Flashcards in Genetics Of Cancer Deck (10):
1) Follicular lymphoma is the most common of the indolent lymphomas and accounts for about 70% of them, and about 22% of all lymphomas in North America and Europe. It is a slow growing type of non-Hodgkin’s lymphoma which responds very well to treatment, but can rarely be cured. What is the most common chromosomal translocation abnormality of this kind of cancer?
Comment: The correct answer is D. 90% of all follicular lymphoma have this translocation that combines the immunoglobulin heavy chain (IgH) locus on chromosome 14 with the BCL-2 locus on chromosome 18. This translocation causes BCL-2 to be expressed at very high levels and prevents the B-cells from undergoing programmed cell death (apoptosis). The t(9;22) translocation is associated with chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) and results from a translocation that fuses the BCR to ABL. The tyrosine kinase domain of ABL is therefore expressed and active in a cell type where this protein is not normally present. The t(11;14) translocation fuses the cyclin D1 on chromosome 11 to the immunoglobulin heavy chain locus on chromosome 14 and induces massive overexpression of cyclin D which pushes the cell through the cell cycle causing mantle cell lymphoma. The t(8;14) translocation places MYC into the control of the IgH enhancer making this pro-proliferation transcription factor overexpressed resulting in Burkitt Lymphoma.
2) A patient has been diagnosed with a melanoma, and molecular analysis has indicated that the tumor has sustained a loss of p16(INK4) activity (inhibitor of cyclin-dependent kinase 4). What cell cycle checkpoint is most likely affected by the loss of this tumor suppressor gene?
Comment: The correct answer is B. p16 plays an important role in cell cycle regulation by decelerating cells progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, and esophageal cancer. p16 is an inhibitor of cyclin dependent kinases such as CDK4 and CDK6. These latter kinases phosphorylate retinoblastoma protein (pRB) which through further events results in progression from G1 phase to S phase.
3) What is the most frequent genetic change that causes follicular lymphoma?
A) Amplification of BAX protein
B) Activation of telomerase
C) Overexpression of BCL2 protein
D) Deletion of RB gene
Comment: The correct answer is C. 90% of all follicular lymphoma have this translocation the combines the immunoglobulin heavy chain locus on chromosome 14 with the bcl-2 locus on chromosome 18. This translocation causes bcl-2 to be expressed at very high levels and prevents the B-cells from undergoing programmed cell death (apoptosis).
4) Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration. Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. What is the most common kind of mutation in the protooncogene, c-ras, which turns it into an oncogene?
A) A mutation that reduces its intrinsic GTPase activity
B) A deletion that removes its intracellular domain
C) A mutation in the transmembrane domain which causes it to dimerize without the binding of a ligand
D) A translocation that moves its C-terminal domain to the N-terminal domain of the tropomyosin gene
E) A deletion of the C-terminal domain that prevents it from being inactivated
Comment: The correct answer is A. Normal Ras needs to be activated by upstream events starting with a mitogen binding to a receptor-tyrosine kinase and ending with Ras binding GTP. The mutation that most often converts a Ras proto-oncogene into a Ras oncogene is a mutation that substitutes a valine for a glycine at amino acid position 12. The mutated protein has a lessened ability to hydrolyze GTP to GDP; Ras with GDP does not activate downstream events. As a result of this mutation, Ras is “constitutively on”. The mutated Ras protein will therefore continue to send signals to the nucleus and stimulate proliferation.
5) A 65-year-old male visits a physician’s clinic for his yearly checkup. One of the procedures performed on him is a digital rectal exam. Hard defined nodules are felt during the examination. The doctor performs a biopsy on his prostate and sends the specimens to the lab for a molecular diagnosis in addition to the examination of the tissue by the pathologist. The lab reports that the cancer is a fast growing cancer and the expression of the Rb protein is normal in the cancer cells. What would be the most likely molecular status of the Rb protein in his prostate cancer cells?
A) Hyperphosphorylated and not bound to E2F
B) Hypophosphorylated and bound to E2F
C) Hyperphosphorylated and bound to E2F
D) Hypophosphorylated and not bound to E2F
E) Hyperphosphorylated and bound to DNA
Comment: The correct answer is A. In rapidly dividing cells such as cancer cells, the G1 checkpoint is in a permissive state to let the cell continue into the S phase. If RB is not phosphorylated by cdk/cyclin complexes, RB will bind E2F and prevent it from turning on genes needed to enter and proceed through S phase. Therefore, since the cancer cell is rapidly proliferating, the RB protein (if normal) would need to be hyperphosphorylated so that it would not bind E2F.
6) What mutational event is often associated with Burkitt’s lymphoma?
A) The RAS protooncogene is mutated at one nucleotide so that it is less able to hydrolyze bound GTP.
B) Viral infection with Simian sarcoma virus leads to release and autocrine stimulation causing proliferation.
C) There is a deletion of the p16 gene which allows unregulated passage through the G1 restriction point.
D) There is a translocation of the MYC gene to one of the immunoglobulin loci.
E) Expression of papilloma virus E7 protein leads to release of E2F leading to proliferation
Comment: The correct answer is D. In Burkitt’s lymphoma, the c-myc gene is translocated to a site near the heavy-chain antibody genes (chr 14) or near the light-chain antibody genes, either the lambda light chain genes on chromosome 22 or the kappa light chain genes on chromosome
2 (only the first of these translocations included in the lecture). The translocated myc gene, now regulated by the antibody enhancer, is continually expressed, causing the B cell to become cancerous.
7) Mutations in the p53 gene are found in a large proportion of human cancers. Mutations in p53 contribute to cancer because they
A. allow cells with DNA damage to escape apoptosis and continue to divide.
B. facilitate cell division by increasing the requirement for growth factors.
C. facilitate metastasis by making cells anchorage independent.
D. prevent cells from entering G1-phase of the cell cycle.
E. prevent cells with DNA damage from completing the cell cycle until the damage is repaired.
Comments: A is the correct answer. Please notice that the question is about the role of mutations, not the role of normal p53. The role of normal p53 is found in E.
8) In the multi-hit model of tumorigenesis, mutations in multiple genes contribute to tumor development. A good example is the development of colon cancer. Which one of the following scenarios is consistent with the multi-hit model of tumorigenesis?
A.Amplification of a tumor suppressor gene; defective DNA repair; activation of a proto-oncogene
B. Amplification of a tumor suppressor gene; defective DNA repair; loss of a proto-oncogene
C. Loss of a tumor suppressor gene; defective DNA repair; activation of a proto-oncogene
D.Loss of a tumor suppressor gene; defective DNA repair; loss of a proto-oncogene
E. Loss of a tumor suppressor gene; enhanced DNA repair; loss of a proto-oncogene
Comments: Correct answer is C, because all three steps mentioned would increase proliferation or increase change of DNA. In all other answers, at least one of the steps is an option countering what would advance the cancer. I realize that there is no explicit mention of a multi-hit model in the lecture but I still feel that this is a question that you should be able to work through.
9) A new patient of yours has just been diagnosed as having retinoblastoma. All of the following possible clinical findings suggest the presence of a germline mutation in the retinoblastoma (Rb) gene except
A.the patient is only two months old
B.the patient is a female
C.there are multiple tumor foci in the eye
D.there are tumors in both eyes
E.a previous sibling died of retinoblastoma
Comment: notice this is an except question. B is the correct answer because it does really not make much difference which sex the child has. All the other observations would indicate inherited mutation.