Chromosome segregation errors: a double-edged sword - TI Pharma

Two striking features of cancer cells are their abnormal chromosome number and the presence of
abnormal chromosomal structures, such as inversions, duplications, deletions and fusions of two
(or more) chromosomal parts, called translocations 232-236 (Fig.5). These chromosomal abnormalities
in cancer cells were already identified about one century ago and it was suggested by Boveri that
these abnormalities could be causal for the formation of tumors 232 . During the last decades, these
genetic abnormalities have been investigated extensively and have indeed been shown to influence
tumorigenesis 231,237-240 .
4.1 Structural chromosomal instability
Translocations, one of the most prominent types of structural chromosomal changes, have been found
in many cancer types 235 . In hematological malignancies, several translocations have been identified that
contribute to specific gene fusions, which are thought to be drivers in the process of tumorigenesis 240 .
The first identified translocation in human cancer was the Philadelphia chromosome 234 , which results
in the formation of a fusion between the BCR and Abl1 genes, and is causative in the development
of chronic myeloid leukemia 241 . Some of the translocations found in cancer are balanced and
homogeneously present in all tumor cells 242 . However, more often, cancer cells within a tumor display
mosaic structural changes, which indicates that chromosomes continue to rearrange at a high rate in the
established tumor 236,243-247 . Generally, these chromosome structure instabilities are thought to promote
tumorigenesis by providing continued genetic diversification within the tumor that might help it adapt
to changes in its environment, through loss of certain tumor suppressors or gain of specific oncogenes
244,248 . Also, this continued genetic diversification could help the tumor acquire resistance to drugs, cope
with increased hypoxia, or escape challenges by the immune system. In line with this, an increased
occurrence of structural chromosomal aberrations correlates with higher grade tumors 235,249,250 .
Structural chromosomal instabilities arise through mis- or unrepaired double-strand breaks
and HR and NHEJ are thought to be the two main repair pathways contributing to formation of
structural aberrations 238,239,251 . Especially the error-prone NHEJ pathway, which ligates any two
broken DNA ends together, is held responsible for the formation of many structural aberrations 251 .
Indeed, individuals with genetic defects that cause defects in the repair of DSBs, such as patients with
Nijmegen Breakage Syndrome, Bloom’s syndrome, Ataxia telangiectasia or mutations in BRCA1 and 2,
show an increased susceptibility to form structural chromosomal changes 252 . Cells from these patients
accumulate translocations due to mutations in DNA repair proteins, such as NBS1 253 , BLM helicase 254 ,
ATM kinase 255 or the BRCA1 256 and BRCA2 257 proteins, both involved in the HR pathway. Moreover,
it was shown more than 40 years ago that several DSB-inducing agents, such as ionizing irradiation,
UV-light and chemical mutagens, can also result in the formation of chromosomal aberrations 258 .
On top of initial genetic defects or exogenous agents that increase the chance of developing
chromosomal aberrations, a pathway that directly contributes to structural instability has also been
described in cancer, termed the Breakage-Fusion-Bridge (BFB) cycle, first described in maize meiosis
259,260 . Chromosomes that are broken by DSBs can fuse with other broken chromosomal parts, for
example through fusion at dysfunctional telomeres 261 . These telomere fusion events have been shown
to cause dicentric (two centromeres) or ring chromosomes, both often found in tumors 261,262 . The
presence of two centromeres on these aberrantly shaped chromosomes can result in uncoordinated
microtubule attachment in mitosis, such that the two centromeres on a single chromatid become
attached to opposite spindle poles (Fig.7). These attachments can subsequently induce chromatin
bridging in telophase, resulting in breakage of the fused chromosome during cytokinesis 259,263 . These
BFB events could go on for a prolonged period of time 259,260 and thereby increase the number of
aberrant chromosomes in the offspring. BFB has indeed been correlated with an increase in intratumor
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General Introduction 1