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The epigenetic state of particular cell types—a feature described as the epigenetic context—also dictates their response to signals that control growth and differentiation. As mentioned earlier, epigenetic modifications regulate gene expression, allowing cells with the same genetic makeup (e.g., a neuron and a keratinocyte) to have completely different appearances and functions. In some instances, the epigenetic state of a cell dramatically affects its response to otherwise identical signals. For example, the NOTCH1 gene has an oncogenic role in T-cell leukemia, yet acts as a tumor suppressor in squamous cell carcinomas. As would be expected, this dichotomy exists because activated NOTCH1 turns on pro-growth genes in T-cell progenitors and tumor suppressor genes in keratinocytes.
Mutationsincancercellsfallintotwomajorclasses,driver(pathogenic)mutationsandpassenger(neutral)mutations.
Passengermutationsmaybecomedrivermutationsifselectivepressureonthetumorchanges,forexample,inthesettingoftreatmentwithaneffectivetherapeuticdrug.
Tumorcellsmayacquiredrivermutationsthroughseveralmeans,includingpointmutationsandnonrandomchromosomalabnormalitiesthatcontributetomalignancy;theseincludegenerearrangements,deletions,andamplifications.
Generearrangements(usuallycausedbytranslocations,butsometimesbyinversionsofothermorecomplexevents)contributetocarcinogenesisbyoverexpressionofoncogenesorgenerationofnovelfusionproteinswithalteredsignalingcapacity.
Deletionsfrequentlyaffecttumorsuppressorgenes,whereasgeneamplificationincreasestheexpressionofoncogenes.
OverexpressionofmiRNAscancontributetocarcinogenesisbyreducingtheexpressionoftumorsuppressors,whiledeletionorlossofexpressionofmiRNAscanleadtooverexpressionofproto-oncogenes.
TumorsuppressorgenesandDNArepairgenesalsomaybesilencedbyepigeneticchanges,whichinvolvereversible,heritablechangesingeneexpressionthatoccurnotbymutationbutbymethylationofthepromoter.
CARCINOGENESIS:AMULTISTEPPROCESS
Fortunately, in most if not all instances, no single mutation is sufficient to transform a normal cell into a cancer cell. Carcinogenesis is thus a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks, discussed later. As mentioned earlier, the presence of driver mutations in some non-neoplastic precursor lesions suggest the need for additional mutations for transition to a full blown cancer and thus support this model.
Beyond tumor initiation from a single founding cell, it is important to recognize that cancers continue to undergo Darwinian selection and therefore continue to evolve (
Fig. 6.16 ). It is well established that during their course cancers generally become more aggressive and acquire greater malignant potential, a phenomenon referred to as tumor progression. At the molecular level, tumor progression most likely results from mutations that accumulate independently in different cells. Some of these mutations may be lethal, but others may affect the function of cancer genes, thereby making the affected cells more adept at growth, survival, invasion, metastasis, or immune evasion. Due to this selective advantage, subclones that acquire these mutations may come to dominate one area of a tumor, either at the primary site or at sites of metastasis. As a result of continuing mutation and Darwinian selection, even though malignant tumors are monoclonal in origin they are typically genetically heterogeneous by the time of their clinical presentation. In advanced tumors exhibiting genetic instability, the extent of genetic heterogeneity may be enormous.