Cancer Biology And Neoplasia - USMLE Step 1

1. This patient's neurologic syndrome is caused by autoantibodies directed against which of the following targets?
   Answer: Presynaptic voltage-gated calcium channels This patient has Lambert-Eaton myasthenic syndrome (LEMS), a paraneoplastic syndrome most commonly associated with small cell lung cancer. LEMS is caused by autoantibodies that target presynaptic voltage-gated calcium channels at the neuromuscular junction. This impairs the influx of calcium required for acetylcholine release, leading to proximal muscle weakness. The characteristic improvement with repeated contraction (facilitation) is due to the accumulation of intracellular calcium with successive nerve impulses, which overcomes the antibody-mediated blockade.
2. The decreased expression of these surface molecules allows the tumor cells to evade CTL recognition by impairing which of the following processes?
   Answer: Antigen presentation to CD8+ cytotoxic T cells Cytotoxic T lymphocytes (CTLs, CD8+ T cells) recognize and kill target cells by binding to peptide antigens presented by MHC class I molecules. HLA-A, HLA-B, and HLA-C are the human MHC class I molecules. By downregulating the expression of these molecules, cancer cells can prevent their tumor antigens from being presented on the cell surface, thereby becoming 'invisible' to and escaping destruction by antigen-specific CTLs. This is a common mechanism of tumor immune evasion.
3. This metabolic phenotype, known as the Warburg effect, provides a growth advantage to cancer cells primarily by which of the following mechanisms?
   Answer: Shunting metabolic intermediates into biosynthetic pathways The Warburg effect, or aerobic glycolysis, describes the phenomenon where cancer cells preferentially use glycolysis for energy production even in the presence of oxygen. While this is less efficient for ATP production compared to oxidative phosphorylation, it is advantageous for rapidly proliferating cells because it allows glycolytic intermediates (e.g., glucose-6-phosphate, fructose-6-phosphate) to be shunted into anabolic pathways, such as the pentose phosphate pathway for nucleotide synthesis and pathways for amino acid and lipid synthesis. These are the building blocks required for creating new cells.
4. The gene responsible for this condition encodes a protein that acts as a negative regulator of the cell cycle. This protein primarily exerts its effect by binding to and inhibiting which of the following transcription factors?
   Answer: E2F Retinoblastoma is caused by mutations in the RB1 tumor suppressor gene. The Rb protein is a critical regulator of the G1/S cell cycle checkpoint. In its active, hypophosphorylated state, Rb binds to the E2F transcription factor, preventing it from activating the transcription of genes required for S-phase entry (e.g., cyclins, DNA polymerase). When a cell is stimulated to divide, cyclin/CDK complexes phosphorylate Rb, causing it to release E2F, thus allowing the cell cycle to proceed.
5. The overexpression of Bcl-2 contributes to tumorigenesis by promoting which of the following 'hallmarks of cancer'?
   Answer: Resistance to cell death The B-cell lymphoma 2 (Bcl-2) protein is a key anti-apoptotic protein. It functions by inhibiting pro-apoptotic proteins like BAX and BAK, thereby stabilizing the mitochondrial membrane and preventing the release of cytochrome c, a critical step in the intrinsic pathway of apoptosis. In follicular lymphoma, the t(14;18) translocation places the BCL2 gene under the control of the strong immunoglobulin heavy chain promoter, leading to its overexpression. This makes the lymphoma cells resistant to programmed cell death (apoptosis), allowing them to accumulate and survive.
6. The therapeutic effect of this drug is primarily achieved by inhibiting which of the following processes essential for tumor growth and metastasis?
   Answer: Angiogenesis Bevacizumab is a monoclonal antibody that targets and neutralizes vascular endothelial growth factor (VEGF). VEGF is the primary signaling molecule that stimulates the formation of new blood vessels, a process called angiogenesis. Solid tumors require angiogenesis to grow beyond a few millimeters in size, as they need a blood supply for oxygen and nutrients. By sequestering VEGF, bevacizumab inhibits angiogenesis, thereby starving the tumor and preventing its growth and metastasis.
7. Unlike receptor tyrosine kinases, the mutated protein in this patient's condition requires association with a cytokine receptor to initiate downstream signaling through which of the following pathways?
