Chapter 19 Lecture

Concepts of GeneticsTenth Edition

Cancer and Regulation of the Cell Cycle

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• Cancer is a genetic disease at the somatic level resulting from gene products from mutated or abnormally expressed genes

• Cancer cells share two fundamental properties: – unregulated cell proliferation– metastatic spread

Cancer is a genetic disease

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• Genomic alterations that are associated with cancer range from single-nucleotide substitutions to large-scale chromosomal rearrangements, amplifications, and deletions

© 2012 Pearson Education, Inc. Figure 19.1

A) Normal Cell

B) Cancer Cell

See many translocations, deletions and aneuploidy in the cancer karyotype

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• Most cancers are somatic, with only 1% due to germ-line mutations

• Cancers rarely arise from single gene mutations but from the accumulation of mutations in many genes (6–12)

• These mutations affect multiple cellular functions: DNA repair, cell division, apoptosis, cellular differentiation, migratory behavior and cell-cell contact

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• Age-related cancer is an indication that cancer develops from the accumulation of several mutagenic events in a single cell– The incidence of most cancers rises

exponentially with age – Many independent mutations, occurring

randomly and with a low probability, are necessary before a cell becomes malignant

Cancer is a multistep process requiring multiple mutations

© 2012 Pearson Education, Inc. Figure 19.2

© 2012 Pearson Education, Inc.

• Cancers develop in progressive steps beginning with mildly aberrant cells and progressing to increasingly tumorigenic and malignant cells

• Each step in tumorigenesis appears to be the result of one or more genetic alterations that progressively release the cell from the normal controls on cell proliferation and malignancy

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Cancer cells contain genetic defects affecting cell cycle regulation

• Growth and differentiation of cells are strictly regulated

• Normal regulation over cell proliferation involves a large number of gene products that control steps in the cell cycle

• In cancer cells these are mutated or aberrantly expressed, leading to uncontrolled cell proliferation

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• Interphase of the cell cycle is when a cell grows and replicates its DNA (G1, S, G2)

• Cells that stop proliferating enter G0, in which they do not grow or divide but are metabolically active– Neurons

• Cancer cells are unable to enter G0 and cycle continuously

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• Signal transduction initiates a program of gene expression that propels the cell out of G0 and back into the cell cycle

• Cancer cells often have defects in signal transduction pathways

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• At the G1/S, G2/M, and M checkpoints, cells decide whether to proceed to the next stage of the cell cycle

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• Regulation of cell-cycle progress is mediated by cyclins and cyclin-dependent kinases (CDKs) that regulate synthesis and destruction of cyclin proteins

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• Cells halt progress through the cell cycle if DNA replication, repair, or chromosome assembly is aberrant

• If DNA damage is so severe that repair is impossible, the cell may initiate apoptosis, or programmed cell death Prevents cancer– Also eliminates cells not contributing the final

adult organism

Control of Apoptosis

© 2012 Pearson Education, Inc. Figure 19.8a

© 2012 Pearson Education, Inc.

• Proto-oncogenes are genes whose products promote cell growth and division These genes encode – transcription factors that stimulate expression

of other genes– signal transduction molecules that stimulate

cell division– cell-cycle regulators that move through the

cell cycle

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• An oncogene is a proto-oncogene that is mutated and contributes to the development of cancer– Gain of function alteration– Only one allele of the proto-oncogene needs

to be mutated or misexpressed to contribute to cancer• Confers a dominant cancer phenotype

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• The products of tumor-suppressor genes normally regulate cell-cycle checkpoints and initiate the process of apoptosis

• When tumor-suppressor genes are mutated or inactivated, cells are unable to respond normally to cell-cycle checkpoints or are unable to undergo apoptosis if DNA damage is extensive– Leads to more mutations and development of

cancer

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RB1 tumor-suppressor gene

• Loss or mutation of both alleles of the RB1 tumor-suppressor gene contributes to the development of many cancers due to unregulated progression through the cell cycle

© 2012 Pearson Education, Inc. Figure 19.11

© 2012 Pearson Education, Inc.

• Most cancers result from somatic cell mutations, but 50 forms of hereditary cancer (1–2%) are known

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• Most inherited cancer-susceptibility alleles are not sufficient in themselves to trigger cancer development

• At least one other somatic mutation in the other copy of the gene must occur to drive a cell toward tumorigenesis– Loss of heterozygosity

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• Mutations in other genes are also usually necessary to fully express the cancer phenotype

• An example is the development of familial adenomatous polyposis (FAP)

© 2012 Pearson Education, Inc. Figure 19.13