MtDNA mutation pattern in tumors and human evolution are shaped by similar selective constraints

Abstract

Multiple human mutational landscapes of normal and cancer conditions are currently available. However, while the unique mutational patterns of tumors have been extensively studied, little attention has been paid to similarities between malignant and normal conditions. Here we compared the pattern of mutations in the mitochondrial genomes (mtDNAs) of cancer (98 sequences) and natural populations (2400 sequences). De novo mtDNA mutations in cancer preferentially colocalized with ancient variants in human phylogeny. A significant portion of the cancer mutations was organized in recurrent combinations (COMs), reaching a length of seven mutations, which also colocalized with ancient variants. Thus, by analyzing similarities rather than differences in patterns of mtDNA mutations in tumor and human evolution, we discovered evidence for similar selective constraints, suggesting a functional potential for these mutations.

Figure 1.

mtDNA positions harboring de novo cancer mutations preferentially occur in deep branches of human phylogenetic tree. Using maximum parsimony to assign mutations to branches of the human mtDNA phylogenetic tree, a maximal depth of fixation (MDF) value was calculated for 3328 mtDNA positions that vary in a compendium of coding region sequences (for description of the compendium, see text). The distributions of MDF values were compared to reported mutations in cancer data sets (A) and to noncancer positions, i.e., positions that were mutated only in the human compendium (B). To control for difference in the variability levels of the two types of positions, a sample of noncancer positions was used, sampled such that their variability levels precisely matched the variability level of the cancer positions. For estimating the statistical significant of the bias toward higher MDF values in cancer positions compared with noncancer positions (\, {\bar p}), the P-value estimate from a one-sided Mann-Whitney U-test was averaged over 1000 independently generated variability matched samples. To ensure the repeated sampling is meaningful, highly variable positions (assigned to 13 or more inner nodes) were ignored, since these could not be matched between the cancer and noncancer sets.

Figure 2.

Recurrent tumor-related mutation combinations of HNSCC and pancreatic tumors. Tumor-related mutations reported in HNSCC (Zhou et al. 2007) and pancreatic cancer patients (Kassauei et al. 2006) were scanned for COMs, defined as recurrent mutation of at least two positions in two different patients. (A) Mutations involved in the COMs. For each tumor (left column), the cancer type and patient identifier are provided as shown in the above-mentioned references. Nucleotide positions of mutations are according to the revised Cambridge reference sequence (GenBank AC_000021.2). Heteroplasmic mutations are marked with an asterisk (*). (B) A proposed naming convention for COMs. Overlapping COMs are considered to be part of a larger COM group, designated using Greek letters (α, β, γ, δ). In particular, COMs that belong to a certain group are named using a Greek letter in combination with a number.