MCDB XL 100 Chapter 20

Among the following cancers, one is currently leading to the most number of deaths in the United States and in the rest of the world. In the United States, it contributes to cancer mortality more than the next three killing cancers combined. Worldwide, it claims more than 1.5 million lives every year. Which cancer is this? A. Lung cancer B. Breast cancer C. Colon cancer D. Pancreatic cancer E. Stomach cancer

A

Compared to cells of a normal tissue, which of the following occurs less frequently in cells within a solid tumor? [12] A. Apoptosis B. Necrosis C. Cell division D. Mitotic recombination E. Stress

A Although cancer cells tend to avoid apoptosis, they still die on a massive scale by necrosis in solid tumors.

Carcinoma of the uterine cervix in humans: [46] A. can be largely prevented by vaccination. B. is caused by a retrovirus. C. is caused by activation of a viral Src kinase. D. rapidly progresses (from uterine warts) to malignancy. E. All of the above.

A Cervical cancer is mostly a result of papillomavirus infection transmitted sexually. Accidentally, genes in this DNA virus that interfere with p53 function are expressed in basal epithelial cells of the uterine cervix, leading to lesions that can very slowly develop into cancer.

You have karyotyped cells from two colorectal tumor samples, one from a hereditary nonpolyposis colorectal cancer (HNPCC) patient, and the other from a familial adenomatous polyposis coli (FAP) patient. One group of the karyotypes shows gross chromosomal abnormalities with extra or deleted chromosomes and several translocations and deletions. The other group, however, is almost normal, and comparable to noncancerous samples. Which group would you expect to have loss-of-function mutations in the DNA mismatch repair system genes MSH2 and MLH1 as their primary driver mutations? [39] A. HNPCC, which has an almost normal karyotype B. HNPCC, which has a grossly abnormal karyotype C. FAP, which has an almost normal karyotype D. FAP, which has a grossly abnormal karyotype

A HNPCC tumor cells show an almost normal karyotype, in sharp contrast to FAP tumor cells.

Chondroma

A benign neoplasia of cartilage is called a:

Chondrosarcoma

A malignant neoplasia of cartilage is called a:

For each of the following genes involved in regulation of cell growth through the mTOR pathway, indicate whether the gene is activated (A) or inactivated (I) in cancer cells compared to normal healthy cells. Your answer would be a four-letter string composed of letters A and I only, e.g. AAAA. [25] ( ) mTOR ( ) Akt ( ) PTEN ( ) PI3K

AAIA Activation of the kinase subunit of mTOR (stimulated by PI3K and Akt kinases, and inhibited by PTEN phosphatases) can lead to an increase in nutrient uptake and utilization in cancer cells.

According to the cancer stem-cell model for tumor growth and propagation: [32] A. transit amplifying cells are incapable of cell division, which is reserved for the cancer stem cells. B. transit amplifying cells constitute the great majority of the cells in the tumor. C. if each stem cell divides to create one stem cell and one transit amplifying cell, the abundance of stem cells in the tumor will increase exponentially over time. D. tumors are genetically heterogeneous, even though they show high phenotypic homogeneity. E. the transit amplifying cells, even though each acts transiently, carry the whole responsibility for maintenance of the tumor in the long term.

B Cancer stem cells can be responsible for tumor growth and maintenance, yet remain only a small part of the tumor cell population.

Which of the following sequential barriers to metastasis is the easiest to overcome for cancer cells in general? [30] A. Vessel entry through acquisition of local invasiveness B. Exit from the blood into a remote tissue or organ C. Survival of cells in the foreign tissue D. Initial growth of cells in the foreign tissue E. Persistence of growth in the remote site

B Traveling through the body's circulation, which includes survival in the circulation, arrest in capillaries or small vessels, and extravasation into remote tissues, is generally more efficient than the prior phase of escape from the parent tissue and the later phase of colonization of a remote site.

