Cancer Flashcards
Which of the following statements is TRUE concerning the retinoblastoma protein (RB1)? RB1:
A. Is an important downstream effector controlling the G2 checkpoint
B. Once phosphorylated, releases E2F
C. Is encoded by an oncogene
D. Is phosphorylated by ATM
E. Activity is altered in approximately 10% of cancers
B
RB1 is the product of the RB1 tumor suppressor gene (not an oncogene). Once phosphorylated by CDK4/6, RB1 releases E2F, which then activates genes associated with the G1 checkpoint. RB1 is functionally inactivated in virtually all human cancers, either directly or indirectly, via p53 (TP53). p53-dependent induction of p21 (CDKN1A) regulates cyclin E/CDK2 and cyclin A/CDK2 complexes, both of which phosphorylate RB1. The RB1 and p53 signaling pathways are dysregulated in the majority of human cancers.
Which of the following pairs of cancer type and corresponding genetic alterations in that cancer is FALSE?
A. Pancreatic — K-RAS
B. Lung adenocarcinoma — ALK
C. Colon — PTCH
D. Thyroid — RET
E. Melanoma - BRAF
C
Carcinogenesis is a multistep process with multiple genetic alterations occurring at particular stages of cancer progression. Alterations in PTCH are associated primarily with basal cell skin carcinoma and medulloblastoma. EGFR and VEGF are frequently overexpressed in colon cancer, but their lack of a relationship with progression and survival has led to their prognostic value being questioned. For example, over 90% of human pancreatic cancers harbor an activating point mutation in the KRAS gene at codon 12. Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. BRAF mutation is present in 50% of cutaneous melanomas and provide the therapeutic target for vemurafenib. Alk mutation is present in ~5% of lung adenocarcinomas and provides a target for crizotinib.
Which of the following pairs of tumor suppressor proteins and their corresponding functions is INCORRECT?
A. APC — signal transduction
B. RB1 — cell cycle regulation
C. p53 (TP53) — cell cycle and apoptosis regulation
D. WT1 — post-translational regulation
E. BRCA1 — DNA damage repair
D
WT1 is a transcription factor which, when mutated or absent, is associated with the development of Wilms tumor. Loss of APC plays a role in gastrointestinal carcinogenesis due to its normal involvement in cell signal transduction. RB1 and p53 are both tumor suppressors that regulate cell cycle progression; p53 also regulates apoptosis. BRCA1 protein is part of the DNA repair complex, but likely has several other functions as well, including regulation of the cell cycle and maintenance of genomic stability.
Which of the following statements is TRUE concerning p53 (TP53)? p53:
A. Is encoded by an oncogene that is activated in the majority of human cancers
B. Is activated by acute cellular hypoxia
C. Inhibits expression of the GADD45A, p21 (CDKN1A) and PCNA genes
D. Can be inactivated by Epstein-Barr virus (EBV)
E. Is modified by phosphorylation in response to DNA damage
E
p53 is modified post-translationally by phosphorylation or by acetylation in response to DNA damage. p53 is encoded by a tumor suppressor gene (not an oncogene) that is inactivated in more than half of all human cancers. The DNA repair pathways that regulate p53 include not only NHEJ and HRR, but also MMR, BER, and NER so that p53 plays a universal role in DNA damage surveillance and repair. DNA damage causes p53 to become stabilized and active, not inactive. p53 increases expression of GADD45A, p21, and PCNA. Viruses that contain proteins that inactivate p53 include HPV, SV40 and adenovirus, but not EBV.
Oncogenes were first discovered from the study of:
A. Chicken Retroviruses
B. Bacteria
C. Yeast
D. Mice
E. Human cells in culture
A
Retroviruses, viruses with genomes composed of RNA instead of DNA, can cause cancers in animals (example: Rous sarcoma virus [RSV] in chickens). Usually, this occurs because the retroviruses contain modified (often mutated) proto-oncogenes captured from the genomes of their vertebrate hosts.
Which one of the following is NOT a tumor suppressor gene?
A. PTEN
B. BRCA2
C. WT1
D. NF1
E. ABL
E
ABL is an oncogene whereas PTEN, BRCA2, WT1, and NF1 are all tumor suppressor genes.
Which of the following statements is TRUE concerning p53 (TP53)?
A. MDM2 binding to p53 inhibits its degradation
B. Irradiation of cells stimulates ATM to act as a phosphatase and remove phosphate groups from p53
C. Following irradiation, p53 activates Cdc25C to stimulate the G2 to M phase transition
D. p53 stimulates the activity of BAX and BID in irradiated cells, resulting in apoptosis
D
p53 stimulates the activity of BAX and BID in irradiated cells, resulting in apoptosis. MDM2 binding to p53 stimulates degradation of p53. Irradiation of cells activates ATM to add phosphate groups to p53. Following irradiation, p53 inhibits CDC25C which inhibits the G2 to M phase transition. Lymphocytes and thymocytes with a mutant p53 tend to be more radioresistant than their normal counterparts.
Which of the following statements is TRUE concerning the products of the INK4A/ARF locus?
A. p16INK4A (CDKN2A) stimulates the hyper-phosphorylation of the RB (RB1) protein resulting in release of the E2F transcription factor
B. p14ARF is induced by the RAS/MEK/MAPK pathway and stimulates cell growth
C. p16INK4A is encoded by a proto-oncogene
D. p16INK4A is activated by the PI(3)K/AKT pathway and increases synthesis of cyclin D
E. p14ARF inhibits the MDM2-mediated degradation of p53
E
p14 (ARF) inhibits the MDM2-mediated degradation of p53. p16INK4A is a cell cycle inhibitor that prevents phosphorylation of RB by CDK4. p14ARF is an MDM2 inhibitor thereby causing p53 levels to increase, resulting in greater cell cycle inhibition. p16 (INK4A) is encoded by a tumor suppressor gene.
Which of the following represents a potential/actual therapeutic target in the oncogene-addicted tumor?
A. Mutated KIT and/or PDGFR in gastrointestinal stromal tumors (GIST).
B. Translocated ABL1 (previous symbol ABL) in T-cell acute lymphoblastic leukemia.
C. Amplified EGFR in non-small cell lung carcinoma.
D. Translocated ALK in small cell lung carcinoma.
E. Mutated Notch1 in chronic myeloid leukemia.
A
The oncogene addiction model postulates that some tumors rely on the continued activity of single dominant oncogene for growth and survival. Thus, according to the oncogene addition model, inactivation of this key single oncogene will halt malignant proliferation by inducing cell-cycle arrest, differentiation, senescence, or other forms of cell death, depending on tissue context. Each of the listed oncogene products in this question is an addictive oncoproteins in human cancer, however Choices B-E are incorrectly paired to the listed cancer. The receptor kinases KIT and/or PDGFR display activating mutations in more than 90% of gastrointestinal stromal tumors (GIST) (choice A). This observation supported the use of the multi-target small-molecule tyrosine kinase inhibitor imatinib mesylate (Gleevac) in GISTs. The correct matches in other choices are: translocated ABL1 in chronic myeloid leukemia (Answer Choice B); mutated, not amplified, EGFR in non-small-cell lung carcinoma (Answer Choice C); translocated ALK in non-small cell lung carcinoma (Answer Choice D); mutated Notch1 in T-cell acute lymphoblastic leukemia (Answer Choice E).
