1. GENETICS A Conceptual Approach
Benjamin A. Pierce
GENETICS
A Conceptual Approach
FIFTH EDITION
CHAPTER 23
Cancer Genetics
© 2014 W. H. Freeman and Company

2. Villa designed by Renaissance architect Andrea Palladio, for whom the palladin gene is named. Palladin encodes an essential component of a cell’s cytoskeleton; when mutated, palladin contributes to the spread of pancreatic cancer. [La Rotunda a Vicenzo by Giovanni Giaconi.]

3. Figure 23.1 Pancreatic cancer is inherited as an autosomal dominant trait in a family that possesses a mutant palladin gene. [After K. L. Pogue et al., Plos Medicine 3:2216–2228, 2006.]

4. 23.1 Cancer Is a Group of Diseases Characterized by Cell Proliferation
Tumor Formation
Cancer as a Genetic Disease
The Role of Environmental Factors in Cancer

5. Figure 23.2 Abnormal proliferation of cancer cells produces a tumor that crowds out normal cells. (a) Metastatic lung-tumor masses (white protrusions) growing on a human liver. (b) A light micrograph of the section in part (a) showing areas of small, dark tumor cells invading a region of larger, lighter normal liver cells.

6. ****Hallmarks of Pathways to Malignant Cancer
Cancer cells acquire self-sufficiency in the signaling processes that stimulate division and growth.
Cancer cells are abnormally insensitive to signals that inhibit growth.
Cancer cells can evade programmed cell death.
Cancer cells acquire limitless replicate potential.
Cancer cells develop ways to nourish themselves by stimulating angiogenesis.
Cancer cells acquire the ability to invade other tissues and colonize them (metastasize).

8. Tumor Formation: A Distinct Mass of Abnormal Cells
Benign tumor: the tumor remains localized.
Malignant tumor: tumor cells invade other tissues.
Metastasis: the tumor cells induce secondary tumors.

9. Cancer as a Genetic Disease
Genetic evidence for cancer
Carcinogens, chromosomal abnormalities, inheritance
Knudson’s multistep model of cancer
Requires several mutations
The clonal evolution of tumors
Tumor cells acquire more mutations that allow them to become increasingly more aggressive in their proliferate properties.

10. Figure 23.3 Alfred Knudson proposed that retinoblastoma results from two separate genetic defects, both of which are necessary for cancer to develop.

11. Figure 23.4 Through clonal evolution, tumor cells acquire multiple mutations that allow them to become increasingly aggressive and proliferative. To conserve space, a dashed arrow is used to represent a second cell of the same type in each case.

12. Role of Environmental Factors in Cancer
Cancer is a genetic disease, but most are not inherited
Different cancer incidence in different parts of the world (Table 23.2)
Factors contributing to cancer (Table 23.3):
Tobacco use
Obesity
Alcohol
UV radiation

15. 23.2 Mutations in a Number of Different Types of Genes Contribute to Cancer
Oncogenes and Tumor-Suppressor Genes
Genes That Control the Cycle of Cell Division
DNA-Repair Genes
Genes That Regulate Telomerase
Genes That Promote Vascularization and the Spread of Tumors
MicroRNAs and Cancer
The Cancer Genome Project

16. Oncogenes and Tumor-Suppressor Genes
Oncogenes: mutated, dominant-acting stimulatory genes that cause cancer
Proto-oncogenes: responsible for basic cellular functions in normal cells; when mutated, they become oncogenes
Tumor-suppressor genes: mutated recessive-acting inhibitory genes that are inactive
Loss of heterozygosity

17. Figure 23.5 Both oncogenes and tumor-suppressor genes contribute to cancer but differ in their modes of action and dominance.

19. Figure 23.6 Loss of heterozygosity often leads to cancer in a person heterozygous for a tumor-suppressor gene.

21. Mutations in Genes That Control the Cycle of Cell Division
Control of the cell cycle
Cyclin-dependent kinases (CDKs), cyclins
G1-to-S transition
Retinoblastoma protein (RB)
G2-to-M transition
Mitosis-promoting factor (MPF)
Spindle assembly checkpoint
Mutations in cell-cycle control and cancer

22. Figure 23.7 The RB protein helps control the progression through the G1/S checkpoint by binding transcription factor E2F.
RB name comes from a protein mutated in a genetically inherited cancer of the retina.
RB is a tumor suppressor gene that controls the progression of the cell cycle to move past the S phase.

