Unit 6 Genetics – Flashcards
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Malignant tumor
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Consists of cells that are capable of invading other tissues
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Metastasis
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Refers to cells that separate from malignant tumors and travel to other sites, where they establish secondary tumors
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Clonal evolution
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Process by which mutations that enhance the ability of cells to proliferate predominate in a clone of cells, allowing the clone to become increasingly rapid in growth and increasingly aggressive in proliferation properties
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Apoptosis
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Programmed cell death, in which a cell degrades its own DNA, the nucleus and cytoplasm shrink, and the cell undergoes phagocytosis by other cells without leakage of its contents
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Cyclin
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A key protein in the control of the cell cycle; combines with a cyclin-dependent kinase (CDK). The levels of cyclin rise and fall in the course of the cell cycle
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Cyclin-dependent kinase
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A key protein in the control of the cell cycle; combines with cyclin
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Haploinsufficiency
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The appearance of a mutant phenotype in an individual cell or organism that is heterozygous for a normally recessive trait
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Human papilloma virus
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Virus associated with cervical cancer
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Loss of heterozygosity
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At a locus having a normal allele and a mutant allele, inactivation or loss of the normal allele
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Mutation driver
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A mutation found in a cancer cell that contributes to the process of cancer development
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Mutation passenger
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A mutation found in a cancer cell that does not contribute to the development of cancer
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Oncogene
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Dominant-acting gene that stimulates cell division, leading to the formation of tumors and contributing to cancer; arises from mutated copies of a normal cellular gene (proto-oncogene).
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Proto-oncogene
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Normal cellular gene that controls cell division. When mutated, it may become an oncogene and contribute to cancer progression
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Signal transduction pathway
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System in which an external signal (initiated by a hormone or growth factor) triggers a cascade of intracellular reactions that ultimately produce a specific response
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Tumor-suppressor gene
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Gene that normally inhibits cell division. Recessive mutations in such genes often contribute to cancer
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What types of evidence indicate that cancer arises from genetic changes?
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Higher incidences of many types of cancer are associated with exposure to radiation and other environmental mutagens. In addition, the occurrence of some types of cancer runs in families, and a few cancers have been linked to chromosomal abnormalities. Finally, the discovery of oncogenes and specific mutations that cause proto-oncogenes to become oncogenes, or inactivate tumor suppressor genes, proved that cancer has a genetic basis.
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How is cancer different from most other types of genetic diseases?
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Most cancers arise from genetic changes in somatic cells that arise during an individual's lifetime, whereas other types of genetic diseases are inherited through the germ line.
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Outline Knudson's two-hit hypothesis of retinoblastoma and describe how it helps to explain unilateral and bilateral cases of retinoblastoma.
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The multistage theory of cancer states that more than one mutation is required for most cancers to develop. Most retinoblastomas are unilateral because the likelihood of any cell acquiring two rare mutations is very low, and thus retinoblastomas develop in only one eye. Bilateral cases of retinoblastoma occur in people born with a predisposing mutation, so that as few as one additional mutational event can result in cancer. Thus, the probability of retinoblastoma is higher in these individuals and likely to occur in both eyes. Because the predisposing mutation is inherited, people with bilateral retinoblastoma have relatives with retinoblastoma.
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Briefly explain how cancer arises through clonal evolution.
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A mutation that relaxes growth control in a cell will cause it to divide and form a clone of cells that are growing or dividing more rapidly than their neighbors. Successive mutations that cause even more rapid growth, or the ability to invade and spread, each produce progeny cells with more aggressive, malignant properties that outgrow their predecessors and take over the original clone.
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What is the difference between an oncogene and a tumor-suppressor gene? Give some examples of the functions of proto-oncogenes and tumor suppressors in normal cells.
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An oncogene stimulates cell division, whereas a tumor-suppressor gene inhibits cell growth. Proto-oncogenes are normal cellular genes that function in cell growth and regulation of the cell cycle: from growth factors such as sis to receptors like ErbA and ErbB, protein kinases such as src, and transcription factors like myc. Tumor suppressors inhibit cell cycle progression: RB and p53 are transcription factors and NF1 is a GTPase activator.
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What is haploinsufficiency? How might it affect cancer risk?