Three fundamental controls seem to have been subverted in essentially every type of cancer. Choose these three among the following regulatory axes. Your answer would be a three-letter string composed of letters A to F only, in alphabetical order, e.g. BDF. [24] (A) Wnt pathway (B) Rb pathway (C) RTK/Ras/PI3K pathway (D) p53 pathway (E) Hippo pathway (F) GPCR/PKA pathway

BCD

Mutation in which of the following genes is most prevalent in human colorectal cancer cells? A. K-Ras B. β-Catenin C. Apc D. p53 E. MLH

C

Which of the following is estimated to be the leading cause of death from cancer in the United States? [40] A. UV light B. Obesity C. Smoking D. Alcohol consumption E. Sedentary lifestyle

C

Once the molecular aberrations in a cancer are understood, drugs can be designed with a rational approach to treat the cancer. Which of the following is NOT true regarding such drugs? [49] A. The drug imatinib (Gleevec®) can inhibit the chimeric tyrosine kinase Bcr-Abl in chronic myelogenous leukemia (CML). B. Even if a protein is not the product of a cancer-critical gene, drugs that specifically block its activity can be effective in curing cancer. C. Imatinib is most effective in treating chronic myelogenous leukemia (CML) in its acute blast-crisis phase. D. Protein kinases have turned out to be relatively easy to inhibit with small molecules. E. The success of imatinib relies on the phenomenon of oncogene dependence in cancer cells.

C Imatinib is not very successful in treating CML once the cancer has advanced to a terminal phase, blast crisis, and no longer behaves like a "chronic" leukemia.

Genetically knocking out both copies of the p53 gene in rats: A. is embryonic lethal. B. results in a lower malignancy rate, but the rats are otherwise seemingly normal. C. results in a higher rate of cancer onset, but the rats are otherwise seemingly normal. D. increases cell death by apoptosis, leading to developmental defects. E. does not have any effect unless the rats live outside of the laboratory and are exposed to various types of stress.

C Most rats (or mice) with a homozygous knockout of the gene encoding p53 develop cancer within a few months after birth but appear normal otherwise, suggesting that p53 function is required only in special circumstances.

Most DNA tumor viruses inhibit the products of: [47] A. Apc and Rb B. Brca1 and Rb C. p53 and Rb D. Brca1 and Apc E. Brca1 and p53

C Small DNA tumor viruses encode proteins that interfere with the Rb and p53 pathways, allowing the replication of the viral genome.

Carcinoma cells that have acquired malignancy and started local invasiveness to begin metastasis: A. decrease the expression of E-cadherin and undergo mesenchymal-epithelial transition. B. increase the expression of E-cadherin and undergo mesenchymal-epithelial transition. C. decrease the expression of E-cadherin and undergo epithelial-mesenchymal transition. D. increase the expression of E-cadherin and undergo epithelial-mesenchymal transition.

C The transition in cancer cells to become invasive involves shifting to a less adhesive and more motile character, resembling the epithelial-mesenchymal transition in normal development. A key part in this process involves switching off the expression of E-cadherin, which is a cell adhesion molecule.

Indicate whether each of the following cancers can be best classified as a carcinoma (C), sarcoma (S), or neither of the two (N). Your answer would be a four-letter string composed of letters C, S, and N only, e.g. SSNC. [4] ( ) Breast cancer ( ) Lung cancer ( ) Colorectal cancer ( ) Myeloma

CCCN

Indicate whether each of the following descriptions better applies to a cancer cell (C) or a normal adult cell (N). Your answer would be a four-letter string composed of letters C and N only, e.g. CCNC. [10] ( ) Higher lactate production ( ) Higher oxidative phosphorylation ( ) Contact inhibition ( ) Anchorage independence

CNNC Transformed cells display an altered growth control (e.g. lack of contact inhibition or anchorage dependence) and an altered sugar metabolism (e.g. de-emphasized oxidative phosphorylation, increased glucose uptake, and increased lactic acid fermentation).

