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Genetics: From Genes to Genomes

Leland Hartwell, Michael L. Goldberg, Janice Fischer

Chapter 20

The Genetics of Cancer - all with Video Answers

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Chapter Questions

04:30

Problem 1

For each of the terms in the left column, choose the best matching phrase in the right column.
a. mitogenic growth
1. mutations in these genes are factor dominant for cancer formation
b. tumor-suppressor
2. programmed cell death genes
c. cyclin-dependent
3. series of steps by which a message is protein kinases transmitted
d. apoptosis
4. proteins that are active cyclically during the cell cycle
e. oncogenes
5. control progress in the cell cycle in response to DNA damage
f. growth factor
6. mutations in these genes are recessive receptor at the cellular level for cancer formation
g. signal transduction
7. signals a cell to leave $\mathrm{G}_{0}$
h. checkpoints
8. cell-cycle enzymes that phosphorylate proteins
i. cyclins
9. protein that binds a horm

Bryan Valdivia
Bryan Valdivia
Numerade Educator
11:20

Problem 2

Characterize the differences between tumor cells and normal cells in terms of the following properties. In cancer cells, how might each of these properties contribute to tumor progression?
a. contact inhibition
b. autocrine stimulation
c. apoptosis
d. telomerase expression
e. senescence due to telomere shortening
f. genomic stability
g. angiogenesis
h. metastasis
i. susceptibility to immune surveillance

Khalida Dawar
Khalida Dawar
Numerade Educator
03:13

Problem 3

The incidence of colon cancer in the United States is 30 times higher than it is in India. Differences in diet and/or genetic differences between the two populations may contribute to these statistics. How would you assess the role of each of these factors?

Syed Vasi
Syed Vasi
Numerade Educator
02:12

Problem 4

Some germ-line mutations predispose individuals to cancer, yet often environmental factors (chemicals, exposure to radiation) are considered major risks for developing cancer. Do these views of the cause of cancer conflict, or can they be reconciled?

VS
Vivek Singh
Numerade Educator
01:28

Problem 5

A carcinogenic compound is placed on the skin of inbred laboratory mice. In many of these mice, skin tumors develop at the site of exposure, but only months after the chemical is no longer detectable. Why don't all the mice develop tumors, and why don't the tumors appear much sooner?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
02:34

Problem 6

You have decided to study genetic factors associated with colon cancer. An extended family from Morocco in which the disease presents itself in a large percentage of family members at a very early age has come to your attention. (The pedigree is shown in the accompanying diagram.) In this family, individuals either get colon cancer before the age of $16,$ or they don't get it at all.
a. Based on the information you have been given, what evidence, if any, suggests an inherited contribution to the development of this disease?
b. You decide to take a medical history of all of the 33 people indicated in the pedigree and discover that a very large percentage drink a special coffee on a daily basis, while the others do not. The only ones who don't drink the coffee are individuals numbered I-1, II-2, II-4, II-9, III-7, III-13, IV-1, and IV-3. Could the drinking of this special coffee possibly play a role in colon cancer? Explain your answer.

Lucas Finney
Lucas Finney
Numerade Educator
00:37

Problem 7

B cells are specialized blood cells that secrete antibodies. Normally, human blood has millions of different types of B cells making millions of different kinds of antibody molecules. This variety occurs because, as described in the Fast Forward Box in Chapter 13 entitled Programmed DNA Rearrangements and the Immune
System, antibody genes undergo rearrangements in the precursors of B cells. Individual B cell precursors rearrange their antibody genes in different ways. In the blood of patients with cancers called $B$ cell lymphomas, almost all of the antibody molecules are all of one type, but this single type of antibody is different in different lymphoma patients.
a. Based on this information, provide a brief description of the genesis of $\mathrm{B}$ cell lymphomas, focusing on the cells that are overproliferating.
b. How does the nature of $\mathrm{B}$ cell lymphomas provide support for the clonal theory of cancer shown in Fig. $20.6 ?$

Rikhil Makwana
Rikhil Makwana
Numerade Educator
07:32

Problem 8

Molecules outside and inside the cell regulate the cell cycle, making it start or stop.
a. What is an example of an external molecule that regulates the cell cycle?
b. What is an example of a molecule inside the cell that is involved in cell-cycle regulation?

