrial tumors was 23, 17, and 11%, respectively, which paralleled the relative extent of microsatellite instability in long mononucleotide repeats observed in tumors with mismatch repair deficiency (colon > stomach > endometrium, relative ratio 10:8:4). Colon tumors with mutations of more than one nucleotide were more advanced in tumor progression. Further, two tumors showing a T > C mutation that restored the homopolymeric repeat, harbored sequential deletion mutations of up to 4 and 6 nucleotides. These results illustrate that the increased mutability of repeated mitochondrial sequences is dependent on the repetitive structure of the DNA molecule and suggest that mutations in the (C) n repeat, whether homoplasmic or not, and by extrapolation, mitochondrial mutations in general, are not the result of selective pressure during tumorigenesis. We also suggest that the (C) n repeat may be used as an universal molecular clock to estimate the relative mitotic history of tumors. © 2006 Wiley‐Liss, Inc.