Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1108 Chapter 20: Cancer
NORMAL, HEALTHY INDIVIDUAL HEREDITARY RETINOBLASTOMA NONHEREDITARY RETINOBLASTOMA
inherited
mutant
Rb gene
occasional cell inactivates
one of its two good Rb genes
occasional cell
inactivates one of its two
good Rb genes
occasional cell
inactivates its only
good Rb gene copy
occasional cell
inactivates its only
good Rb gene copy
excessive cell
proliferation leading
to retinoblastoma
RESULT: NO TUMOR
RESULT: MOST PEOPLE WITH INHERITED
MUTATION DEVELOP MULTIPLE TUMORS
IN BOTH EYES
excessive cell
proliferation leading
to retinoblastoma
RESULT: ONLY ABOUT 1 IN 30,000
NORMAL PEOPLE DEVELOP ONE
TUMOR IN ONE EYE
multiple tumors usually arise independently, affecting both eyes; in the nonhereditary
form, only one eye is affected, and by only one tumor. A few individuals
with retinoblastoma have a visibly abnormal karyotype, with a deletion of a specific
band on chromosome 13 that, if inherited, predisposes an individual to the
disease. Deletions of this same region are also encountered in tumor cells from
some patients with the nonhereditary disease, which
MBoC6 m20.30/20.20
suggested that the cancer
was caused by loss of a critical gene in that location.
Using the location of this chromosomal deletion, it was possible to clone and
sequence the Rb gene. It was then discovered that those who suffer from the
hereditary form of the disease have a deletion or loss-of-function mutation present
in one copy of the Rb gene in every somatic cell. These cells are predisposed
to becoming cancerous, but do not do so if they retain one good copy of the gene.
The retinal cells that are cancerous are defective in both copies of Rb because of a
somatic event that has eliminated the function of the previously good copy.
In patients with the nonhereditary form of the disease, by contrast, the noncancerous
cells show no defect in either copy of Rb, while the cancerous cells have
become defective in both copies. These nonhereditary retinoblastomas are very
rare because they require two independent events that inactivate the same gene
on two chromosomes in a single retinal cell lineage (Figure 20–20).
The Rb gene is also missing in several common types of sporadic cancer,
including carcinomas of lung, breast, and bladder. These more common cancers
arise by a more complex series of genetic changes than does retinoblastoma, and
they make their appearance much later in life. But in all of them, it seems, loss of
Rb function is frequently a major step in the progression toward malignancy.
The Rb gene encodes the Rb protein, which is a universal regulator of the cell
cycle present in almost all cells of the body (see Figure 17–61). It acts as one of
the main brakes on progress through the cell-division cycle, and its loss can allow
cells to enter the cell cycle inappropriately, as we discuss later.
Figure 20–20 The genetic mechanisms
that cause retinoblastoma. In the
hereditary form, all cells in the body lack
one of the normal two functional copies of
the Rb tumor suppressor gene, and tumors
occur where the remaining copy is lost
or inactivated by a somatic event (either
mutation or epigenetic silencing). In the
nonhereditary form, all cells initially contain
two functional copies of the gene, and the
tumor arises because both copies are lost
or inactivated through the coincidence of
two somatic events in a single line of cells.
Both Genetic and Epigenetic Mechanisms Can Inactivate Tumor
Suppressor Genes
For tumor suppressor genes, it is their inactivation that is dangerous. This inactivation
can occur in many ways, with different combinations of mishaps serving
to eliminate or cripple both gene copies. The first copy may, for example, be lost
by a small chromosomal deletion or inactivated by a point mutation. The second
copy is commonly eliminated by a less specific and more probable mechanism: