Chapter 19 Lecture

Concepts of Genetics Tenth Edition

Cancer and Regulation of the Cell Cycle

Chapter Contents

19.1 Cancer Is a Genetic Disease That Arises at the Level of Somatic Cells

19.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications

19.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation

19.4 Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells

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Chapter Contents

19.5 Cancer Cells Metastasize and Invade Other Tissues 19.6 Predisposition to Some Cancers Can Be Inherited 19.7 Viruses Contribute to Cancer in Both Humans and

Animals 19.8 Environmental Agents Contribute to Human Cancers

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19.1 Cancer Is a Genetic Disease That Arises at the Level of Somatic Cells

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Section 19.1

• 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

• Genomic alterations that are associated with cancer

range from single-nucleotide substitutions to large-scale chromosomal rearrangements, amplifications, and deletions

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Section 19.1

• 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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Section 19.1 • Benign tumors result from unregulated cell growth

forming a multicellular mass that can be removed by surgery, causing no serious harm

• Malignant tumors may result from metastasized cells invading other tissue and causing life-threatening problems

• All cancer cells in primary and secondary tumors are clonal, meaning that they originated from a common ancestral cell that accumulated numerous specific mutations

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Section 19.1

• Reciprocal translocations are characteristic of many cancers

• Burkitt’s lymphoma shows reciprocal translocations between chromosome 8 and chromosomes 2, 14, or 22

• X-chromosome inactivation occurs early in development and occurs at random. All cancer cells within a tumor, both primary and metastatic, within one female individual, contain the same inactivated X chromosome

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Section 19.1

• Many scientists believe that tumors are composed of a mixture of cells, many of which do not proliferate

• The cancer stem cell hypothesis: those tumor cells that do proliferate and give rise to all the cells are cancer stem cells that have the capacity for self-renewal

• Evidence is accumulating that cancer stem cells do exist and have been identified in – leukemia - brain cancer – breast cancer - colon cancer – ovary cancer - pancreatic cancer – prostate cancer

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Section 19.1

• Cancer is a multistep process requiring multiple mutations

• 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

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Section 19.1

• Another indication of the multistep process in cancer formation is the delay that occurs between exposure to carcinogens and the appearance of the cancer – An incubation period of five to eight years separated exposure to

radiation from atomic explosions at Hiroshima and Nagasaki and the onset of leukemia

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Section 19.1

• 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 two or more genetic alterations that progressively release the cell from the controls

• Driver mutations give growth advantage to tumor cells

• Passenger mutations have no direct contribution to the cancer phenotype. The mutations may be acquired over time, perhaps as a result of the increased levels of DNA damage that accumulate in cancer cells 14

19.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability,

DNA Repair, and Chromatin Modifications

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Section 19.2

• Cancer cells show higher than normal rates of – mutation – chromosomal abnormalities – genomic instability

• The high level of genomic instability in cancer cells is known as the mutator phenotype

• The genomic instability in cancer cells manifests itself in gross defects such as translocations, aneuploidy, chromosome loss, DNA amplification, chromosomal deletions

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DNA amplifications in neuroblastoma cells. (a) Two cancer genes are amplified as small DNA fragments that remain separate from chromosomal DNA within the nucleus. These units of amplified DNA are double minute chromosomes (b) Multiple copies of the MYCN gene are amplified within one large region called a heterogeneous staining region (green). Single copies of the MYCN gene are visible as green dots at the ends of the normal parental chromosomes

Section 19.2 • Often cancers show specific chromosomal defects that

are used to diagnose the type and stage of the cancer – Chronic myelogenous leukemia (CML): translocation of the

C-ABL gene on chr 9 into the BCR gene on chr 22

– This structure is known as the Philadelphia chromosome

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Section 19.2

• A number of inherited cancers are caused by defects in genes that control DNA repair

• Xeroderma pigmentosum (XP) – Defective nucleotide excision repair leading to skin cancer

• Hereditary nonpolyposis colorectal cancer (HNPCC)

– Autosomal dominant syndrome (1/200-1000 affected) – Increased risk of colon, ovary, uterine, and kidney cancers – Eight genes implicated, with four involved in DNA mismatch repair

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Section 19.2

• Epigenetics is the study of factors that affect gene expression but do not alter the nucleotide sequence of DNA – DNA methylation – histone acetylation and phosphorylation

• The genomic patterns and locations of these modifications can affect gene expression

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Section 19.2

• DNA methylation is responsible for gene silencing associated with parental imprinting, heterochromatin gene expression, and X chromosome inactivation

• Genes that encode histone acetylases, deacetylases, methyltransferases, and demethylases are often mutated or aberrantly expressed in cancer cells

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19.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation

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Section 19.3

• 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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Section 19.3 • Interphase of the cell cycle is the interval between mitotic divisions. During this, the 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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Section 19.3

• 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

• 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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Section 19.3

• 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

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Section 19.3

• The steps in apoptosis are – fragmentation of nuclear envelope – disruption of internal cellular structures – dissolution of cell into small, spherical apoptotic bodies – engulfing of the apoptotic bodies by phagocytic cells

• A series of proteases called caspases are responsible for initiating apoptosis and for digesting intracellular components

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