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

2. 19.1 Cancer Is a Genetic Disease That Arises at the Level of Somatic Cells

4. Figure 19-1 (a) Spectral karyotype of a normal cell
Figure 19-1 (a) Spectral karyotype of a normal cell. (b) Karyotype of a cancer cell showing translocations, deletions, and aneuploidy—characteristic features of cancer cells.
Figure 19.1

5. Figure 19-1a (a) Spectral karyotype of a normal cell
Figure 19-1a (a) Spectral karyotype of a normal cell. (b) Karyotype of a cancer cell showing translocations, deletions, and aneuploidy—characteristic features of cancer cells.
Figure 19.1a

6. Figure 19-1b (a) Spectral karyotype of a normal cell
Figure 19-1b (a) Spectral karyotype of a normal cell. (b) Karyotype of a cancer cell showing translocations, deletions, and aneuploidy—characteristic features of cancer cells.
Figure19.1b

7. 19.1 Cancer Is a Genetic Disease
What Is Cancer?
The Clonal Origin of Cancer Cells
The Cancer Stem Cell Hypothesis
Cancer As a Multistep Process, Requiring Multiple Mutations

9. Figure 19-2 Copyright © 2006 Pearson Prentice Hall, Inc.
Figure 19-2 The incidence of most cancers rises exponentially with age. This graph shows that the logarithmic plot of the incidence rate has a linear relationship with the logarithmic plot of the patient’s age.
Figure Copyright © 2006 Pearson Prentice Hall, Inc.

10. 19.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair and Chromatin Modifications
Genomic Instability and Defective DNA Repair

11. Figure 19-3a DNA amplifications in neuroblastoma cells
Figure 19-3a DNA amplifications in neuroblastoma cells. (a) Two cancer genes (MYCN in red and MDM2 in green) are amplified as small DNA fragments that remain separate from chromosomal DNA within the nucleus. These units of amplified DNA are known as double minute chromosomes. Normal chromosomes are stained blue. (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 on the normal parental chromosomes (white arrows). Normal chromosomes are stained red.
Figure 19.3a

12. Homogeneous
Figure 19-3b DNA amplifications in neuroblastoma cells. (a) Two cancer genes (MYCN in red and MDM2 in green) are amplified as small DNA fragments that remain separate from chromosomal DNA within the nucleus. These units of amplified DNA are known as double minute chromosomes. Normal chromosomes are stained blue. (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 on the normal parental chromosomes (white arrows). Normal chromosomes are stained red.
Figure 19.3b

13. Figure 19-4 A reciprocal translocation involving the long arms of chromosomes 9 and 22 results in the formation of a characteristic chromosome, the Philadelphia chromosome, which is associated with chronic myelogenous leukemia (CML). The t(9;22) translocation results in the fusion of the C-ABL proto-oncogene on chromosome 9 with the BCR gene on chromosome 22. The fusion protein is a powerful hybrid molecule that allows cells to escape control of the cell cycle, contributing to the development of CML.
Figure 19.4

16. Scientists Decode Set of Cancer Genes
Thursday, November 6, 2008
Scientists Decode Set of Cancer Genes
By DENISE GRADY
Published: November 5, 2008
For the first time, researchers have decoded all the genes of a person with cancer and found a set of mutations that may have caused the disease or aided its progression. Using cells donated by a woman in her 50s who died of leukemia, the scientists sequenced all the DNA from her cancer cells and compared it to the DNA from her own normal, healthy skin cells. Then, they zeroed in on 10 mutations that occurred only in the cancer cells, apparently spurring abnormal growth, preventing the cells from suppressing that growth and enabling them to fight off chemotherapy.

17. Link:
NYTimes article on new teatment

18. Study Divides Breast Cancer Into Four Distinct Types
Published: September 23, 2012
Study Divides Breast Cancer Into Four Distinct Types
Triple negative
Luminal A
Luminal B
HER2-enriched
link to article

19. HNPCC- Hereditary Nonpolyposis Colorectal Cancer
Pedigree of a family with HNPCC. Families with HNPCC are defined as those in which at least three relatives in two generations have been diagnosed with colon cancer, with one relative diagnosed at less than 50 years of age. Colon cancer: C; stomach cancer: S; endometrial cancer: E; pancreatic cancer: P; bladder/urinary cancer: B. Blue symbols indicate family members with colon cancer; diagonal stripes mean that diagnosis is uncertain; orange symbols indicate other tumors. Symbols with slashes indicate deceased individuals. Reprinted with permission from Aaltonen et.al. Clues to the pathogenesis of familial colorectal cancer. Science 260: , Figure 1. Copyright 1993 AAAS.

20. 19.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair and Chromatin Modifications
Chromatin Modifications and Cancer Epigenetics

21. 19.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation
The Cell Cycle and Signal Transduction
Cell Cycle Control and Checkpoints

22. Figure 19-5 Checkpoints and proliferation decision points monitor the progress of the cell through the cell cycle.
Figure 19.5
© 2012 Pearson Education, Inc.