   Answer: JAK-STAT pathway Polycythemia vera is a myeloproliferative neoplasm most commonly caused by a gain-of-function mutation in JAK2, a cytoplasmic (non-receptor) tyrosine kinase. JAK2 associates with hematopoietic cytokine receptors, such as the erythropoietin receptor. The V617F mutation makes JAK2 constitutively active, leading to ligand-independent activation of the STAT (Signal Transducer and Activator of Transcription) pathway. This results in uncontrolled proliferation of hematopoietic precursors, primarily of the erythroid lineage.
8. The gene mutated in this disorder encodes a protein, merlin, which normally functions as a tumor suppressor by which of the following mechanisms?
   Answer: Regulating cell-cell adhesion and contact inhibition Neurofibromatosis type 2 is caused by mutations in the NF2 gene, which encodes the protein merlin (also known as schwannomin). Merlin is a tumor suppressor protein that links transmembrane proteins, such as E-cadherin, to the actin cytoskeleton. This connection is crucial for establishing stable cell-cell junctions and mediating contact-dependent inhibition of proliferation. Loss of merlin function disrupts these connections, leading to loss of contact inhibition and uncontrolled cell growth, resulting in the formation of tumors like schwannomas and meningiomas.
9. This patient's secondary polycythemia is an example of a paraneoplastic syndrome caused by ectopic production of a hormone by the renal tumor. Which of the following is the most likely mechanism?
   Answer: Autonomous production of erythropoietin by neoplastic cells This patient has paraneoplastic polycythemia secondary to a renal cell carcinoma (RCC). RCC, along with hepatocellular carcinoma and cerebellar hemangioblastoma, can ectopically produce erythropoietin (EPO). This autonomous, unregulated production of EPO by the tumor cells leads to excessive stimulation of the bone marrow, resulting in an overproduction of red blood cells (polycythemia). This is distinct from polycythemia vera, where EPO levels would be low due to a primary bone marrow disorder.
10. The limitless replicative potential of these cancer cells is most commonly maintained by the activity of which enzyme?
    Answer: Telomerase Normal somatic cells have a finite lifespan due to the progressive shortening of telomeres at the ends of chromosomes with each round of DNA replication. Once telomeres become critically short, cells enter a state of replicative senescence or apoptosis. Most cancer cells achieve immortality by upregulating the expression of telomerase, a reverse transcriptase that adds repetitive nucleotide sequences to the ends of chromosomes, thus maintaining telomere length and allowing the cells to bypass senescence and divide indefinitely.
11. This 'two-hit' model of carcinogenesis is characteristic of genes that function as which of the following?
    Answer: Tumor suppressor genes The 'two-hit' hypothesis, proposed by Alfred Knudson, applies to tumor suppressor genes. In familial cancer syndromes like FAP, an individual inherits one defective (mutated) allele in every cell (the 'first hit'). Cancer develops only after the second, normal allele is lost or mutated in a somatic cell (the 'second hit'), leading to a complete loss of function of the tumor suppressor protein. In contrast, proto-oncogenes are typically activated by a single gain-of-function mutation ('one hit').
12. This patient's symptoms are caused by the secretion of which of the following substances from the neuroendocrine tumor?
    Answer: Serotonin This patient has carcinoid syndrome, a paraneoplastic syndrome caused by a well-differentiated neuroendocrine (carcinoid) tumor that has metastasized to the liver. The primary tumor, often in the small bowel, secretes serotonin and other vasoactive substances (e.g., bradykinin, histamine) into the portal circulation, where they are metabolized by the liver. When liver metastases are present, these substances are secreted directly into the systemic circulation, bypassing hepatic metabolism and causing the classic symptoms of flushing, diarrhea, and bronchospasm. 5-HIAA is the primary metabolite of serotonin.
13. The protein product of the gene mutated in this family normally functions as a 'guardian of the genome' by inducing cell cycle arrest and which other critical process in response to DNA damage?
    Answer: Apoptosis This family's history is classic for Li-Fraumeni syndrome, an autosomal dominant condition caused by a germline mutation in the TP53 tumor suppressor gene. The p53 protein is a transcription factor that is activated in response to cellular stress, such as DNA damage. Activated p53 can halt the cell cycle (primarily at the G1/S checkpoint) to allow time for DNA repair. If the damage is too severe to be repaired, p53 triggers apoptosis (programmed cell death) by upregulating pro-apoptotic genes like BAX.
