Chapter 19 Lecture Concepts of Genetics Tenth Edition Cancer and Regulation of the Cell Cycle

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

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 © 2012 Pearson Education, Inc.

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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. At the G1/S, G2/M, and M checkpoints, cells decide whether to proceed to the next stage of the cell cycle

© 2012 Pearson Education, Inc. Regulation of cell-cycle progress is mediated by cyclins and cyclin-dependent kinases (CDKs) that regulate synthesis and destruction of cyclin proteins

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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

© 2012 Pearson Education, Inc. 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