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

1104 Chapter 20: Cancer
CANCER-CRITICAL GENES: HOW THEY ARE FOUND
AND WHAT THEY DO
As we have seen, cancer depends on the accumulation of inherited changes in
somatic cells. To understand it at a molecular level we need to identify the mutations
and epigenetic changes involved and to discover how they give rise to cancerous
cell behavior. Finding the relevant cells is often easy; they are favored by
natural selection and call attention to themselves by giving rise to tumors. But
how do we identify those genes with the cancer-promoting changes among all
the other genes in the cancerous cells? A typical cancer depends on a whole set
of mutations and epigenetic changes—usually a somewhat different set in each
individual patient. In addition, a given cancer cell will also contain a large number
of somatic mutations that are accidental by-products—so-called passengers
rather than drivers—of its genetic instability, and it can be difficult to distinguish
these meaningless changes from those changes that have a causative role in the
disease. Despite these difficulties, many of the genes that are repeatedly altered
in human cancers have been identified over the past 40 years. We will call such
genes, for want of a better term, cancer-critical genes, meaning all genes whose
alteration contributes to the causation or evolution of cancer by driving tumorigenesis.
In this section, we shall first discuss how cancer-critical genes are identified.
We shall then examine their functions and the parts they play in conferring on
cancer cells the properties outlined in the first part of the chapter. We shall end
the section by discussing colon cancer as an extended example, showing how a
succession of changes in cancer-critical genes enables a tumor to evolve from one
pattern of bad behavior to another that is worse.
The Identification of Gain-of-Function and Loss-of-Function
Cancer Mutations Has Traditionally Required Different Methods
Cancer-critical genes are grouped into two broad classes, according to whether the
cancer risk arises from too much activity of the gene product or too little. Genes of
the first class, in which a gain-of-function mutation can drive a cell toward cancer,
are called proto-oncogenes; their mutant, overactive or overexpressed forms are
called oncogenes. Genes of the second class, in which a loss-of-function mutation
can contribute to cancer, are called tumor suppressor genes. In either case,
the mutation may lead toward cancer directly (by causing cells to proliferate
when they should not) or indirectly—for example, by causing genetic or epigenetic
instability and so hastening the occurrence of other inherited changes that
directly stimulate tumor growth. Those genes whose alteration results in genomic
instability represent a subclass of cancer-critical genes that are sometimes called
genome maintenance genes.
As we shall see, mutations in oncogenes and tumor suppressor genes can
have similar effects in promoting the development of cancer; overproduction of a
signal for cell proliferation, for example, can result from either kind of mutation.
Thus, from the point of view of a cancer cell, oncogenes and tumor suppressor
genes—and the mutations that affect them—are flip sides of the same coin. The
techniques that led to the discovery of these two categories of genes, however, are
quite different.
The mutation of a single copy of a proto-oncogene that converts it to an oncogene
has a dominant, growth-promoting effect on a cell (Figure 20–17A). Thus, we
can identify the oncogene by its effect when it is added—by DNA transfection, for
example, or through infection with a viral vector—to the genome of a suitable type
of tester cell or experimental animal. In the case of the tumor suppressor gene, on
the other hand, the cancer-causing alleles produced by the change are generally
recessive: often (but not always) both copies of the normal gene must be removed
or inactivated in the diploid somatic cell before an effect is seen (Figure 20–17B).
This calls for a different experimental approach, one focusing on discovering what
is missing in the cancer cell.