1. Chapter 18 The Genetics of Cancer

2. Cancer- loss of cell cycle control
Begins as single abnormal cell divides & produce more like itself
Grow into a mass called a malignant tumor
Is genetically controlled (because the biochemical which controls mitosis are under genetic control)
Control of telomere length is another function which when lost, causes cancer

3. Telomeres
Chromosome tips that consist of DNA sequence TTAGGG, repeated thousands of times.
Repeats are normally lost as a cell matures (rate of about nucleotides per cell division).
The more specialized the cell, the shorter the telomeres (skin, nerve, & muscle-short telomeres; gametes-long telomeres)
Control of telomere length is another function which when lost, causes cancer.

4. 3 Factors Explain the Role Genes Play in Cancer
Cancer may develop only after several genes mutate.
A gene may confer a cancer susceptibility that is only realized in the presence of an environmental trigger.
Cancer-causing mutations may be present in every cell or only in affected somatic cells.

5. Origin of Cancer Mutations can occur:
In somatic cells - sporadic cancer only affecting the individual
In germline cells - mutations that are inherited (usually require second somatic mutation)

6. General Characteristics of Cancer Cells
Smallest detectable fast growing tumor is half a centimeter in diameter and contains a billion cells. These cells divide at a rate that produces a million or so new cells in an hour. If 99% of the tumor’s cells are destroyed, a million would still be left to multiply. Other cancers are very slow to develop and may not be noticed for years.

7. 6 Characteristics of Cancer
Cancer is heritable because it is passed from parent cell to daughter cells.
Cancer is transplantable. If cancer cells are injected into healthy animal, the disease spreads as more cancer cells divide from the original.
Cancer is dedifferentiated. Less specialized than the cell it descends from.
Cancer cells lack control inhibition. Cancer cells lack the ability to stop dividing once it touches other cells.
Cancer displays invasiveness. An invasive malignant tumor grows irregularly, sending tentacles in all directions. In fact the word “cancer” means crab in Latin because malignant tumors resemble a crab.
Cancer can metastasize- means that it can spread and move to a new location in the body. After cancer spreads, it becomes more difficult to treat, because the DNA of secondary tumor cells often mutate many times causing chromosome abnormalities.

8. Loss of Cell Cycle Control
Timing, rate, and number of cell divisions depend on
Protein growth factors
Signaling molecules from outside the cell
Transcription factors within
Checkpoints control the cell cycle
Loss of control of telomere length may contribute

9. Figure 18.3

10. Cancer-Causing Genes Oncogenes More than 100
Cause cancer when inappropriately activated
Tumor suppressor genes
Deletion or inactivation causes cancer

11. Telomeres Affect the Cell Cycle
Telomerase is the protein and enzyme complex that adds telomere sequences to the ends of chromosomes
Presence of telomerase and telomeres allows cells to pass a cell cycle checkpoint and divide

12. Figure 18.4

13. Germline vs Sporadic Cancer
Figure 18.5

14. Characteristics of Cancer Cells
Divide continually (given space and nutrients)
Contain heritable mutations
Transplantable
Dedifferentiated: lose their specialized identity
Different appearance: reflects dedifferentiation
Lack contact inhibition
Induce angiogenesis (local blood vessel formation)
Increased mutation rate
Invasive: squeeze into any space available
Metastasize: move to new location in the body

15. Figure 18.7

16. Cell Division Rates for Normal and Cancer Cells
Table 18.1
Some cancer cell types grow more slowly than some normal cell types

17. Cancer Can Progress Slowly over Years
Figure 18.6

18. Cancer Stem Cells
Figure 18.8

19. Cancer by Loss of Specialization
Specialized cells lose some of their distinguishing features
Result is dedifferentiation
A chemical “reversine” may stimulate differentiated cells to divide and produce progenitor cells in mice

20. Figure 18.9

21. Cancers from Shifting Balance of Cell Types in a Tissue
Figure 18.10

22. Uncontrolled Tissue Repair May Cause Cancer
Figure 18.11

23. Table 18.3

24. Oncogenes
Proto-oncogenes are normal versions of genes that promote cell division
Expression at the wrong time or in the wrong cell type leads to cell division and cancer
Proto-oncogenes are called oncogenes in their mutated form
One copy of an oncogenic mutation is sufficient to promote cell division

25. Oncogenes: Overexpression of a Normal Function
Viruses integrated next to a proto-oncogene can cause transcription when the virus is transcribed
Moving a proto-oncogene to a new location can separate the coding region from regulatory regions of the gene leading to incorrect expression
Moving a proto-oncogene next to a highly transcribed gene can lead to erroneous transcription of the proto-oncogene

26. Translocation Can Cause Cancer
Figure 18.12

27. Fusion Proteins
Oncogenes are activated when a proto-oncogene moves next to another gene
The gene pair is transcribed together
The double gene product is a fusion protein
Example: chronic myeloid leukemia (CML)

