Essential Cell Biology 5th edition

Cancer
725
(B)
(A)
loss-of-function mutation
in tumor suppressor gene
in maternal chromosome
normal tumor
suppressor gene in
paternal chromosome
Figure 20–48 Several kinds of genetic
events can eliminate the activity of
a tumor suppressor gene. Note that
both copies of such a gene must be
lost to eliminate its function. (A) A cell
in which the maternal copy of the tumor
suppressor gene is inactive because of a
loss-of-function mutation; this cell is one
step away from a complete loss of this
tumor-suppressor function. (B) Cells in
which the paternal copy of the gene is also
inactivated in different ways, as shown.
WHOLE PATERNAL
CHROMOSOME LOST
REGION CONTAINING
NORMAL GENE DELETED
FROM PATERNAL
CHROMOSOME
LOSS-OF-FUNCTION
MUTATION IN
PATERNAL GENE
PATERNAL GENE
ACTIVITY SILENCED BY
EPIGENETIC MECHANISM
Proto-oncogenes and tumor suppressor genes code for proteins of many
ECB5 e20.50-20.51
different types, contributing to the many kinds of misbehavior that cancer
cells display. Some of these proteins are involved in signaling pathways
that regulate cell survival, cell growth, cell division, or some combination
of these. Others take part in DNA repair, help mediate the DNA damage
response, modify chromatin, or help regulate the cell cycle or apoptosis.
Still others (such as cadherins) are involved in cell adhesion or other
properties critical for metastasis, or have roles that we do not yet properly
understand.
Cancer-critical Mutations Cluster in a Few Fundamental
Pathways
From the point of view of a cancer cell, proto-oncogenes and tumor suppressor
genes—and the mutations that affect them—are flip sides of the
same coin. Activation of a proto-oncogene and inactivation of a tumor
suppressor gene can both promote the development of cancer. And both
types of mutations contribute to the development of most cancers. In
classifying cancer-critical genes, it seems that the type of mutation—
gain-of-function or loss-of-function—matters less than the pathway in
which it acts.
Today, rapid, low-cost DNA sequencing is providing an unprecedented
amount of information about the mutations that drive a variety of cancers.
We can now compare the complete genome sequences of the cancer
cells from a patient’s tumor to the genome sequence of the noncancerous
cells in the same individual—or of cancer cells that have spread to
another location in the body. By putting together such data from many
different patients, we can begin to draw up exhaustive lists of the genes
that are critical for specific classes of cancer. And by analyzing data from
a single patient, we can deduce the “family tree” of his or her cancer cells,
showing how the progeny of the original founder cell have evolved and
diversified as they multiplied and metastasized to different sites.
One remarkable finding has been that many of the driver mutations in
individual tumors affect genes that fall into a small number of key regulatory
pathways: those that govern cell proliferation, cell growth, cell
survival, and the cell’s response to DNA damage and stress. For example,
in almost every case of glioblastoma—the most common type of human
brain cancer—mutations disrupt all four of these fundamental pathways,
and the same pathways are subverted, in one way or another, in almost