Download GENOMIC INSTABILITY: PHENOMENA AND ITS ROLE IN CANCER

GENOMIC INSTABILITY: PHENOMENA AND ITS ROLE IN CANCER
INDUCTION
Streffer, Christian
University Clinics, Essen, Germany
[email protected]
DNA is not a stable molecule, chromosomes are not stable structures and
chromosomal breaks can be increased by ionizing radiation. However, it was accepted
for a long time that radiation-induced chromosomal breaks are expressed in the first
mitosis after radiation exposure. Only in the end of the eighties it was observed that a
new increase of chromosomal breaks occurs at much later times in cells twenty to
thirty cell generations after the exposure. This phenomenon was termed “increase of
instability of the genome” (“genomic instability”). During the last decades a vast
amount of information has been collected. The increase of genomic instability occurs
after low LET- as well as high LET-radiation, apparently in all chromosomes and all
DNA-structures. No specificity has been recognized until now. In mice it has been
shown that the increased genomic instability is inherited to the next mouse generation
to some extent. The mutation rate can be enormously enhanced in the affected cells.
Until now the mechanism of this increase is unsolved. The influence of mitochondria
with oxidative metabolism, the structure of telomeres and other phenomena are
discussed.
The development of cancer occurs with several mutation steps which is shown with
good experimental and clinical evidence. Individuals with a genetic predisposition for
increased radiosensitivity and high susceptibility for certain malignant diseases also
show an increased genomic instability connected with some deficiency in certain DNA
repair pathways as well as changes in regulatory processes of the cell cycle especially
during G1-phase (mutations in the genes of P-53, Rb and others). Further an increase
of genomic instability has been observed in cancer patients not only in the cancer cells
but also in normal blood lymphocytes and in patients with recurrences. Individuals
with increased genomic instability may have a higher risk to develop cancer. Hypoxia
is also important for cancer development. Mutations in the HIF-1α system promote
hypoxia as well as genomic instability. Further it will be shown that genomic
instability influences not only carcinogenesis but also other biological processes like
prenatal development.