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Haploinsufficiency is a condition where a normally recessive trait affects a heterozygous individual. Haploinsufficiency arises in situations where a single functional copy of a gene is insufficient to produce a wild-type phenotype. In most cases, haploinsufficiency reflects the need for a larger quantity of a gene product than is normally produced by a single wild-type allele. In the case of tumor- suppressor genes like RB, a single functional copy is often enough for the cell to have a normal phenotype, but leaves no "backup" copy in reserve. In this case, the mutation of the single remaining wild-type allele in any one of the millions of cells in the retina will lead to formation of a cancer cell, hence the "predisposition to cancer" phenotype associated with haploinsufficiency of RB.
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How do cyclins and CDKs differ? How do they interact in controlling the cell cycle?
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The CDKs, or cyclin-dependent kinases, have enzymatic activity and phosphorylate multiple substrate molecules when activated by binding the appropriate cyclin. Cyclins are regulators of CDKs and have no enzymatic activity of their own. Each cyclin molecule binds to a single CDK molecule. Whereas CDK levels remain relatively stable, cyclin levels oscillate through the cell cycle.
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Briefly outline the events that control the progression of cells through the G1/S checkpoint in the cell cycle.
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In G1, cyclins D and E accumulate and bind to their respective CDKs. The cyclin D-CDK and cyclin-E-CDK phosphorylate RB protein molecules. Phosphorylation of RB inactivates RB and releases active E2F protein. E2F protein transcribes genes required for DNA replication and progression into S phase.
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Briefly outline the events that control the progression of cells through the G2/M checkpoint of the cell cycle.
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Cyclin B accumulates through G2 and binds to its partner CDK, forming an inactive mitosis-promoting factor (MPF) that is activated by dephosphorylation. When MPF activity exceeds a threshold level, the cell commits to mitosis.
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What is a signal-transduction pathway? Why are mutations in components of signal-transduction pathways often associated with cancer?
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A signal-transduction pathway is the system that enables a cell to respond appropriately to an external signal. It begins with binding or perception of the external signal molecule, then proceeds through a cascade of intracellular events that relay and amplify the signal to bring about changes in transcription, metabolism, morphology, or other aspects of cell function. Since cell growth and division are regulated by external signals, mutations in signal-transduction components may cause the cell to grow and divide in the absence of external growth stimuli, or may cause the cell to stop responding to external growth inhibitory signals.
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How is the Ras protein activated and inactivated?
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Ras protein with GDP bound is inactive. Exchanging GDP for GTP activates the Ras protein. This guanine nucleotide exchange is stimulated by adaptor proteins that bind to activated signal receptors.
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Why do mutations in genes that encode DNA-repair enzymes often produce a predisposition to cancer?
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Mutations that affect DNA repair result in high rates of mutation. Mutations may convert proto-oncogenes into oncogenes or inactivate tumor-suppressor genes.
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What role do telomeres and telomerase play in cancer progression?
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DNA polymerases are unable to replicate the ends of linear DNA molecules. Therefore, the ends of eukaryotic chromosomes shorten with every round of DNA replication, unless telomerase adds back special non-templated telomeric DNA sequences. Normally, somatic cells do not express telomerase; their telomeres progressively shorten with each cell division until vital genes are lost and the cells undergo apoptosis. Transformed cells (cancerous cells) induce the expression of the telomerase gene, in order to keep proliferating.
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How is an epigenetic change different from a mutation?
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Unlike mutations, epigenetic changes do not alter the sequence of nucleotides in the DNA. Although epigenetic changes are usually transmitted to mitotic progeny cells, epigenetic changes are more readily reversible than mutations.
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How is DNA methylation related to cancer?
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DNA methylation is associated with transcriptional repression. Methylation and silencing of tumor-suppressor genes would increase the risk of cancer; demethylation and activation of proto-oncogenes would also increase the risk of cancer. Hypomethylation (loss of DNA methylation) may also increase the risk of cancer by increasing genomic instability, by mechanisms that are not yet clear.
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Briefly outline some of the genetic changes commonly associated with the progression of colorectal cancer.
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Colorectal cancer begins as benign tumors, called polyps, that enlarge and acquire further mutations that turn them malignant and, finally, invasive and metastatic. These progressive changes are associated with multiple mutations. One common sequence in colorectal cancer is a mutation of the APC gene that leads to faster cell division and polyp formation. Oncogenic mutations of the ras gene are found in cells from larger polyps. Mutations in p53 and other genes are found in malignant tumor cells, which may lead to genomic instability and additional changes that lead to greater malignancy and invasiveness.