PARP inhibitors can efficiently kill many breast cancer cells that lack functional Brca1 or Brca2 genes. How do these drugs accomplish this? [48] A. By increasing the ability of p53 in cancer cells to limit cell proliferation B. By inhibiting proteins that are normally inhibited by the Brca1 or Brca2 gene products C. By increasing the occurrences of homologous recombination D. By inhibiting a DNA repair pathway E. By increasing the ability of the cancer cells to repair the mutations in their cancer-critical genes

D PARP inhibitors interfere with a DNA repair pathway that becomes essential for cancers that lack the alternative Brca-dependent pathway.

The effect of the deletion of one copy of the gene encoding p53 is different from the effects caused by other p53 mutations. For example, some loss-of-function mutations in the DNA-binding domain of p53 cripple its function as a transcription regulator. Such a mutation in only one copy of the p53 gene can be enough to confer a p53 loss-of-function phenotype, even when the other copy of the gene on the homologous chromosome is wild type. This is because: [20] A. p53 is a proto-oncogene. B. these mutations are recessive. C. p53 is a tumor suppressor. D. p53 forms a tetramer. E. p53 can induce apoptosis.

D The dominant negative effect of p53 mutations is due to the fact that defective p53 monomers can block the function of the tetramers in which they participate.

Which of the following can lead to p53 stabilization and activation? [27] A. Hypoxia B. Overexpression of Myc C. DNA damage D. Telomere loss E. All of the above

E

The Rb gene in retinoblastomas is similar to the Apc gene in polyposis colon carcinomas in that both genes: A. are tumor suppressors. B. are mutated in one copy in all cells of patients with a hereditary form of the cancer. C. are in a locus that shows loss of heterozygosity in the hereditary form of the cancer. D. should be inactivated in both copies to cause the nonhereditary form of the cancer. E. All of the above.

E Apc and Rb are tumor suppressors, and inactivation of both copies of each gene occurs in colorectal cancers and retinoblastomas, respectively. The hereditary forms, however, are easier to develop since the person receives only one functional copy to begin with, which can become lost or defective.

Which of the following proteins is NOT encoded by a proto-oncogene? [14] A. Src B. Ras C. EGF receptor D. Myc E. E-cadherin

E Loss-of-function mutations in the tumor suppressor E-cadherin promote the epithelial-mesenchymal transition and local invasiveness.

Indicate true (T) and false (F) statements below regarding cancer. ( ) Cancers become less and less heterogeneous as they progress. ( ) Knocking out Ras or Myc genes individually leads to a higher incidence of cancers in mice, and knocking out both genes simultaneously has an even stronger phenotype. ( ) Wnt signaling is important in colon epithelial cells and, correspondingly, mutations in genes in the Wnt pathway are present in most colorectal cancers. ( ) Genome destabilization in a subset of colorectal cancers that have defects in DNA mismatch repair takes the form of chromosome breaks, translocations, and deletions.

FFTF Cancer risk is increased by gain-of-function mutations in Ras and Myc, not by their knockout. It is not surprising that in cancer cells with defects in DNA mismatch repair, many point mutations are found throughout the genome. Cancer progression coincides with increasing heterogeneity of the tumor cell population.

Indicate true (T) and false (F) statements below regarding cell proliferation in human somatic cancer cells. Your answer would be a four-letter string composed of letters T and F only, e.g. TFFF. [13] ( ) Cancer cells show replicative cell senescence. ( ) Cancer cells maintain their telomeres by inhibiting the enzyme telomerase. ( ) Some cancer cells do not rely on telomerase for telomere lengthening. ( ) Most cancer cells lack telomeres.

FFTF Mammalian cancer cells avoid replicative cell senescence (which generally depends on telomere shortening) in two ways: they can either maintain telomerase activity to prevent telomere shortening, or evolve an alternative mechanism based on homologous recombination to lengthen their telomeres.

Indicate true (T) and false (F) statements below regarding the mutational landscape of cancer cells. Your answer would be a four-letter string composed of letters T and F only, e.g. TFFF. [22] ( ) In each cancer, usually there is one driver mutation and a large number of passenger mutations. ( ) It is estimated that about 20% of our genes are cancer-critical. ( ) Cancer-critical genes can encode metabolic enzymes or components of the RNA splicing machinery. ( ) The karyotype is often severely disordered in cancer cells.

