138
U N I T 1
Cell and Tissue Function
human cancers. Mutations in the p53 gene can occur in
virtually every type of cancer including lung, breast, and
colon cancer—the three leading causes of cancer death.
2
Sometimes called the “
guardian of the genome
,” the p53
gene acts as a molecular police officer that prevents the
propagation of genetically damaged cells.
2
Located on
the short arm of chromosome 17, the p53 gene normally
senses DNA damage and assists in DNA repair by caus-
ing arrest of the cell cycle in G
1
and inducing DNA repair
or initiating apoptosis in a cell that cannot be repaired.
2,3
With homologous loss of p53 gene activity, DNA dam-
age goes unrepaired and mutations occur in dividing
cells leading to malignant transformations. The p53
gene also appears to initiate apoptosis in radiation- and
chemotherapy-damaged tumor cells. Thus, tumors that
retain normal p53 function are more likely to respond to
such therapy than tumors that carry a defective p53 gene.
2
The RB gene was isolated in studies involving a
malignant tumor of the eye known as
retinoblastoma
.
The tumor occurs in a hereditary and sporadic form and
becomes evident in early life. Approximately 60% of
cases are sporadic, and the remaining 40% are heredi-
tary, inherited as an autosomal dominant trait.
2
Known
as the “two hit” hypothesis of carcinogenesis, both nor-
mal alleles of the RB gene must be inactivated for the
development of retinoblastoma (Fig. 7-6).
2,3
In heredi-
tary cases, one genetic change (“first hit”) is inherited
from an affected parent and is therefore present in all
somatic cells of the body, whereas the second mutation
(“second hit”) occurs in one of the retinal cells (which
already carries the first mutation). In sporadic (nonin-
herited) cases, both mutations (“hits”) occur within a
single somatic cell, whose progeny then form the cancer.
The RB gene represents a model for other genes that
act similarly. In persons carrying an inherited mutation,
such as a mutated RB allele, all somatic cells are per-
fectly normal, except for the risk of developing cancer.
That person is said to be
heterozygous
or carrying one
mutated gene at the gene locus. Cancer develops when
a person becomes homozygous with two defective genes
for the mutant allele, a condition referred to as
loss
of heterozygosity.
2
For example, loss of heterozygos-
ity is known to occur in hereditary cancers, in which a
mutated gene is inherited from a parent and other con-
ditions (e.g., radiation exposure) are present that cause
mutation of the companion gene, making an individual
more susceptible to cancer.
Epigenetic Mechanisms
In addition to mechanisms that involve DNA and chro-
mosomal structural changes, there are molecular and
cellular mechanisms termed “epigenetic” mechanisms
that involve changes in the patterns of gene expression
without a change in the DNA.
18
Epigenetic mechanisms
may “silence” genes, such as tumor-suppressor genes,
so that even if the gene is present, it is not expressed
and a cancer-suppressing protein is not made. One such
mechanism of epigenetic silencing is by methylation of
the promoter region of the gene, a change that prevents
transcription and causes gene inactivity. Genes silenced
by hypermethylation can be inherited, and epigenetic
silencing of genes can be considered a “first hit” in the
“two hit” hypothesis described earlier.
19
MicroRNAs (miRNA) are small, noncoding, single-
stranded ribonucleic acids (RNAs), about 22 nucleotides
in length, which function at the post-transcriptional level
as negative regulators of gene expression.
2,3,20
miRNAs
pair with messenger RNA (mRNA) containing a nucle-
otide sequence that complements the sequence of the
microRNA, and through the action of the RNA-induced
silencing, mediate post-transcriptional gene silencing.
miRNAs have been shown to undergo changes in expres-
sion in cancer cells, and frequent amplifications and dele-
tions of miRNA loci have been identified in a number
of human cancers, including those of the lung, breast,
colon, pancreas, and hematopoietic systems.
3
They can
participate in neoplastic transformation by increasing the
expression of oncogenes or reducing the expression of
tumor suppressor genes. For example, down-regulation
or deletion of certain miRNAs in some leukemias and
lymphomas results in increased expression of BCL2, an
Mutant
Rb gene
Mutation
Normal
Rb gene
A
Offspring
Retinoblastoma
Retinoblastoma
Offspring
B
First
mutation
Second
mutation
FIGURE 7-6.
Pathogenesis of retinoblastoma.Two mutations
of the mutant retinoblastoma (Rb) gene lead to development of
neoplastic proliferation of retinal cells.
(A)
In the familial form
all offspring become carriers of the mutant Rb gene. A second
mutation affects the other Rb gene locus after birth.
(B)
In the
sporadic form, both mutations occur after birth.
