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In addition, thecooperation between different altered genes makes it harder to test the significance of an inherited change in any individual gene. To make matters worse, agiven cancer cell will also contain a large number of somatic mutations that areaccidental by-products of its genetic instability, and it can be difficult to distinguish these meaningless changes from those changes that have a causative rolein the disease.Despite these difficulties, many genes that are repeatedly altered in humancancers have been identified-several hundred of them-although it is clearthat many more remain to be discovered.We will call such genes,for want of abetter term, cancer-critical genes, meaning all genes whose alteration frequently contributes to the causation of cancer.
Our knowledge of these geneshas accumulated piecemeal through many different and sometimes circuitousapproaches,ranging from early studies of cancer-causinginfections in chickensto investigations of embryonic development. Analyses of rare but highly revealing inherited forms of cancer have also added to our understanding.
Morerecently, sequencing of DNA from multiple casesof specific types of cancers hasbegun to give a more systematic picture of the genetic changes that are a regular feature ofthose diseases.In this section, we discuss both the methods used for identifying cancercritical genes and the varied kinds of inherited changes that occur in them during the development of cancer.and Loss-of-Functionof Gain-of-FunctionTheldentificationMutationsRequiresDifferentMethodsCancer-critical genes are grouped into two broad classes, according towhether the cancer risk arises from too much activity of the gene product, ortoo little. Genes of the first class, in which a gain-of-function mutation candrive a cell toward cancer, are called proto-oncogenes; their mutant, overactive or overexpressedforms are called oncogenes. Genes of the second class,in which a loss-of-function mutation can contribute to cancer, are calledtumor suppressor genes. A third class, whose effects are more indirect, arethose genes whose mutation results in genomic instabiliry a class we describeas Dl/A maintenance genes.As we shall see, mutations in both oncogenes and tumor suppressor genescan have similar effects in enhancing cell proliferation and cell survival, as wellas in promoting tumor development.
Thus, from the point of view of a cancercell, oncogenes and tumor suppressor genes-and the mutations that affectthem-are flip sides of the same coin. The techniques needed to find thesegenes, however, differ-depending on whether the genes are overactive orunderactive in cancer.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 2O-271^)'Thus, we can identifu the oncogene by its effect when it is added-by DNAtransfection, for example, or through infection with a viral vector-to thegenome of a suitable type of tester cell. In the case of the tumor suppressorgene, on the other hand, the cancer-causing alleles produced by the changeare generally recessive:often (but not always) both copies of the normal genemust be removed or inactivated in the diploid somatic cell before an effect isseen (Figure 20-278).
This calls for a different approach, aimed at detectingwhat is missingin the cancer cell.In some cases,a specific gross chromosomal abnormality, visible under themicroscope, is repeatedly associatedwith a particular tlpe of cancer. This cangive a clue to the location of an oncogene that is activated as a result of the chromosomal rearrangement (as in the example of the chromosomal translocationresponsible for chronic myelogenous leukemia, discussedearlier). Alternatively,a visible deletion of a chromosomal segment may reveal the site of a deletedtumor suppressor gene.12311232Chapter20:Cancer(A) overactivity m u t a t i o n ( g a i no f f u n c t i o n )s i n g l em u t a t i o ne v e n tcreatesoncogene/t\n o r m a lc e l lactivating mutatione n a b l e so n c o g e n et opromote cell transformationc el l se n r o u t et ocancer(B) underactivitymutation (lossof function)n o r m a lc e l lsecondmutationmutationeventevent++inactivatesinactivatestumorsecondgenesuppressorcopygeneno effect ofm u t a t i o ni n o n etwo inactivatingmutationsg e n ec o p yf u n c t i o n a l l ye l i m i n a t et h et u m o r S u p p r e s s ogre n e ,p r o m o t i n gc e l lt r a n s f o r m a t i o nt1\Retrovirusescan Act asvectorsfor oncogenesThatAlter cellBehaviorTumor viruses have played a remarkable part in the search for the geneticcausesof human cancer.Although viruses have no role in the majority of common human cancers,they are more prominent as causesof cancer in some animal species.Analysis of these animal tumor viruses provided a critical key tounderstanding the mechanisms of cancer in general and to the discovery ofoncogenes in particular.one of the first animal viruses to be implicated in cancer was discoverednearly 1.00years ago in chickens, which are subject to infections that cause connective-tissue tumors, or sarcomas.The infectious agent was characterized as airus-theRous sarcoma Ltirus,which we now know to be an RNA virus.
Like allthe other RNA tumor uiruses discovered since, it is a retrovirus. lVhen it infectsa cell, its RNA is copied into DNA by reverse transcription, and the DNA isinserted into the host genome, where it can persist and be inherited by subsequent generations of cells. The Rous sarcoma virus carries an oncogene thatcauses cancer in chickens. This oncogene is not necessaryfor the virus's or,rmsurvival or reproduction, as demonstrated by the discovery of mutant forms ofthe virus that multiply normally but no longer make their host cells cancerousa process called cell transformation. Some of these mutants were found to havedeleted all or part of a gene that codes for a protein called src (pronounced"Sarc"). other mutations in this gene made the transforming effect of the virustemperature-sensitive:infected cells show a transformed phenotype at 34.c, butreturn to the normal phenotype within a few hours when the temperature israised to 39'C.A large number of other oncogeneshave since been identified in other retroviruses and analyzed in similar ways.
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