Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

606 Mutator Phenotype
nance of genetic stability. Among the many
mutations produced are ones that promote
growth, invasion and metastasis, the hallmarks
of cancer.
Characteristics
Mutations and cancer
The ability of cancer cells to continually mutate
may be central to how tumors evolve. In the
case of solid tumors, there is approximately a
twenty-year interval from the exposure of an
individual to a carcinogen until the clinical detection
of a tumor. During this interval, cancer
cells acquire properties that allow them to
flourish in a changing environment. By the
time a tumor is detectable, the cancer cells
are able to divide where normal cells do not,
to invade adjacent cellular architectures, to metastasize
and eventually to kill the host. In addition,
tumors have the capacity to rapidly develop
resistance to a variety of chemotherapeutic
agents. Each of these phenotypes can be mimicked
by mutations in normal cells.
Chromosomal alterations in human cancers
Mutations can be defined as a change in the nucleotide
sequence in DNA. Mutations in cancer
cells cover a wide spectrum from chromosomal
alterations that encompasses millions of nucleotides
to point mutations that involve only
a few nucleotide substitutions in single genes.
Multiple somatic chromosomal alterations
are diagnostically associated with cancer cells
and involve translocations, deletions, amplifications
and aneuploidy (a change in the number
of chromosomes in individual cells). Unique
chromosomal changes occur at high frequencies
in certain tumors and are of diagnostic
significance. However, there is a striking heterogeneity
of chromosomal alterations in cancer
cells within individual tumors. In general,
there is a positive correlation between the number
of chromosomal changes within a tumor
and the malignant potential of that tumor.
As molecular techniques are becoming more
sensitive, more and more chromosomal abnormalities
are being reported in different tu-
mors. In some tumors there is evidence for a
sequential order in chromosomal mutations
during tumor progressions. Measurements of
the number of copies of segments of the genome
in tumor cells (DNA copy number) and
the loss of pieces of DNA (loss of heterozygosity)
have established that many tumors harbor
as many as 40 chromosomal alterations. It
should be emphasized that these methodologies
only score a very small fraction of the genome
and as a result may greatly underestimate
the number of small chromosomal rearrangements
within the genome.
Point mutations in human cancer
Only recently has evidence accumulated indicating
that cancer cells not only contain multiple
chromosomal alterations, but also contain
thousands of smaller changes in nucleotide sequence.
These studies have provided strong
support of the mutator phenotype hypothesis
involving a reduction in the fidelity of DNA replication
and/or a decrease in the efficiency of
DNA repair. An early clue to the large numbers
of mutations in cancer cells was the observations
that the resistance of cancer cell lines
to divergent chemotherapies was mediated by
gene amplification. The first direct evidence
in support of a mutator phenotype in cancer
was provided by the demonstration that cells
from patients with HNPCC (hereditary nonpolyposis
colon cancer) exhibit microsatellite
instability in association with mutations in
DNA repair genes. Microsatellites are short repetitive
sequences of nucleotides in DNA that
are subjected to slippage during copying by
DNA polymerases. In normal individuals, mutations
in microsatellites are corrected by the
DNA mismatch repair system. In HNPCC tumors,
the deficits in mismatch repair result
in expansions and contractions in the length
of repetitive nucleotide sequences. Based on
the enormous number of microsatellites in
the human genome, it has been calculated
that each tumor could harbor more than
100,000 mutations in these sequences alone. Repetitive
sequences located within genes are also
mutated at high frequencies in these tumors.
Changes in the lengths of repetitive sequences