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Explain how chromosome deletions, inversions, and translations may cause cancer.
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Deletions, inversions and translations are chromosomal rearrangements that all involve breakage and rejoining of chromosomal DNA. In all three, the rejoining brings together segments of DNA that were previously distant from each other. These chromosomal rearrangements may inactivate tumor suppressor genes if the breakpoint occurs within the gene. Alternatively, rearrangements may juxtapose a strong promoter upstream of a proto-oncogene, causing overexpression or unregulated expression of the proto-oncogene. Finally, rearrangements may bring parts of two different genes together, causing the synthesis of a novel protein that is oncogenic.
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Briefly outline how the Philadelphia chromosome leads to chronic myelogenous leukemia.
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The Philadelphia chromosome is an abnormally shortened chromosome 22 with a translocated tip of chromosome 9. A part of the c-ABL proto-oncogene from chromosome 9 is fused with BCR gene on chromosome 22. The resulting fusion protein is more active at promoting cell proliferation than the normal c-ABL protein, and causes leukemia.
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What is genomic instability? Give some ways in which genomic instability may arise.
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Genomic instability is a condition or process that leads to numerous chromosomal rearrangements and aneuploidy, often found in cells of advanced tumors. Mutations that affect the mitotic spindle checkpoint may cause a high frequency of aneuploidy. Other mutations, such as mutations in the APC gene, may affect the spindle itself or other aspects of the chromosome segregation mechanism. Still other mutations that affect centrosome duplication, such as some p53 mutations, could also lead to aneuploidy.
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How do viruses contribute to cancer?
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Retroviruses have strong promoters. Upon integration into the host genome, the retrovirus promoter may drive overexpression of a cellular proto-oncogene. Alternatively, integration of the retrovirus may inactivate a tumor-suppressor gene. A few retroviruses carry oncogenes that are altered versions of host proto- oncogenes. Other viruses, such as human papilloma virus, express gene products (proteins or RNA molecules) that interact with the host cell cycle machinery and inactivate tumor-suppressor proteins.
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What characteristics of a pedigree that would suggest that a type of cancer is inherited as an autosomal dominant trait?
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The presence of cancer and precancerous growths does not skip generations. Every affected individual has an affected parent. Pancreatic cancer and precancerous growths considered together are found in males and females.
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If cancer is fundamentally a genetic disease, how might an environmental factor such as smoking cause cancer?
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Environmental factors can cause cancer by acting as mutagens. Higher rates of mutation will lead to higher rates of inactivation of tumor-suppressor genes or conversion of proto-oncogenes to oncogenes.
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Both genes and environmental factors contribute to cancer. Table 23.2 shows that prostate cancer is 30 times as common among Caucasians from Utah as among Chinese from Shanghai. Briefly outline how you might determine if these differences in the incidence of prostate cancer are due to differences in the genetic makeup of the two populations or to differences in their environments.
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If the differences in cancer rates are due to genetic differences in the two populations, then people who migrated from Utah or Shanghai to other locations would have similar rates of cancer incidence as people who stayed in Utah or Shanghai. Moreover, different ethnic groups in Utah or Shanghai would have different rates of cancer. If the cancer rates are due to environmental factors, then people who migrated from Utah or Shanghai would have rates of cancer determined by their location and not by their place of origin, and different ethnic groups in the same location would have similar rates of cancer.
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A couple has one child with bilateral retinoblastoma. The mother is free from cancer, but the father had unilateral retinoblastoma and he has a brother who has bilateral retinoblastoma. If the couple has another child, what is the probability that this next child will have retinoblastoma?
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Familial retinoblastoma is caused by mutation of the RB tumor-suppressor gene. Because the loss of a functional RB allele means that only one additional mutation event will completely eliminate RB function and lead to retinoblastoma, loss-of-function RB mutations have dominant effects with regard to retinoblastoma. If the father with unilateral retinoblastoma is heterozygous for an RB mutation, then the chance of another child inheriting the mutant RB allele is ½. Note that the father is almost certainly not homozygous for the RB mutation because he has only unilateral retinoblastoma and because individuals homozygous for RB mutations would be extremely susceptible to multiple types of cancer at early age.
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A couple has one child with bilateral retinoblastoma. The mother is free from cancer, but the father had unilateral retinoblastoma and he has a brother who has bilateral retinoblastoma. If the next child has retinoblastoma, is it likely to be bilateral or unilateral?