Khalida Dawar
Khalida Dawar
Numerade Educator
02:21

Problem 9

Put the following steps in the correct ordered
sequence.
a. kinase cascade
b. activation of a transcription factor
c. hormone binds transmembrane receptor
d. expression of target genes in the nucleus
e. Ras molecular switch

Kemuel Roberts
Kemuel Roberts
Numerade Educator
01:28

Problem 10

a. Would you expect a cell to continue or to stop dividing at a nonpermissive high temperature if it is a temperature-sensitive Ras mutant whose protein product is fixed in the GTP-bound form at nonpermissive temperature?
b. What would you expect if you had a temperaturesensitive mutant in which the Ras protein stays in the GDP-bound form at high temperature?

Jennifer Stoner
Jennifer Stoner
Numerade Educator
01:09

Problem 11

Two different protein complexes called $S C F$ and $A P C$ covalently add a small polypeptide called ubiquitin to cyclin proteins. The addition of ubiquitin to a protein targets that protein to be degraded by another protein complex called the proteasome. The SCF complex is activated during S phase, and the APC complex is activated during M phase.
a. To which cyclins (A, B, D, or E in Fig. 20.14) do you think SCF couples ubiquitin? What about the APC?
b. How might cells activate SCF and APC only at the correct times?

Manish Jain
Manish Jain
Numerade Educator
04:20

Problem 12

One of the hallmarks of mitotic anaphase is the separation of sister chromatids. A protein complex called cohesin holds sister chromatids together, as described
in Fig. $12.25 .$ Based on the answer you have just given for Problem $11,$ propose a mechanism that would allow sister chromatids to separate during anaphase. How might your proposed mechanism also explain the checkpoint operating in $\mathrm{M}$ phase that prevents sister chromatid separation until all the chromosomes have connected properly to the mitotic spindle?

John Barone
John Barone
Numerade Educator
02:20

Problem 13

Concerning the Tools of Genetics Box Analysis of Cell-Cycle Mutants in Yeast:
a. Describe how you would use replica plating of mutagenized, haploid yeast cells to identify temperature-sensitive (ts) mutations in essential genes needed for yeast growth and survival.
b. Among the many ts mutations you found in part
(a), how would you distinguish mutations in genes needed for cell-cycle progression from those in genes needed for other aspects of the life of yeasts?
c. If you had a large collection of yeast cell-cycle mutants, how would you determine which of the mutations are in the same gene and which are in different genes?
d. Figures $A$ and $B$ in the Tools of Genetics Box show a culture of a single yeast $t s$ cell-cycle mutant. The two figures show the same petri plate of cells examined at different times: Fig. A before the shift to restrictive temperature, and Fig. $\mathrm{B}$ after the temperature shift. Cells with small buds in Fig. A arrest as a single large-budded cell in Fig. B (the yellow arrows point to an example). In contrast, cells with large buds in Fig. A arrest as two large-budded cells in Fig. B $(\text {red arrows}) .$ What do these observations tell you about when during the cell cycle the protein product of the gene in question normally functions?
e. Describe in detail an experiment to show that the human gene for the cyclin-dependent kinase CDK1 can replace the function of the homologous gene in yeast.

James Kiss
James Kiss
Numerade Educator
01:47

Problem 14

Are genome and karyotype instabilities consequences or causes of cancer?

Nicholas Mogoi
Nicholas Mogoi
Numerade Educator
02:54

Problem 15

Which one of the following events is unlikely to be associated with cancer?
a. mutation of a cellular proto-oncogene in a normal diploid cell
b. a chromosomal translocation with a breakpoint near a cellular proto-oncogene
c. deletion of a cellular proto-oncogene
d. mitotic nondisjunction in a cell carrying a deletion of a tumor-suppressor gene
e. incorporation of a cellular oncogene into a retrovirus chromosome

Bryan Valdivia
Bryan Valdivia
Numerade Educator
02:24

Problem 16

Why don't all loss-of-function mutations that are recessive at the cellular level behave as dominants at the organismal level? Is this property restricted to tumorsuppressor gene mutations?