FFTT The number of driver mutations in most cancers is estimated to be on the order of 10. About 300 genes (less than 2% of our genes) are strongly suspected to be cancer-critical. They encode proteins of various functions. In addition to DNA sequence changes, chromosomal breaks and translocations are common in cancer cells.

Indicate true (T) and false (F) statements below regarding colorectal cancers. Your answer would be a four-letter string composed of letters T and F only, e.g. TFFF. [34] ( ) Observation of polyps in the colon epithelium of a patient is an indication of a malignant carcinoma. ( ) Progression of colorectal cancer is very slow and normally takes over 10 years to turn into malignancy. ( ) Colorectal cancers are usually diagnosed later in life. ( ) Invasive colorectal cancer cells usually metastasize to lymph nodes via lymphatic vessels and then into the bloodstream.

FTTT The adenomatous polyps are believed to be the precursors of most colorectal cancers, but progression into malignancy is slow and the average time from detection of the polyp to cancer diagnosis is about 12 years. This usually happens later in life. Colorectal cancers tend to metastasize through lymphatic nodes after spreading through the layers of tissues lining the gut.

B Cells in the original HeLa line better respond to the drug since they can trigger apoptosis through the p53 pathway. Knocking out p53 makes the cells more resistant to this effect of the drug.

From an immortalized human HeLa cell line with wild-type p53 genes, you have derived a line that lacks both copies of the gene. You then treat the original and derived cells with the anticancer drug doxorubicin, which can activate the p53 pathway in the cell by stalling DNA replication forks and inducing double-strand breaks in DNA. You measure cell proliferation in the presence of different doses of the drug in each of the two cell lines, and plot the results as shown in the graph below. Which cell line (A or B) do you expect to be the original HeLa line? Write down A or B as your answer.

Indicate whether each of the following descriptions better applies to trastuzumab (T) which targets Her2, imatinib (I) which targets Bcr-Abl, or ipilimumab (P) which targets the CTLA4 protein. ( ) It is NOT an antibody. ( ) It counters the immunosuppressive microenvironment of tumors. ( ) It does not bind to a cancer cell component.

IPP By binding to an inhibitory receptor on T cells, the monoclonal antibody ipilimumab helps block immunosuppression in tumors. Trastuzumab is also a monoclonal antibody, but it directly binds to EGF receptors on some cancer cells to block their function.

1 Only the germ line contributes to the organism in the next generation; however, by sacrificing their survival to support the germ cells, the somatic cells help to propagate copies of their own genome.

In the following simplified diagram of cell divisions in a multicellular species, the germ-cell and somatic-cell lineages are depicted. Which of the indicated cells (1 or 2) represents the germ line? Write down 1 or 2 as your answer

Indicate whether each of the following viruses is mostly associated with cervical cancer (C), Kaposi's sarcoma (K), liver cancer (L), or stomach cancer (S). ( ) Hepatitis-B virus (HBV) ( ) Human immunodeficiency virus (HIV) ( ) Human papillomavirus (HPV) ( ) Helicobacter pylori

LKCS

Mutations in two important cancer-critical genes, encoding p53 and Rb, respectively, are commonly found in cancers. What type of mutations are these expected to be?

Loss-of-function mutations in both genes Both p53 and Rb are coded by tumor suppressor genes, and their inactivation promotes cancer.

5 Translocation between immunoglobulin loci and proto-oncogene loci activates the proto-oncogenes and can transform the cell. These translocations are common in myelomas, where each one takes advantage of the powerful transcription potential of the immunoglobulin genes.

Myelomas are cancers of blood plasma cells—white blood cells that are normally responsible for producing large quantities of antibodies. In the following "Circos plot" for myelomas in a hypothetical mammalian genome, the interchromosomal rearrangements are indicated by red lines and variations in copy numbers are indicated in blue. The positions of named genes are indicated with arrows. On which chromosome do you expect to find the antibody genes?