28. Chronic Myeloid Leukemia (CML)
Most patients have a translocated Philadelphia chromosome (tip of 9 on 22)
Abl gene (from Chromosome 9) and bcr (from chromosome 22) gene produce fusion protein
BCR-ABL oncoprotein is a form of tyrosine kinase that excessively stimulates cell division
Understanding cellular changes allowed development of new drug, Gleevec, for treatment

29. Figure 18.13

30. Acute Promyelocystic Leukemia
Translocation of chromosome 15 and 17
Combination of retinoic acid cell surface receptor and an oncogene, myl
Fusion protein functions as a transcription factor; when overexpressed causes cancer
Some patients respond to retinoid drugs

31. Her-2/neu Product of an oncogene
Excessive levels in approximately 25% of breast cancer patients
Too many receptors
Too many signals to divide
Monoclonal antibody drug, Herceptin, binds to receptors, blocking signal to divide

32. Tumor Suppressor Genes
Cancer can be caused by loss of genes that inhibit cell division
Tumor suppressor genes normally stop a cell from dividing
Mutations of both copies of a tumor suppressor gene is usually required to allow cell division
Examples include
Wilms’ tumor, retinoblastoma gene, p53 gene, and BRCA1

33. Retinoblastoma A rare childhood eye cancer
Alfred Knudson, 1971, examined cases of retinoblastoma and determined:
One eye or two with tumor
Age of diagnosis
Relatives with retinoblastoma
Number of tumors per eye
Observed that 50% of children of an affected parent were affected
Frequently, boys and girls were affected equally
Children with bilateral (both eyes) tumors were diagnosed earlier

34. Knudson’s Two Hit Hypothesis
Two mutations are required
One in each copy of the RB gene
For sporadic cases
Retinoblastoma is a result of two somatic mutations
For familial cases
Retinoblastoma is inherited as an autosomal recessive mutation
Followed by a somatic mutation in the normal allele.
The chance of a second somatic mutation is high
Creates a dominant “susceptibility” to cancer in the family

35. p53 p53 acts as a cell cycle protein
Determines if a cell has repaired DNA damage
If damage cannot be repaired, p53 can induce apoptosis
More that 50% of human cancers involve an abnormal p53 gene
Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome
Family members have many different types of cancer at early ages.

36. Figure 18.14

37. BRCA1 Gene A breast cancer susceptibility gene Tumor suppressor gene
Increases risk of developing breast and ovarian cancer
Within families a mutation in BRCA1 inherited as a dominant trait
One mutation in the BRCA1 gene is inherited
Tumors in people acquire a second mutation in the normal allele of BRCA1
Lack of any functional BRCA1 leads to cancer cells
At the level of the cell, BRCA1 acts in a recessive manner

38. Complexities in Genetic Counseling for Familial Breast Cancer
Table 18.5

39. Other Genes BRCA2 encodes for a nuclear protein
Functions in cytokinesis
Increases risk of breast, ovarian, colon, prostate, pancreas, gallbladder, and stomach cancers–also melanomas
Acts with other genes
Table 18.7 in textbook lists other cancer genes

40. Lifetime Risk
Table 18.6

41. Types of Genes Gatekeeper Genes directly control mitosis and apoptosis
Caretaker Genes
control mutation rates and may have an overall effect, when mutant destabilizing the genome

42. An Example of a Series of Changes in a Rapidly Dividing Astrocytoma
Rapidly growing
Loss of both p53 alleles
Mutations of both alleles of several genes on chromosome 9 (an interferon-producing and tumor suppression genes)
An oncogene is activated on chromosome 7
Final stage–loss of chromosome 10, in
end-stage tumor cells

43. Figure 18.15

44. Familial Adenomatuous Polyposis FAP
5% of colon cancer cases are inherited
1 in 5000 in U.S. has FAP
Causes multiple polyps at an early age
Several mutations contribute
APC genes mutate
Activation of oncogenes
Mutations in TGF, p53, and other genes
PRL-3 triggers metastasis
Caretaker genes cause instability

45. Figure 18.16

46. Environment Impacts on Cancer
Exposure to carcinogens increases risk
Smoking increases lung cancer incidence
Exposure to radiation
Burns from overexposure to sunlight can cause skin cancer
Variation in diet
Fatty diets are correlated with increased estrogen and increased breast cancer
“Chemopreventative” nutrients may help decrease risk

47. Cruciferous Vegetables Can Lower Cancer Risk
Figure 18.17

48. Table 18.8

49. Revealing Correlations between Environmental Exposure and Cancers
Population Study
Compares incidence of a type of cancer among different groups of people
Case Control
Identify differences between patients with a type of cancer and healthy individuals matched for multiple characteristics
Prospective Studies
Two or more groups of individuals follow a specific regimen ( e.g., diet or activity plan) and are checked regularly for cancer

50. Human Genome Data and Cancer
Predict risk
May tailor diagnosis and treatment
Specialized drugs
Identifying specific characteristics of cancer cells

51. Table 18.9