23. P53 and RB have critical roles in the regulation of the cell cycle

25. Figure 23.8 Progression through the G2/M checkpoint is regulated by cyclin B.

26. Figure 1. Cytosolic and mitochondrial p53 apoptotic pathways
Figure 1. Cytosolic and mitochondrial p53 apoptotic pathways. In the cytosolic p53 apoptotic pathway, nuclear p53 induces Puma expression, which in turn releases cytosolic p53 held inactive in the cytoplasm through binding to Bcl-XL. Then, cytosolic p53 induces Bax oligomerization and mitochondrial translocation. Accumulation of p53 in the cytosol as a consequence of normal intracellular transport or stable monoubiquitination is the major source for mitochondrial p53. In the mitochondria, p53 induces Bax and Bak oligomerization, antagonizes the Bcl-2 and Bcl-XL antiapoptotic effect, and forms a complex with cyclophilin D in the mitochondrial inner membrane. These changes result in marked disruption of mitochondrial membranes and subsequent release of both soluble and insoluble apoptogenic factors. MPT, mitochondrial permeability transition; U, ubiquitin.

28. Concept Check 1
What would be the most likely effect of a mutation that caused cyclin B to be unable to bind to CDK?
Cells pass through the G2/M checkpoint and enter mitosis even when DNA has not been replicated.
Cells never pass through the G1/S checkpoint.
Cells pass through mitosis more quickly than unmutated cells do.
Cells fail to pass through the G2/M checkpoint and do not enter into mitosis.

29. Concept Check 1
What would be the most likely effect of a mutation that caused cyclin B to be unable to bind to CDK?
Cells pass through the G2/M checkpoint and enter mitosis even when DNA has not been replicated.
Cells never pass through the G1/S checkpoint.
Cells pass through mitosis more quickly than unmutated cells do.
Cells fail to pass through the G2/M checkpoint and do not enter into mitosis.

30. Mutations in Genes That Control the Cycle of Cell Division
Signal-transduction pathways
Signals trigger a cascade of intracellular reactions producing a specific response
Ras protein
Receptors

31. Figure 23.9 The Ras signal-transduction pathway conducts signals from growth factors and hormones to the nucleus and stimulates the cell cycle. Mutations in this pathway often contribute to cancer.

32. Ras proteins are activated when they .
Concept Check 2
Ras proteins are activated when they
bind GTP
release GTP
bind GDP
undergo acetylation

33. Ras proteins are activated when they .
Concept Check 2
Ras proteins are activated when they
bind GTP
release GTP
bind GDP
undergo acetylation

34. Mutations in Genes That Control the Cycle of Cell Division
DNA-Repair Genes
Genes That Regulate Telomerase
Genes That Promote Vascularization and the Spread of Tumors
MicroRNAs and Cancer
The Cancer Genome Project

35. Concept Check 3
Which type of mutation in telomerase could be associated with cancer cells?
mutations that produce an inactive form of telomerase
mutations that decrease the expression of telomerase
mutations that increase the expression of telomerase
All of the above.

36. Concept Check 3
Which type of mutation in telomerase could be associated with cancer cells?
mutations that produce an inactive form of telomerase
mutations that decrease the expression of telomerase
mutations that increase the expression of telomerase
All of the above.

37. 23.3 Epigenetic Changes Are Often Associated with Cancer
Alterations to DNA methylation or chromatin structure are seen in many cancers
Hypermethylation or hypomethylation
Reversible and not a mutation

38. 23.4 Colorectal Cancer Arises Through the Sequential Mutation of a Number of Genes
Excellent example of sequential mutation
Led to tumor progression model

39. Figure 23.10 Mutations in multiple genes contribute to the progression of colorectal cancer.

40. Chromosomal instability is a general feature of cancer cells
23.5 Changes in Chromosome Number and Structure Are Often Associated with Cancer
Chromosomal instability is a general feature of cancer cells
Deletions, inversions and translocations
Example: a reciprocal translocation between chromosome 9 and 22 causes chronic myelogenous leukemia.
Aneuploidy

41. Figure A reciprocal translocation between chromosomes 9 and 22 causes chronic myelogenous leukemia.

42. Figure 23.12 A reciprocal translocation between chromosomes 8 and 14 causes Burkitt lymphoma.

43. Figure Cancer cells often possess chromosome abnormalities, including extra chromosomes, missing chromosomes, and chromosome rearrangements. Shown here are chromosomes from a colon-cancer cell, which has numerous chromosome abnormalities. [Courtesy of Dr. Peter Duesberg, University of California at Berkeley.]

44. 23.6 Viruses Are Associated with Some Cancers
Retroviruses cause cancer by
mutating and rearranging proto-oncogenes
inserting strong promoters near proto-oncogenes
Human papilloma virus and cervical cancer

46. Figure Retroviruses cause cancer by (a) mutating and rearranging proto-oncogenes or (b) inserting strong promoters near proto-oncogenes.