is a disease, first of all, of cellular mutations.
The sources of these mutations
are charted in the figure above.
Many researchers believe that five
to ten critical mutations must accumulate to
create a cancer cell line, also known as a clone
Cancer can be viewed as an accumulation of genetic
incidents, that begin with DNA damage, mutation
or silencing. These precancerous cells undergo selection for
specific growth advantage that ultimately
leads to metastasis. These mutations can
continue at a higher rate after the clone line
has multiplied due to a breakdown in cell cycle
quality control checkpoints, much like a runaway
train. As in antiobitic resistance scenarios,
most methods of treatment kill all the cancer
cells except those that have the ability to grow
in the more difficult circumstances.
The resistant tumor cells are then selected and
continue to grow and proliferate in a true Darwinian survival
of the fittest fashion. The applicability
of Darwin's theories to molecular biology is thus
astonishingly accurate. New biologic therapies
such as Herceptin and
even thalidomide may
provide a "Darwinian
bypass" to circumvent this process of
molecular evolution. Therapies like Tamoxifen circumvent
growth cycling of hormone sensitive tissues,
which makes such tissues more vulnerable to the
mutations that cause cancer.
are two categories of genes implicated in cancer.
The first category contains tumor suppressor
genes, such as p53. Tumor suppressor genes can
the brake pedals in a car, that slow it down
when it is moving (growing) too fast. When brakes
don't work, the car doesn't stop and the cell keeps
growing. The second category contains oncogenes,
or growth genes.
genes are expressed in a cell, the cell grows
Oncogenes can be likened to the accelerator pedal
of a car. It is also disaster when the accelerator
repeat this useful analogy another way.
The brake pedal can fail to actuate the brakes,
and the accelerator
pedal can stick in the on position. Similarly,
a cell can fail to turn off properly, or it can
go into an uncontrolled growth mode. Genes that
tell a cell when to turn off are called tumor suppressor
genes. Genes that tell cells to grow are called
cells originate as stem cells, primal undifferentiated
cells. On receiving certain chemical signals these
stem cells differentiate or morph into
the specific tissue type required. It may be possible
that mature cells of specific
tissue types can
revert to more primal
signaled to do so, but this reversion is usually
limited. In cancer, some fully differentiated cells
appear to "back up" to their more primitive
states, and then grow out of control. There is
some thinking now that some cancers may originate
in stem cells for given tissue types, and that
it is the duplication of stem cells that make cancer
you likely know genes consist of sequences of DNA
bases chosen from the
set C,T,A or G. These letters are called nucleotide
bases. Groups of three of these letters taken three
at a time specify which amino acid will be chosen
next for incorporation into a protein. There is
a short alphabet of twenty amino acids that make
all proteins. Some chemicals that cause cancer,
or carcinogens, mimic
bases, and get incorporated into the DNA by
mistake. When the DNA
cell growth, an error may then occur. Lexically,
there are three categories of errors in DNA, deletion,
and insertion. DNA bases can be thought of as letters
that must satisify parsing rules.
the first error category of deletion mutations,
one or more of the
DNA bases are read in groups of three to produce
one amino acid at a time. DNA bases taken in
groups of three letters are called codons.
Deletion of one or more of these letters throw
off the entire protein coding sequence for that
gene. This results in nonsense downstream of the
mutation. DNA has
some built in error correction, due
to the double helix. This bears similarity to a
Hamming code and reference to the work of Shannon
and Norbert Wiener is a useful sidebar.
Nucleotide bases pair across the helix with their
Cytosine, C, always pairs with guanine G,
by hydrogen bonding across the rung of the DNA
Similarly adenine, A, pairs with thymine, T.