VS
Vivek Singh
Numerade Educator
05:29

Problem 17

Chromothripsis is a rare phenomenon, first discovered in cancer cells, where a single chromosome "shatters" into many fragments and is reassembled in a rearranged form by the DNA repair machinery. (The underlying mechanism causing the shattering is not understood.) Approximately $2 \%$ of cancers contain cells with a shattered chromosome. Explain how chromothripsis could contribute to cancer.

Khalida Dawar
Khalida Dawar
Numerade Educator
03:46

Problem 18

The chromosome $9 / 22$ translocation associated with CML (chronic myelogenous leukemia) is called the Philadelphia chromosome after the city in which its cancer association was first discovered in 1960 . People with CML do not inherit this translocation it occurs in somatic cells. Why do you think that this particular translocation that fuses the $b c r$ and $a b l$ genes happens independently in the somatic cells of many different people?

Jessica Wolf
Jessica Wolf
Numerade Educator
01:18

Problem 19

A female patient 19 years old, whose symptoms are anemia and internal bleeding due to a massive buildup of leukemic white blood cells, is diagnosed with chronic myelogenous leukemia (CML). Karyotype analysis shows that the leukemic cells of this patient are heterozygous for a reciprocal translocation involving chromosomes 9 and $22 .$ However, none of the normal, nonleukemic cells of this patient contain the translocation. Which of the following statements is true and which is false?
a. The translocation results in the inactivation (loss of function) of a tumor-suppressor gene.
b. The translocation results in the inactivation (loss of function) of an oncogene.
c. There is a $50 \%$ chance that any child of this patient will have CML.
d. This patient is a somatic mosaic in terms of the karyotype.
e. DNA extracted from leukemic cells of this patient, if taken up by normal mouse tissue culture cells, could potentially transform the mouse cells into cells capable of causing tumors.
f. The normal function of the affected tumor-suppressor gene or proto-oncogene at the translocation breakpoint could potentially block the function of the cyclin proteins that drive the cell cycle forward.
g. Two rare events must have occurred to disrupt both copies of the tumor-suppressor gene or proto-oncogene at the translocation breakpoint in the leukemic cells.
h. A possible treatment of the leukemia would involve a drug that would turn on the expression of the tumor-suppressor gene or oncogene at the translocation breakpoint in the leukemic cells.

James Kiss
James Kiss
Numerade Educator
02:39

Problem 20

Describe a molecular test to determine if chemotherapy given to the patient described in Problem 19 would be completely successful. That is, devise a method to make sure that the patient's blood would be free of leukemic cells. Be as specific as possible in describing the reagents you would need for the test, how you would perform it, and what the different results would show.

Raymond Matshanda
Raymond Matshanda
Numerade Educator
05:16

Problem 21

A generic signaling cascade is shown in the following figure. A growth factor (GF) binds to a growth factor receptor, activating the kinase function of an intracellular domain of the growth factor receptor. One substrate of the growth factor receptor kinase is another kinase, kinase A, that has enzymatic activity only when it is itself phosphorylated by the GF receptor kinase. Activated kinase A adds phosphate to a transcription factor. When it is unphosphorylated, the transcription factor is inactive and stays in the cytoplasm. When it is phosphorylated by kinase $A$, the transcription factor moves into the nucleus and helps turn on the transcription of a mitosis factor gene whose product stimulates cells to divide. a. The following list contains the names of the genes encoding the corresponding proteins. Which of these could potentially act as a proto-oncogene? Which might be a tumor-suppressor gene?
i. growth factor
ii. growth factor receptor
iii. kinase $A$
iv. transcription factor
v. mitosis factor
Though it is not pictured, the cell in the figure also has a phosphatase, an enzyme that removes phosphates from
proteins - in this case, from the transcription factor. This phosphatase is itself regulated by kinase A.
b. What would you expect to be the effect when kinase A adds a phosphate group to the phosphatase? Would this activate the phosphatase enzyme or inhibit it? Explain.
c. Is the phosphatase gene likely to be a proto-oncogene or a tumor-suppressor gene or neither?
d. Several mutations are listed below. For each, indicate whether the mutation would lead to excessive cell growth or decreased cell growth if the cell were either homozygous for the mutation, or heterozygous for the mutation and a wild-type allele. Assume that $50 \%$ of the normal activity of all these genes is sufficient for normal cell growth.
i. A null mutation in the phosphatase gene
ii. A null mutation in the transcription factor gene
iii. A null mutation in the kinase $A$ gene
iv. A null mutation in the growth factor receptor
gene
v. A mutation that causes production of a constitutively active growth factor receptor whose kinase function is active even in the absence of the growth factor
vi. A mutation that causes production of a constitutively active kinase $A$
vii. A reciprocal translocation that places the transcription factor gene downstream of a strong
enhancer
viii. A mutation that prevents phosphorylation of the phosphatase enzyme
ix. A mutation that causes the production of a phosphatase that acts as if it is always phosphorylated

