Theodore Boveri, eminent German biologist, embryologist and pathologist,
observed aneuploidy in cancer cells more than a century ago and suggested that cancer
cells derived from a single progenitor cell that acquires the potential for uncontrolled
continuous proliferation. Currently, it is well known that aneuploidy is observed in
virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is
considered a process of diversification that leads to survival of the fittest clones.
According to Darwin’s theory of evolution, the environment determines the grounds
upon which selection takes place and the genetic characteristics necessary for better
adaptation. This concept can be applied to the carcinogenesis process, connecting the
ability of cancer cells to adapt to different environments and to resist chemotherapy,
genomic instability being the driving force of tumor development and progression.
What causes this genome instability? Mutations have been recognized for a long time as
the major source of genome instability in cancer cells. Nevertheless, an alternative
hypothesis suggests that aneuploidy is a primary cause of genome instability rather than
solely a simple consequence of the malignant transformation process. Whether genome
instability results from mutations or from aneuploidy is not a matter of discussion in this
review. It is most likely both phenomena are intimately related; however, we will focus
on the mechanisms involved in aneuploidy formation and more specifically on the
epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular
information—other than the DNA sequence itself—that is heritable during cell division.
DNA methylation and histone modifications comprise two of the main epigenetic
modifications that are important for many physiological and pathological conditions,
including cancer. Aberrant DNA methylation is the most common molecular cancer-cell
lesion, even more frequent than gene mutations; global hypomethylation and aberrant
local hypermethylation are perhaps the most frequent epigenetic modifications in cancer
cells. Epigenetic characteristics of cells may be modified by several factors including
environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these
alterations have been correlated with the formation of aneuploid cells in vivo. A
growing body of evidence suggests that aneuploidy is produced and caused by
chromosome instability. We propose and support in this manuscript that not only
genetics but also epigenetics, and specifically alterations in DNA methylation,
contribute in a major fashion to aneuploid cell formation.
Keywords: Aneuploidy, arsenic, cadmium, cancer, centromere, centrosome,
chromatin, chromosome instability, chromosomes, DNA methylation, dnmt,
epigenetics, heterochromatin, histone marks, hypomethylation, methyltransferases,
mitosis, pericentromeric chromatin, subtelomeric regions, telomeres.