14. The hypercalcemia in this patient is most likely caused by the tumor's ectopic production of which of the following substances?
    Answer: Parathyroid hormone-related protein (PTHrP) This patient's presentation is classic for hypercalcemia of malignancy, a common paraneoplastic syndrome. Squamous cell carcinoma of the lung (strongly associated with smoking and central masses) is the most common cause. These tumors often secrete parathyroid hormone-related protein (PTHrP), which mimics the action of PTH on bone and kidney, leading to increased bone resorption and renal calcium reabsorption. The resulting hypercalcemia causes feedback suppression of the parathyroid glands, leading to low PTH levels.
15. The prominent neovascularization seen in this patient's tumor is primarily driven by the overexpression of which of the following factors, which is normally degraded in a VHL-dependent manner?
    Answer: Hypoxia-inducible factor 1-alpha (HIF-1α) The von Hippel-Lindau (VHL) protein is a tumor suppressor that is part of a ubiquitin ligase complex. Under normoxic conditions, VHL targets hypoxia-inducible factor 1-alpha (HIF-1α) for ubiquitination and proteasomal degradation. When VHL is mutated, HIF-1α is stabilized even in the presence of oxygen. HIF-1α then acts as a transcription factor, upregulating the expression of pro-angiogenic factors like vascular endothelial growth factor (VEGF) and PDGF, leading to intense neovascularization.
16. The genetic translocation in this patient's lymphoma leads to the overexpression of a gene that encodes which of the following types of protein?
    Answer: A transcription factor The clinical presentation and t(8;14) translocation are characteristic of Burkitt lymphoma. This translocation places the c-MYC proto-oncogene from chromosome 8 under the control of the strong immunoglobulin heavy chain gene enhancer on chromosome 14. MYC is a transcription factor that upregulates the expression of numerous genes involved in cell growth, proliferation, and metabolism, leading to uncontrolled cell division.
17. The BRAF gene is an example of a proto-oncogene that, when mutated, leads to constitutive activation of which of the following signaling pathways?
    Answer: MAP kinase (RAS-RAF-MEK-ERK) pathway BRAF is a serine/threonine kinase that is a key component of the MAP kinase signaling pathway. This pathway is typically activated by growth factor binding to a receptor tyrosine kinase, which activates RAS, which in turn activates RAF (of which BRAF is a member). The V600E mutation in BRAF makes the kinase constitutively active, leading to constant downstream signaling through MEK and ERK, which promotes cell proliferation and survival, independent of upstream growth signals.
18. The ability of this patient's tumor cells to detach from the primary mass and invade surrounding tissues is most directly facilitated by the decreased expression of which of the following?
    Answer: E-cadherin Metastasis involves a series of steps, beginning with the dissociation of cells from the primary tumor. This is a key feature of the epithelial-to-mesenchymal transition (EMT). E-cadherin is a transmembrane protein that forms adherens junctions, mediating homotypic cell-cell adhesion in epithelial tissues. Downregulation or mutational inactivation of E-cadherin is a critical event that reduces intercellular adhesion, allowing cancer cells to detach and become motile.
19. The process of tumor cell invasion through the basement membrane and extracellular matrix to reach the portal circulation was most likely facilitated by the secretion of which of the following?
    Answer: Matrix metalloproteinases For tumor cells to metastasize, they must first breach the basement membrane and invade the surrounding extracellular matrix (ECM). This is accomplished by secreting proteolytic enzymes. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are crucial for degrading components of the ECM, such as collagen, laminin, and fibronectin. Increased expression and activity of MMPs are hallmarks of invasive cancers.
20. The protein overexpressed in this patient's tumor functions as which of the following?
    Answer: A receptor tyrosine kinase HER2/neu (also known as ERBB2) is a proto-oncogene that encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Amplification or overexpression of HER2 leads to constitutive activation of the receptor, resulting in ligand-independent dimerization and autophosphorylation. This activates downstream signaling pathways, such as the PI3K/AKT and MAP kinase pathways, driving cell proliferation and survival. Trastuzumab is a monoclonal antibody that targets the HER2 receptor.

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