Sana Riaz
Sana Riaz
Numerade Educator
03:11

Problem 22

Neurofibromatosis type 1 (NF1; also known as von Recklinghausen disease is an inherited dominant disorder. The phenotype (see Fig. 11.19 ) usually involves the production of many skin neurofibromas (benign tumors of the fibrous cells that cover the nerves.
a. Is it likely that $N F 1$ is a tumor-suppressor gene or an oncogene?
b. Are the $N F 1$ neurofibromatosis-causing mutations that are inherited by affected children from affected parents likely to be loss-of-function or gain-offunction mutations?
c. Neurofibromin, the protein product of $N F 1$, has been found to be associated with the Ras protein. Ras is involved in the transduction of extracellular signals from growth factors. The active form of Ras (the form initiating the signal transduction cascade causing proliferation) is complexed with GTP; the inactive form of Ras is complexed with GDP. Would the wild-type neurofibromin protein favor the formation of Ras-GTP or Ras-GDP?
d. Which of the following events in a normal cell from an individual inheriting a neurofibromatosiscausing allele could cause the descendants of that cell to grow into a neurofibroma?
i. A second point mutation in the allele of $N F 1$ inherited from the affected parent
ii. A point mutation in the allele of $N F 1$ inherited from the normal parent
iii. A large deletion that removes the $N F 1$ gene from the chromosome inherited from the affected parent
iv. A large deletion that removes the $N F 1$ gene from the chromosome inherited from the normal parent
v. Mitotic chromosomal nondisjunction or chromosome loss
vi. Mitotic recombination in the region between the $N F 1$ gene and the centromere of the chromosome carrying $N F 1$
vii. Mitotic recombination in the region between the $N F 1$ gene and the telomere of the chromosome carrying $N F 1$
e. A much rarer form of neurofibromatosis exists called segmental neurofibromatosis. In this form of the disease, neither parent of the patient has any clinical sign of the disease. The tumors in the patient are restricted to one part of the body, like the right leg. Suggest an explanation for the genesis of segmental neurofibromatosis that clarifies why it is restricted to one part of the body.

James Kiss
James Kiss
Numerade Educator
03:27

Problem 23

Families with germ-line $B R C A l$ or $B R C A 2$ loss-offunction mutations usually display Hereditary Breast and Ovarian Cancer $(\mathrm{HBOC})$. The accompanying
diagram shows a $B R C A 2$ pedigree.
a. $B R C A I$ and $B R C A 2$ are tumor-suppressor genes; cells homozygous for loss-of-function mutations in either gene can become cancerous due to a loss of DNA repair machinery. Explain why the pedigree shows a dominant inheritance pattern of HBOC.
b. Can you tell from the pedigree diagram whether or not HBOC is completely penetrant?
c. Does HBOC show varying expressivity?
d. Explain your answers to parts
(b) and (c) in terms of current models for the origins of cancers.