The immortalized non-malignant mouse cell line NIH-3T3 was derived from normal mouse fibroblasts in the early 1960s. These cells are able to readily take up exogenous DNA and are prone to transformation by cancer-causing agents, including some retroviruses. DNA extracted from a human bladder carcinoma line is able to transform these cells, as judged by a significant increase in the number of foci (cell clumps) in the cell-culture plates when the DNA is added. The malignant cells contain human DNA, and the DNA can be shown by sequence analysis to contain a single mutant gene that is present in the original bladder carcinoma cell line. The gene codes for a monomeric G protein and was one of the first cancer-critical genes to be identified in this way. The protein encoded by this gene is:

Ras Ras was also found earlier to be the oncogene carried by some sarcoma viruses, and the identification of the same gene (with similar mutations) in both cases was an important discovery that advanced our understanding of the molecular biology of cancer.

Retinoblastoma is an early-onset cancer of the retina with a rapid progression, and is mostly diagnosed in children. In its hereditary form, multiple eye tumors usually arise in both eyes, while the nonhereditary form usually causes fewer tumors in only one eye. Treatment may involve a combination of chemotherapy, radiotherapy, and other therapies and the majority of patients can be cured if given the right treatment. However, survivors of one form of retinoblastoma (and not the other form) have a markedly increased frequency of subsequent neoplasms that can lead to other cancers later in life, especially soft-tissue sarcomas. These patients should therefore be closely monitored throughout their lives. Which gene is affected by the primary driver mutation in this cancer as well as the later sarcomas? Which form of retinoblastoma do you think is associated with a higher risk of subsequent neoplasms?

Rb; hereditary

The homologous chromosome pairs in our cells do not carry identical sequences in all loci. This heterozygosity (difference between the two copies) can be altered in cancer: in fact, loss of heterozygosity at many loci is observed in cancer cells, through an increase in either homozygosity (two identical copies) or hemizygosity (i.e. loss of one copy). Researchers can take advantage of this loss of heterozygosity in cancer cells to identify genomic loci that contain cancer-critical genes. What type of gene would you expect to find in chromosomal regions with a loss of heterozygosity? Proto-oncogenes (P) or tumor suppressor genes (T)?

T Once the first copy of a tumor suppressor gene is lost or inactivated, the remaining copy is commonly lost by a less specific mechanism, leading to loss of heterozygosity in the gene as well as in its neighboring loci. This represents a way of finding loci that contain tumor suppressor genes.

Indicate true (T) and false (F) statements below regarding the properties of cancer cells. Your answer would be a four-letter string composed of letters T and F only, e.g. TFFF. [3] ( ) Cancer cells invade and colonize territories that normally belong to other cells. ( ) Unlike in normal tissues, cell death is extremely rare in tumors. ( ) Cancer cells grow and proliferate in defiance of normal restraints. ( ) Malignant tumors are composed of cells that grow and proliferate, but still have not acquired invasiveness.

TFTF

Indicate true (T) and false (F) statements below regarding cancer incidence and cancer prevention. ( ) Over half of all cancers are preventable by lifestyle changes. ( ) The age-adjusted cancer death rates have increased steadily since 1900, mostly due to the industrial way of life. ( ) Currently, more than half of all cancer patients survive at least five years post-diagnosis. ( ) About half of all cancers are thought to arise by infection with viruses, bacteria, or parasites.

TFTF Except for the increase in cancers caused by smoking, age-adjusted death rates for most common cancers have either stayed the same since half a century ago, or have even declined significantly. Survival rates have also improved: currently, more than two-thirds of cancer patients live more than five years from the time of diagnosis. Fifty percent of cancers could be prevented by changes in lifestyle such as altered smoking, eating, and exercise habits. Only a small proportion of human cancers (perhaps ~15%) are thought to arise from infection.

Indicate whether each of the following descriptions better applies to proto-oncogenes (P) or tumor suppressor genes (T). Your answer would be a four-letter string composed of letters P and T only, e.g. PPPT. [16] ( ) Cancer mutations in these genes are usually recessive. ( ) Cancer mutations in these genes include gene duplications. ( ) Cancer mutations in these genes are responsible for most hereditary cancers. ( ) Cancer mutations in these genes are commonly in the form of nonsense (truncating) mutations that abort protein synthesis.