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Because retinoblastoma in this family is most likely an inherited disorder, a child with retinoblastoma will more likely have bilateral retinoblastoma. Unilateral retinoblastomas are usually spontaneous in origin, requiring two independent mutations in a single somatic retinal cell. Familial retinoblastomas occur in family members that inherited one of the two mutations required for retinoblastoma. As only one additional mutation is required in the somatic retinal cells, retinoblastoma occurs in both eyes and at earlier ages than spontaneous unilateral retinoblastomas. Although the probability of the next child inheriting the RB mutation from the father is only 50%, the question specifies that this next child has retinoblastoma, making it likely that he inherited the RB mutation from the father, rather than being a new spontaneous case of unilateral retinoblastoma.
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A couple has one child with bilateral retinoblastoma. The mother is free from cancer, but the father had unilateral retinoblastoma and he has a brother who has bilateral retinoblastoma. Explain why the father's case of retinoblastoma is unilateral, whereas his son's and brother's cases were bilateral.
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The father may have unilateral retinoblastoma because of variable expressivity of the mutation in the RB gene. Alleles at another locus or multiple other loci may have contributed to resistance to retinoblastoma in the father so that he suffered retinoblastoma in only one eye. Alternatively, it may have been just good fortune (random chance) that one of his eyes was spared the second mutation event that led to retinoblastoma in his other eye.
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The palladin gene, which plays a role in pancreatic cancer (see the introduction to this chapter), is said to be an oncogene. Which of its characteristics suggest that it is an oncogene rather than a tumor-suppressor gene?
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Because oncogenes promote cell proliferation, they act in a dominant manner. In contrast, mutations in tumor suppressor genes cause loss of function and act in a recessive manner. The mutated palladin gene caused increased cell migration when introduced into cells that contain wild-type palladin genes. Such a dominant effect suggests that palladin is an oncogene.
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Mutations in the RB gene are often associated with cancer. Explain how a mutation that results in a nonfunctional RB protein contributes to cancer.
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RB protein is a tumor suppressor, acting at the G1/S checkpoint to prevent cells from beginning DNA replication. Without functional RB protein, cells are more prone to begin a round of cell division.
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Cells in a tumor contain mutated copies of a particular gene that promotes tumor growth. Gene therapy can be used to introduce a normal copy of this gene into the tumor cells. Would you expect this therapy to be effective if the mutated gene were an oncogene? A tumor-suppressor gene?
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Gene therapy to introduce a normal copy of the gene into tumor cells will not work for oncogenes because oncogenes are dominant, activating mutations of proto- oncogenes. Gene therapy may work if the tumor arises from a mutation that inactivates a tumor-suppressor gene. Loss-of-function mutations are recessive; therefore, a normal copy of the gene will be dominant and restore regulation of cell proliferation in the tumor cells. However, one would have to insert and express the tumor suppressor gene in all of the tumor cells, which is not possible at this time.
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What would be the effect on the cell cycle of a drug that inhibited MPF?
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The cell would not progress from G2 to M.
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What would be the effect on the cell cycle of a drug that inhibited cyclin-E-CDK?
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The cell would not progress from G1 to S.
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What would be the effect on the cell cycle of a drug that inhibited cyclin-D-CDK?
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The cell would not progress from G1 to S.
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What would be the effect of a drug that inhibited the breakdown of cyclin B?
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The cell would not transition from metaphase to anaphase and would remain stuck in mitosis.
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Some cancers are consistently associated with the deletion of a particular part of a chromosome. Does the deleted region contain an oncogene or a tumor-suppressor gene?
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The deleted region contains a tumor-suppressor gene. Tumor suppressors act as inhibitors of cell proliferation. The deletion of tumor-suppressor genes will therefore permit the uncontrolled cell proliferation that is characteristic of cancer. Oncogenes, on the other hand, function as stimulators of cell division. Deletion of oncogenes will therefore prevent cell proliferation, and usually cannot cause cancer.
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Many cancer cells are immortal (will divide indefinitely) because they have mutations that allow telomerase to be expressed. How might this knowledge be used to design anticancer drugs?
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Because cancer cells depend on telomerase activity to preserve their telomeres, drugs that target telomerase enzymatic activity may limit the ability of cancer cells to divide indefinitely.
