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Page 2 of 12 Herrera et al. J Cancer Metastasis Treat 2018;4:42 I http://dx.doi.org/10.20517/2394-4722.2018.35

suggest an important connection between mitochondria heterogeneity and genomic heterogeneity that has
key implications for our understanding of cancer development.

GENOMIC INSTABILITY IN CANCERS
Genomic instability has long been associated with cancer development and can range from single point
[4]
mutations to massive genomic rearrangements (e.g., chromothripsis) . Parallel genome sequencing studies
[7,8]
[5,6]
of cancer cells have revealed a wide variety of mutations and chromosomal abnormalities existent in cancer
genomes: studies looking at mutations identified averages of 47-84 non-silent clonal mutations per tumor .
[9]
Studies focusing on clonal somatic chromosomal rearrangements have uncovered similar variation, from cancer
cells containing a single chromosomal rearrangement per cell to cells with > 200 rearrangements, including
deletions, duplications, and inversions [10,11] . Similarly, studies looking at gene copy number abnormalities
identified a mean of 209 somatic copy number abnormalities per cancer genome . A common finding
[12]
throughout these studies is the great heterogeneity in the type of genomic instability as well as in the identity
of the genes affected, with only a small number of genes found to be commonly affected in multiple cancers.

The complexity of genomic heterogeneity in cancer is further expanded when we consider that these
differences are not limited to differences among clonal populations of cancer cells (inter-tumoral
heterogeneity). Sequencing of different regions within a tumor reveals equally staggering intra-tumor
genomic heterogeneity [13-17] , which is dynamic over time [18-22] . Taken together, these results are consistent
with models of rapid genomic evolution within tumors and intra-tumoral genomic heterogeneity increasing
over time, correlating with tumor aggressiveness and decreased patient survival [23,24] .

Genomic instability can be initiated by exogenous or endogenous agents. The role of external genotoxic
agents (e.g., UV-light, x-rays, chemical mutagens) in inducing genomic changes has been extensively reviewed
elsewhere [25-28] . Endogenous causes of genomic instability include errors in DNA replication , transcription-
[29]
induced stress , spontaneous or activation-induced cytosine deamination , transposon mobilization ,
[31]
[30]
[32]
and defective or error-prone DNA repair , among other factors. Another important and widely studied
[33]
source of genomic instability is DNA damage induced by the reactive oxygen species (ROS) produced
in the mitochondria during the respiration process. ROS function in the cell as signaling molecules that
regulate multiple cellular pathways and are key for cell and organism homeostasis . However, ROS can also
[34]
generate direct DNA damage by oxidation of DNA bases [35,36] . Importantly, the complex relationship between
mitochondria function and nuclear processes extends beyond the role of ROS.

MITOCHONDRIA HETEROGENEITY IN CANCER
In addition to their role as the bioenergetics center of the cell, mitochondria are central to a myriad of cellular
functions including iron and calcium homeostasis , metabolism of amino acids, lipids, nucleotides
[37]
[38]
and carbohydrates, apoptosis, and a variety of signaling pathways [38-42] . Dysfunctions in many of these
mitochondrial processes have been associated with cancer development [40,42] and chemoresistance .
[43]
Similar to nuclear genomic heterogeneity, metabolic heterogeneity is also widespread in tumors. The initial
findings by Otto Warburg of metabolic changes in cancer cells have been confirmed at multiple levels, from
in vitro cancer cell models to in situ tumors in patients right before surgery [44,45] . Similar to the observations
in genomic heterogeneity, these studies have revealed metabolic heterogeneity within different sections of
the tumor indicating that metabolic heterogeneity exists between tumors (inter-tumoral), within the
[44]
tumor (intra-tumoral) and most likely also varies dynamically over time.

At the genetic level, comparisons using full genome sequencing in patient-derived pairs of cancer and normal
tissues across multiple tumor types revealed the existence of somatic mtDNA mutations in a majority of