23. Figure 19-6 Relative expression times and amounts of cyclins during the cell cycle. Cyclin D1 accumulates early in G1 and is expressed at a constant level through most of the cycle. Cyclin E accumulates in G1, reaches a peak, and declines by mid S phase. Cyclin D2 begins accumulating in the last half of G1, reaches a peak just after the beginning of S, and then declines by early G2. Cyclin A appears in late G1, accumulates through S phase, peaks at the G2/M transition, and is rapidly degraded. Cyclin B peaks at the G2/M transition and declines rapidly in M phase.
Figure 19.6

24. Figure 19-7 Transition from G2 to M phase is controlled by CDK1 and cyclin B. These molecules interact to form a complex that adds phosphate groups to cellular components. These in turn bring about the structural and biochemical changes necessary for mitosis (M phase).
Figure 19.7

25. 19.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation
Control of Apoptosis

26. Figure 19-8 (a) A normal white blood cell (bottom) and a white blood cell undergoing apoptosis (top). Apoptotic bodies appear as grape-like clusters on the cell surface. (b) The relative concentrations of the Bcl2 and BAX proteins regulate apoptosis. A normal cell contains a balance of Bcl2 and BAX, which form inactive heterodimers. A relative excess of Bcl2 results in Bcl2 homodimers, which prevent apoptosis. Cancer cells with Bcl2 overexpression are resistant to chemotherapies and radiation therapies. A relative excess of BAX results in BAX homodimers, which induce apoptosis. In normal cells, activated p53 protein induces transcription of BAX and inhibits transcription of Bcl2, leading to cell death. In many cancer cells, p53 is defective, preventing the apoptotic pathway from removing the cancer cells.
Figure 19.8

27. 19.4 Proto-oncogenes and Tumor-Suppressor Genes are Altered in Cancer Cells

28. Table 19-1 Some Proto-oncogenes and Tumor Suppressor Genes

29. The ras Proto-oncogenes

30. Figure 19-9 A signal transduction pathway mediated by Ras.

31. Figure 18-12 Copyright © 2006 Pearson Prentice Hall, Inc.
The ras proto-oncogene encodes a protein of 189 amino acids. In the normal protein, glycine is encoded at position 12, and glutamine at position 61. Ras proteins from several tumors contain single amino acid substitutions at one of these positions. These mutations convert the ras proto-oncogene into a tumor-promoting oncogene. K-ras and N-ras are mutant alleles of the ras proto-oncogene.
Figure Copyright © 2006 Pearson Prentice Hall, Inc.

32. The cyclin D1 and cyclin E Proto-oncogenes
The p53 Tumor-Suppressor Gene–
the “guardian of the genome”
The RB1 Tumor-Suppressor Gene

33. Figure 19.10
© 2012 Pearson Education, Inc.

34. Figure (a) In familial retinoblastoma, one mutation (designated as RB1) is inherited and present in all cells. A second mutation at the retinoblastoma locus in any retinal cell contributes to uncontrolled cell growth and tumor formation. (b) In sporadic retinoblastoma, two independent mutations in both alleles of the retinoblastoma gene within a single cell are acquired sequentially, also leading to tumor formation.
Figure 19.11

35. Figure In the nucleus during G1, pRB interacts with and inactivates transcription factor E2F. As the cell moves from G1 to S phase, a CDK4/cyclinD1 complex forms and adds phosphate groups to pRB. As pRB becomes phosphorylated, E2F is released and becomes transcriptionally active, allowing the cell to pass through S phase. Phosphorylation of pRB is transitory; as CDK/cyclin complexes are degraded and the cell moves through the cell cycle to early G1, pRB phosphorylation declines.
Figure 19.12

36. 19.5 Cancer Cells Metastasize and Invade Other Tissues

37. 19.6 Predisposition to Some Cancers Can Be Inherited

38. Table 19-2 Inherited Predispositions to Cancer

39. Figure 19-13 A model for the multistep development of colon cancer
Figure A model for the multistep development of colon cancer. The first step is the loss or inactivation of one allele of the APC gene on chromosome 5. In FAP cases, one mutant APC allele is inherited. Subsequent mutations involving genes on chromosomes 12, 17, and 18 in cells of benign adenomas can lead to a malignant transformation that results in colon cancer. Although the mutations on chromosomes 12, 17, and 18 usually occur at a later stage than those involving chromosome 5, the sum of changes is more important than the order in which they occur.
Figure 19.13

40. But…cancers can vanish on their own

41. 19.7 Viruses Contribute to Cancer in Both Humans and Animals

42. Figure The genome of a typical retrovirus is shown at the top of the diagram. The genome contains repeats at the termini (R), the U5 and U3 regions that contain promoter and enhancer elements, and the three major genes that encode viral structural proteins (gag and env) and the viral reverse transcriptase (pol). RNA transcripts of the entire viral genome comprise the new viral genomes. If the retrovirus acquires all or part of a host cell proto-oncogene (c-onc), this gene (now known as a v-onc) is expressed along with the viral genes, leading to overexpression or inappropriate expression of the v-onc gene. The v-onc gene may also acquire mutations that enhance its transforming ability.
Figure 19.14

43. Human Viruses Associated with Cancer

44. 19.8 Environmental Agents Contribute to Human Cancers

45. Obesity responsible for 100,000 cancer cases annually
By Matt Sloane, CNN Medical News
November 5, :58 p.m. EST