Shiksha Dutta
Shiksha Dutta
Numerade Educator
03:19

Problem 24

The text explained that retroviruses can cause cancer. Some viruses with DNA genomes can also cause cancer. For example, herpes papilloma virus (HPV) causes cervical cancer. The HPV genome encodes a protein called E6 that interferes with p53 function, and another protein called E7 that inhibits the function of Rb protein. Explain how HPV causes cancer. Are the viral E6 and E7 protein functions more similar to oncogenes or tumor suppressors?

Bryan Lynn
Bryan Lynn
Numerade Educator
01:11

Problem 25

Hepatocellular carcinoma is the most frequent form of liver cancer. In a patient with heritable hepatocellular carcinoma, formation of the tumor was associated with eight genetic alterations affecting two different oncogenes and three different tumor-suppressor genes. These alterations are:
i. Mitotic recombination
ii. A deletion of a chromosomal region
iii. Trisomy
iv. A duplication of a chromosomal region
v. Uniparental disomy (see Fig. 20.24 )
vi A point mutation
vii. Another point mutation
viii. Yet another point mutation
For parts a-c below, supply all possible correct answers from the preceding list. Remember that the majority of point mutations are loss-of-function mutations.
a. Which of the mutations from the preceding list is likely to affect a proto-oncogene?
b. Which of the mutations from the preceding list is likely to involve a tumor-suppressor gene?
c. Which of the mutations from the preceding list involves copy -neutral loss-of-heterozygosity (that is, a loss-of-heterozygosity in which the genomes of the cancerous cells still have two copies of the gene in question, whether or not those copies are functional)?
Genomic DNA is prepared from normal white blood cells and from a biopsy of the tumor in this patient. These genomic DNAs are prepared as fluorescent probes that are each hybridized to an ASO microarray of polymorphisms in the human genome (review Figs. 11.16 and 11.17 ). The results for SNPs $a-z$ on chromosomes $14,15,16,$ and 17 are shown in the accompanying figure. Red and orange represent different levels of fluorescence.
d. Based on the microarray data, provide the most accurate localization of the first five types of genetic alterations in the list (i-v). For example, if an alteration involves markers $a-e$ of chromosome 15 write $15 a-e$
e. As precisely as possible, indicate the location of the mitotic recombination event involved in the genesis of this cancer.
f. If these data allow you to map any of the three cancer-promoting point mutations, provide the most accurate mutation location(s) possible.
g. Of all the genetic alterations i-viii, for which one do you see clear-cut evidence that the mutation or other event was inherited from a parent of the patient?
h. For a tumor-suppressor gene to play a role in cancer, normally both of the copies in the tumor cells must be nonfunctional. For each of the three tumor-suppressor genes contributing to the cancer in this patient, provide a scenario explaining which two hits (i-viii in the list, with vi-viii equivalent) could be responsible, the order in which the hits must have occurred, and whether the hits in question could be inherited or could have occurred somatically.

Dominador Tan
Dominador Tan
Numerade Educator
01:59

Problem 26

Suppose that instead of microarrays, you analyzed the normal and cancerous tissue from the patient described in Problem 25 by whole-genome sequencing. What evidence would you find in the whole-genome sequence data for the existence and location of the eight genetic alterations on the list?

Mikayla Stephens
Mikayla Stephens
Numerade Educator
00:37

Problem 27

Suppose that you also analyzed the normal and cancerous tissue from the patient described in Problems 25 and 26 by deep sequencing of the mRNAs in the cancerous and normal cells of the patient (RNA-Seq). What evidence could you obtain for the involvement in tumorigenesis of a novel oncogene or tumorsuppressor gene that would be very difficult to find from the whole-genome sequence?

