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

CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
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By compiling the data for different types of cancer, each with its own range
of identified driver mutations, we can develop a comprehensive catalog of genes
that are strongly suspected to be cancer-critical. Current estimates put the total
number of such genes at about 300, about 1% of the genes in the human genome.
These cancer-critical genes are amazingly diverse. Their products include
secreted signal proteins, transmembrane receptors, GTP-binding proteins, protein
kinases, transcription regulators, chromatin modifiers, DNA repair enzymes,
cell–cell adhesion molecules, cell-cycle controllers, apoptosis regulators, scaffold
proteins, metabolic enzymes, components of the RNA splicing machinery, and
more besides. All these are susceptible to mutations that can contribute, in one
way or another, in one tissue or another, to the evolution of cells with the cancerous
properties that we listed earlier on page 1103.
Clearly, the molecular changes that cause cancer are complex. As we now
explain, however, the complexity is not quite as daunting as it may initially seem.
Disruptions in a Handful of Key Pathways Are Common to Many
Cancers
Some genes, like Rb and Ras, are mutated in many cases of cancer and in cancers
of many different types. The involvement of genes such as Rb and Ras in cancer
is no surprise, now that we understand their normal functions: they control fundamental
processes of cell division and growth. But even these common culprits
feature in considerably less than half of individual cases. What is happening to
the control of these processes in the many cases of cancer where, for example, Rb
is intact or Ras is not mutated? What part do mutations in the hundreds of other
cancer-critical genes play in the development of the disease? With our increasing
knowledge of the normal functions of the genes in the human genome, it is
becoming easier to see patterns in the cataloged driver mutations and to give
some simplifying answers to these questions.
Glioblastoma—the commonest type of human brain tumor—provides a good
example. Analysis of the genomes of tumor cells from 91 patients identified a total
of at least 79 genes that were mutated in more than one individual. The normal
functions of most of these genes were known or could be guessed, allowing them
to be assigned to specific biochemical or regulatory pathways. Three functional
groupings stood out, accounting for a total of 21 of the recurrently mutated genes.
One of these groupings consisted of genes in the Rb pathway (that is, Rb itself,
along with genes that directly regulate Rb); this pathway governs initiation of the
cell-division cycle. Another consisted of genes in the same regulatory subnetwork
as Ras—a more loosely defined system of genes referred to as the RTK/Ras/PI3K
pathway, after three of its core components; this pathway serves to transmit signals
for cell growth and cell division from the cell exterior into the heart of the
cell. The third grouping consisted of genes in a pathway regulating responses to
stress and DNA damage—the p53 pathway. We shall have more to say about each
of these pathways below.
Out of all tumors, 74% had identifiable mutations in all three pathways. If one
were to trace these three pathways further upstream and include all the components,
known and unknown, on which they depend, this percentage would
almost certainly be even higher. In other words, in almost every case of glioblastoma,
there are mutations that disrupt each of three fundamental controls: the
control of cell growth, the control of cell division, and the control of responses to
stress and DNA damage.
Strikingly, in any given tumor-cell clone, there is a strong tendency for no more
than one gene to be mutated in each pathway. Evidently, what matters for tumor
evolution is the disruption of the control mechanism, and not the genetic means
by which that is achieved. Thus, for example, in a patient whose tumor cells have
no mutation in Rb itself, there is generally a mutation in some other component
of the Rb pathway, producing a similar biological effect.
Similar patterns are seen in other types of cancers. A survey of many specimens
of the major variety of ovarian cancer, for example, identified 67% of patients as