DNA polymerase and DNA ligase correct missing
provided that the complementary base
on the other strand is correct and provided
a carcinogenic subsitution has not occurred. Individuals
whose repair enzymes are defective, such as those
XP, Xeroderma pigmentosum, may develop tumors spontaneously
on exposure to sunlight. The UV component of sunlight
is damaging to DNA. In normal individuals, this
is repaired by DNA polymerase. Assymetry of repair
is the rule of the day. The leading and lagging
strands of DNA are copied and
with different enzymes and topological functions
resulting in a different likelihood of
successful replication for each side of the DNA
helix, a 3.4
fold difference in lower organisms.
second category of mutation is substitution,
letter is substituted for another. The seriousness
of this error depends on whether it is the
first, second or third base in the codon. Single
substitutions frequently result in a codon
that specifies the same amino acid. There are 64
codons, because there are 64 ways of ordering a
triple of C, T, A, or G. But nature has caused
these 64 primitive instructions to map to only
20 amino acids, so the 64 codons are not unique.
system, the leading letter of
Two different codons can code for the same amino
acid, thus a substitution mutation will frequently
make no change in the gene product. Often the protein
will function properly if a similar amino
is not always the case. Substitution mutations
are also called point mutations. Sickle cell anemia
is caused by a single point mutation in the gene
that codes for hemoglobin. Hemoglobin is a globular
protein that serves to transport an oxygen diamond
in the setting of a porphyrin ring. Sickle cell
hemoglobin will polymerize with
itself under conditions of low oxygen tension.
Sickle cell and cancer are not related, but the
mechanisms, history and legacy of mutation are
third category of mutation is an insertion mutation.
In this mutation, one or more letters are inserted
into a coding sequence. If three letters or a multiple
of three letters are inserted, the protein may
still function properly. If a non
multiple of three letters is inserted, nonsense
will again result for all codons downstream of
the insertion mutation. Viruses can cause insertion
mutations, since their DNA is incorporated into
the host. An interactive gene sorting illustration
of the genetic wreckage carried by the BRCA1 breast
are two kinds of DNA sequence, those stretches
that code for protein product, called exons,
that do not code for protein, called introns. The
latter are sometimes called, "junk DNA",
because no function is known for this genetic material.
About 96.4% of the human genome is "junk DNA".
This is quite remarkable.
of these three kinds of mutations can be seen
in the BRACA1 gene rollover graphic below. Placing
over the graphic, causes the components of
BRACA1 to be sorted. A common repeated intron is
called an ALU repeat. The ALU repeats in BRACA1
can be seen to be profoundly frame shifted and
Fortunately these repeats do not code for gene
product, but they portend the mutations that do occur
in the exonic regions, that do contribute to
and insertion mutations are also called frame shift
mutations, because they alter the codon reading
frame and produce nonsense. Mutations rarely
result in a gain of function. Mathematically,
loss of function
mutations are much more likely.
are not the only way that important genes can be
damaged or silenced. Genes have switches called promoter
and repressor regions. When certain proteins bind
to the promoters or repressors the amount of protein
be turned up, turned down, or turned off. Another
mechanism for silencing genes is methylation. In
a cystosine base in the gene's promoter region
is endowed with a methyl group. Like protein binding
to promoters, methylation is an important natural
mechanism for gene regulation. But when a tumor
supressor gene is silenced by methylation, serious
trouble may result. See link.
cancer can ultimately be traced to DNA damage, mutation
or gene silencing by methylation. The source of unwanted
methylation is unknown, but one agent that causes
methylation is the enzyme methyl transferase. Thus
tracking down sources of methyl transferase, for
example in viruses that are known to cause cancer,
would be a possible productive line of reasoning.
Looking at mutations that affect the expression of
methyl transferase would be another.
can be inherited from a previous generation, if
the mutation appeared in the germ-line, or they can
be acquired along the way in somatic cells. The same
is true of methylation.
is also a disease of age. When DNA is replicated,
there must be extra length at the ends of the strands
to allow the duplicating enzymes to stay on the tracks,
so to speak. These extra lengths are called telomeres
and are maintained by an enzyme called telomerase.
Telomerase is a reverse transcriptase (much like
the HIV virus). When telomerase is absent, the
of the chromosomes
fray. Important gene products coded by these fraying
ends then fail to be made and the deterioration
of aging continues.