Deck 13: Molecular Genetics of the Cell Cycle and Cancer

Question 1

Many types of cancer cells have defects in the
checkpoint. These also tend to have abnormalities in chromosome number or structure. Why would chromosome abnormalities be expected in such cases?

Answer 1

Sharing of similar attributes of the diseases within the cell leads to a condition called Cancer. As a result of mutations all cancer cells show uncontrolled growth.
The conversion of normal cell in to a cancer cell is a multistep process. Genetic instability in the cell population leads to the formation of precursor cell for the development of cancer cells.
Chromosomal aneuploidy or rearrangement of chromosomes, increased number of mutations and gene amplification leads to the genetic instability of the cell. Alterations in the cell cycle, particularly in the G1-to-S phase and also in G1/S check point mainly associated with these changes.
Hence, chromosomal abnormalities are expected in these cases.

Question 2

DNA from cells of a patient with retinoblastoma was analyzed using a Southern blot with a probe for a particular restriction fragment in the RB1 gene. The result from nontumor cells and the results from cells taken from a tumor in each eye are shown in the accompanying diagram.
(a) Which band should be associated with the mutant allele and which with the nonmutant allele?
(b) How is it possible for the bands from the tumor in the left eye to be different from those from the tumor in theright eye?
(c) Explain how cells in the tumor in the right eye can have a "loss of heterozygosity" even though the bands are indistinguishable from those observed from nontumor cells.

Answer 2

Question 3

A woman has a mammogram (breast x-ray) that reveals a suspicious lump of tissue. Cytological analysis of the lump reveals cells with a highly variable chromosome number and many chromosome rearrangements. What does this finding suggest about the malignant or nonmalignant nature of the suspicious growth? Explain your answer.

Answer 3

When breast tumors are found, they tend to have chromosomes that are varied in number and they are also in different arrangements. Whether or not a tumor is malignant or not depends on which genes are affected. A malignant tumor will have chromosomal complications that promote growth and block cell death while invading other areas of the body. So mixed numbers of chromosomes and their different arrangements can be typically malignant.

Question 4

In familial retinoblastoma, there is an average of three retinal tumors per heterozygous carrier of the mutation. Assuming that the number of retinal cells at risk is
in each eye and that each tumor results from an independent loss of heterozygosity, what is the estimated rate of loss of heterozygosity per cell? Should this be regarded as a "mutation rate"? Why or why not?

Question 5

In an inherited cancer syndrome for pancreatic cancer there is an average of two independent tumors resulting from loss of heterozygosity, and
cells are at risk of causing this type of cancer. What is the penetrance of the familial form of the disease?

Question 6

In patients with bilateral retinoblastoma, would the mechanism of loss of heterozygosity in tumors in different eyes be expected to be the same or different? Explain your answer.

Question 7

Mutations in the KRAS gene are frequently found in colon cancer. These mutations are always missense mutations, primarily in codons 12 or 61. Mutations in the APC gene are also associated with colon cancer. In this case, however, nonsense and frameshift mutations are frequent and are scattered throughout most of the coding region. From this information, answer the following and explain.
(a) Is KRAS an oncogene or a tumor-suppressor gene?
(b) Is APC an oncogene or a tumor-suppressor gene?

Question 8

The accompanying gel diagram shows the pattern of bands observed in a Southern blot for three linked RFLPs in and flanking the p53 gene in a family in which Li-Fraumeni syndrome is found. Shown are an affected mother, an unaffected father, and one affected son. The bands AL and AS are for one RFLP (with alleles AL and AS ), and the bands BL and BS are for another RFLP (with alleles BL and BS ). The
in the son. If DNA from tumor cells in the son were assayed for these RFLPs, what pattern of bands would be expected from each of the following cells?

Question 9

If cancer is a "genetic disease," how can it be true that most cases are sporadic (that is, not familial)?

Question 10

Mutagenesis of a RAS gene of budding yeast yields a temperature-sensitive conditional mutation.
(a) Would you expect a cell that is carrying a mutation that prevents Ras from exchanging GDP for GTP at the restrictive temperature to continue to divide at this temperature?
(b) Would the mutation be dominant or recessive?
(c) Would you expect a cell that is carrying a mutation that inactivates the GTPase activity of Ras at 36°C to continue to divide at the restrictive temperature?
(d) Would this mutation be dominant or recessive?

Question 11

A human cell in culture is homozygous for a temperature-sensitive mutation in a gene necessary to repair double-stranded breaks in DNA. If cells were irradiated at the restrictive temperature, at what stage of the cell division cycle would you expect the mutant cells to accumulate?

Question 12

Human papilloma virus (HPV) is present in greater than 90 percent of cervical cancers. HPV encodes two proteins, E6 and E7, that are potent contributors to its tumorigenicity. E7 is known to disable RB; E6 binds to p53 and targets it for degradation. Discuss how these activities might contribute to the development of the cancerous state in infected cells.

Question 13

What role does Ras-GTP play in intracellular signaling that makes Ras a proto-oncogene?

Question 14

The accompanying pedigree includes individuals affected with adenomatous polyposis, and the diagram of the gel shows a restriction fragment from a number of alleles of APC , mutant forms of which are associated with this cancer. Four sizes of restriction fragments (a through d) are observed. Individuals in generations I and II are old enough to have developed the cancer if they carry a mutant APC allele, but the individuals in generation III are all too young to have developed the disease. Identify the high-risk individuals in generation III and those who are not at risk. (Note that a mutant allele and a nonmutant allele can yield the same size restriction fragment.)

Question 15

Bax is a protein that promotes apoptosis and is normally kept inactive in healthy cells by Bcl2, which forms heterodimers with Bax. Mutations in the gene Bax are found in cancer cells
(a) Is Bax an oncogene or a tumor-suppressor gene?
(b) What type of mutations might be found in this gene in cancer cells?
(c) Will these mutations be recessive or dominant?

Question 16

The p53 protein is defective in more than half of all cancers. Why might this be expected?

Question 17

What does it mean to say that mutations in the retinoblastoma gene RB1 are "dominant at the organismic level but recessive at the cellular level"?

Question 18

Draw a diagram showing how recombination between homologous chromosomes during mitosis can result in a cell lineage with loss of heterozygosity for a p53 mutation. What other genes also lose heterozygosity in this process?

Question 19

How does the normal retinoblastoma protein function to hold mammalian cells at the
restriction point ("start")?

Question 20

What cell-cycle checkpoints were highlighted in this chapter? What event or events cause each checkpoint to be activated to stop the cell division cycle?