A critical reassessment of the role of mitochondria in tumorigenesis

Abstract

Background: Mitochondrial DNA (mtDNA) is being analyzed by an increasing number of laboratories in order to investigate its potential role as an active marker of tumorigenesis in various types of cancer. Here we question the conclusions drawn in most of these investigations, especially those published in high-rank cancer research journals, under the evidence that a significant number of these medical mtDNA studies are based on obviously flawed sequencing results.

Methods and findings: In our analyses, we take a phylogenetic approach and employ thorough database searches, which together have proven successful for detecting erroneous sequences in the fields of human population genetics and forensics. Apart from conceptual problems concerning the interpretation of mtDNA variation in tumorigenesis, in most cases, blocks of seemingly somatic mutations clearly point to contamination or sample mix-up and, therefore, have nothing to do with tumorigenesis.

Conclusion: The role of mitochondria in tumorigenesis remains unclarified. Our findings of laboratory errors in many contributions would represent only the tip of the iceberg since most published studies do not provide the raw sequence data for inspection, thus hindering a posteriori evaluation of the results. There is no precedent for such a concatenation of errors and misconceptions affecting a whole subfield of medical research.

Figure 1. Portion of the Worldwide mtDNA Phylogeny That Explains the Most Relevant Contamination/Sample Mix-Up Episodes Erroneously Interpreted as mtDNA Instabilities in Several Kinds of Tumors or Detected as Germline Mutations, as Commented in the Text

Capital letter-number codes designate haplogroups; bold bars indicate intermediate branching points as inferred from the total mtDNA phylogeny. Variation at position 16519, length polymorphisms of long C-stretches in HVS-I and II, and dinucleotide repeats at 522–523 are disregarded. All mutations are transitions except for those suffixed by A, G, C, or T (transversion) or del (deletion) or + (insertion of the specified nucleotide). Parallel mutations are underlined. Somatic (red squares) and germline (pink circles) mutations are indicated on the left side of each position in the tree as they appear in their original studies.