Rabeya Zahid
Rabeya Zahid
Numerade Educator
01:11

Problem 28

Glioblastoma multiforme $(G B M)$ is the most common and aggressive form of brain cancer in humans. Without any treatment, the mean survival rate is about three months. Even with standard treatments such as surgical resection, radiation, and chemotherapy, the mean survival rate is between seven and 14 months. GBM tumors differ in their spectrum of genetic changes, and these changes may influence the effect of particular treatments. Answer the following questions about the relevance of particular mutations to particular treatments and outcomes.
a. Biopsies of about $20 \%$ of GBMs show the expression of a certain mutational variant of the EGFR (epidermal growth factor receptor) protein called EGFRvIII. The same cancerous cells of these GBMs also show the expression of normal, wildtype EGFR. Is the gene encoding EGFR a tumorsuppressor gene or a proto-oncogene?
b. It is very difficult to induce cells expressing EGFRvIII to undergo apoptosis. If you were a radiologist treating a patient with a GBM that expresses EGFRvIII, would you use a higher or lower dose of X-rays than with patients having GBMs with normal EGFR proteins?
c. EGFR is a protein that extends through the cell membrane, with an N-terminal extracellular part (amino acids $1-500$ ) that binds epidermal growth factor (EGF) and an intracellular C-terminal kinase part (amino acids $501-1000$ ) that is normally activated when EGF binds to EGFR. The active kinase phosphorylates (adds phosphate groups to) other proteins, setting off a signal transduction cascade that promotes cell growth and division. EGFR vIII is a deletion that removes amino acids 6 through 273 of the EGFR protein. How might this mutant protein contribute to cancer?
d. Iressa $^{\mathrm{TM}}$ is a drug that blocks the kinase activity of EGFR. Would you expect Iressa $^{\mathrm{TM}}$ to be a potential treatment for GBMs expressing EGFRvIII, or would you instead anticipate the drug would make the tumors grow faster?
e. Cisplatin is a platinum compound that binds to DNA and damages it, eventually leading to cell death. $E R C C 1$ is a gene that encodes a DNA repair protein. GBMs are found that show much higher levels of transcription of $E R C C 1$ than normal. Would you treat patients having such GBMs with higher or lower doses of cisplatin than patients whose tumors have normal amounts of $E R C C I$ mRNAs?

Dominador Tan
Dominador Tan
Numerade Educator
01:03

Problem 29

a. The legend to Fig. 20.29 identifies which of the analyzed genes are oncogenes and which are tumorsuppressor genes. You could have made most of these assignments yourself without the legend, just by looking at the data. Explain.
b. Which of the mutations in Fig. 20.29 are most likely to be passenger mutations?

Dave Kratz
Dave Kratz
Numerade Educator
01:11

Problem 30

The website CBioPortal (http://www.cbioportal.org) is an exceptionally useful program for visualizing the cancer genes and genomes of tumors from thousands of patients with different kinds of cancer that have been analyzed by whole genome sequencing and in some cases, by RNA-Seq.
Go the the CBioPortal site and click All under Select Cancer Study and in Enter Gene Set type $P T E N,$ then hit Submit. On the page that is returned you will see how the coding region of the $P T E N$ gene is altered in tumors investigated in the various studies. Hitting the tab Mutations will let you see the details of these mutations relative to the PTEN protein, while the tab Expression lets you see how the gene's expression (in terms of cDNA reads) is altered in individual tumor samples.
a. Is $P T E N$ an oncogene or a tumor suppressor gene? What kinds of evidence lead you to this conclusion?
b. What kinds of cancer are most likely to involve alterations of $P T E N ?$
c. How would you identify patients whose tumor cells are particularly likely to have a somatic mutation in the $P T E N$ gene that is outside of the coding region but nonetheless contributes to cancer by affecting the gene's regulation?
Now return to the CBioPortal home page. Again, select All under Select Cancer Study, but this time type $E R B B 2$ under Enter Gene Set and then hit Submit.
d. Is $E R B B 2$ an oncogene or a tumor-suppressor gene? What kinds of evidence lead you to this conclusion?
e. Are any kinds of listed mutations in the $E R B B 2$ gene almost certainly passenger mutations as opposed to driver mutations? What does it mean to be a passenger mutation?
f. If you were looking for regulatory mutations in the $E R B B 2$ gene that are not in the coding sequence but that contribute to cancer, what attributes would you look for under the Expression tag?
g. In comparing your results with the $P T E N$ and $E R B B 2$ genes, how informative are missense mutations in these genes with respect to possible contributions of such mutations to cancer phenotypes?

Dominador Tan
Dominador Tan
Numerade Educator