TPTT Truncating mutations in tumor suppressor genes can create recessive, loss-of-function mutants associated with most hereditary cancers. A proto-oncogene, in contrast, can be activated by a limited set of dominant, gain-of-function mutations (e.g. missense point mutations or other accidents such as gene duplication, which can produce an abnormally large amount of gene product).

Indicate true (T) and false (F) statements below regarding cancer. Your answer would be a four-letter string composed of letters T and F only, e.g. TFFF. [8] ( ) Cancer can be induced by infectious agents such as viruses. ( ) The earlier a cancer is diagnosed, the better the chances are for a cure. ( ) Most cancers originate from a single aberrant cell. ( ) A single mutation is NOT enough to turn a normal cell into a cancer cell.

TTTT A single mutation is not enough to change a normal cell into a cancer cell: most cancers develop gradually from a single aberrant cell by the accumulation of a number of genetic and epigenetic changes over time. Treatment is generally easier if the cancer is diagnosed at earlier stages. Some cancers can be induced by infectious agents.

B More colonies (revertants) appear in the presence of a stronger mutagen, with the distribution of colonies reflecting the dose-response relationship for the mutagen (stronger mutagens will affect bacteria further away from the disc).

The Ames test is used to test the mutagenicity of a compound suspected to be a carcinogen. In a simple form of the test, the carcinogen is first mixed with a rat liver extract. A disc of filter paper is soaked with this mixture and placed on a culture of a strain of Salmonella typhimurium that is defective in a gene involved in the synthesis of histidine, an amino acid that is essential for cell growth and proliferation. The strain is thus normally unable to grow into visible colonies when the histidine in the culture medium is depleted. In the presence of a mutagen, however, mutations (often "reverse mutations" in the same gene) can enable the bacteria to produce histidine on their own, and therefore grow into colonies. The results of the Ames test for three compounds A, B, and C—each used at the same concentration—are shown in the schematic diagram below. Colonies are indicated with black dots, and the disc is indicated with a white circle at the center of each plate. Which compound (A to C) appears to be a stronger mutagen in this assay?

BCA This oversimplified diagram provides a general correspondence between mutations and the stages of cancer progression. In most cases, inactivating Apc mutations appear to occur early, followed by later activation of K-Ras and inactivation of p53. Many other mutations are generally involved. Note that genetic and epigenetic instability rises during the process.

The following simplified diagram shows the typical sequence of genetic changes in a developing colorectal carcinoma. Indicate which event (A to C) corresponds to the following changes.

In medical oncology, PET (positron emission tomography) is used to selectively image tumors in the body and to monitor cancer progression and response to treatment. Before performing a PET scan, the patient should fast for at least several hours for blood glucose to be sufficiently low. At the time of the scan, the positron-emitting glucose analog fluorodeoxyglucose (FDG) is injected into the bloodstream and the patient is asked to wait for up to an hour while avoiding physical activity. Finally, the scanner moves slowly over the body to reveal the location of possible tumors. Why do you think the patient should avoid physical activity before the scan?

To prevent the absorption of the radioactive tracer by healthy tissues. When the blood glucose level is low, the added radioactive glucose analog is preferentially and rapidly taken up by tumor cells as a result of the Warburg effect. Physical activity stimulates uptake by muscle cells also (including heart muscle), which interferes with the imaging.

a; 1 Most cancers arise from dominant somatic mutations in cancer genes; however, most germ-line mutations are recessive, which enables them to be carried through generations.

You have analyzed a large set of human cancer-critical genes for a selected group of carcinomas, classifying each of the genes based on whether they are known to undergo somatic or germ-line mutations, as well as based on whether they are dominant or recessive. You then group them and plot the statistics in the following histograms. Which group (a or b) do you think represents somatic, as compared to germ-line, mutations? Which group (1 or 2) do you think represents dominant, as compared to recessive, mutations? (Note that the sum of percentages of somatic and germ-line mutations is more than 100%, since some genes are mutated in both somatic and germ cells).