Cancer Genetics - USMLE Step 1

1. The protein affected in this patient's disorder normally functions to negatively regulate which of the following signaling proteins?
   Answer: Ras Neurofibromatosis type 1 is caused by a mutation in the NF1 gene, which encodes the protein neurofibromin. Neurofibromin is a GTPase-activating protein (GAP) that accelerates the conversion of active (GTP-bound) Ras to its inactive (GDP-bound) state. Loss of NF1 function leads to constitutively active Ras signaling, promoting cell growth and proliferation.
2. This chromosomal translocation leads to the overexpression of a protein that directly promotes which of the following cellular processes?
   Answer: G1 to S phase transition of the cell cycle The t(11;14) translocation is the hallmark of mantle cell lymphoma. It juxtaposes the Cyclin D1 gene (CCND1) on chromosome 11 with the immunoglobulin heavy chain (IgH) locus on chromosome 14. This results in overexpression of Cyclin D1, a key regulatory protein. Cyclin D1 complexes with CDK4/6 to phosphorylate the retinoblastoma (RB) protein, promoting its release from E2F and thus driving the cell cycle forward from the G1 to S phase.
3. Which of the following statements best describes the genetic events leading to her cancer, according to Knudson's two-hit hypothesis?
   Answer: She inherited one mutated allele and acquired a second somatic mutation in a retinal cell. The patient has the hereditary form of retinoblastoma. According to Knudson's two-hit hypothesis for tumor suppressor genes, individuals with the hereditary form inherit one non-functional (mutated) allele in every cell of their body (the 'first hit'). Cancer develops when a second, somatic mutation (the 'second hit') occurs in the remaining normal allele within a specific cell, such as a retinal cell. This explains the early onset and increased risk of bilateral tumors.
4. The protein encoded by this gene is most directly involved in which of the following cellular processes?
   Answer: Homologous recombination repair of double-strand DNA breaks BRCA1 and BRCA2 are tumor suppressor genes whose protein products are critical for repairing double-strand DNA breaks through the high-fidelity homologous recombination pathway. Mutations in these genes lead to genomic instability and an increased risk of breast, ovarian, prostate, and pancreatic cancers.
5. This patient's condition is caused by a loss-of-function mutation in a gene whose product directly antagonizes the action of which signaling enzyme?
   Answer: Phosphoinositide 3-kinase (PI3K) Cowden syndrome is caused by a germline mutation in the PTEN tumor suppressor gene. The PTEN protein is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2). This action directly opposes the function of phosphoinositide 3-kinase (PI3K), thus downregulating the pro-survival and pro-proliferative PI3K/AKT/mTOR signaling pathway.
6. The genetic mechanism responsible for this finding is best described as which of the following?
   Answer: Gene amplification The presence of multiple copies of the ERBB2 (also known as HER2/neu) gene is due to gene amplification. This mechanism leads to overexpression of the HER2 receptor tyrosine kinase on the cell surface, driving tumor cell proliferation. HER2 amplification is a key prognostic and predictive biomarker in breast cancer, indicating eligibility for targeted therapies like trastuzumab.
7. p53 carries out its pro-apoptotic function primarily by acting as a transcription factor for which of the following target genes?
   Answer: BAX The p53 protein acts as a transcription factor that upregulates the expression of several pro-apoptotic genes. One of its key targets is the BAX gene. The BAX protein is a member of the Bcl-2 family that promotes apoptosis by increasing the permeability of the outer mitochondrial membrane, leading to the release of cytochrome c and the activation of caspases. In contrast, BCL2 is an anti-apoptotic protein, which is often downregulated by p53.
8. This patient's personal and family history is most characteristic of an inherited mutation in which of the following genes?
   Answer: TP53 This clinical presentation is classic for Li-Fraumeni syndrome, an autosomal dominant disorder caused by a germline mutation in the TP53 tumor suppressor gene. It is characterized by a predisposition to a wide range of cancers, including sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas, often at a young age.
9. This analysis is most likely to reveal an activating mutation in a gene that encodes a protein with which of the following functions?
   Answer: GTP-binding signal transducer Pancreatic adenocarcinoma is strongly associated with activating mutations in the KRAS oncogene, occurring in over 90% of cases. KRAS encodes a G-protein (a GTP-binding signal transducer) that is a key component of the MAPK signaling pathway. Activating mutations lock KRAS in its GTP-bound, active state, leading to uncontrolled cell proliferation.
10. The protein encoded by the proto-oncogene mutated in this patient's condition is best classified as which of the following?
    Answer: A receptor tyrosine kinase This patient has Multiple Endocrine Neoplasia type 2 (MEN 2), caused by a germline activating mutation in the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase that is crucial for the development of neural crest-derived cells, including the parafollicular C-cells of the thyroid and adrenal medullary cells. The activating mutation leads to ligand-independent dimerization and signaling.
11. This genetic translocation leads to the overexpression of a protein that primarily functions as which of the following?
    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 highly active immunoglobulin heavy chain (IgH) promoter from chromosome 14. MYC is a transcription factor that regulates the expression of numerous genes involved in cell growth, proliferation, and metabolism.
12. Loss-of-function mutations in the gene encoding which of the following proteins is most characteristically responsible for this histologic appearance?
    Answer: E-cadherin Invasive lobular carcinoma is classically associated with loss of E-cadherin (encoded by the CDH1 gene). E-cadherin is a transmembrane protein that mediates calcium-dependent, homophilic cell-cell adhesion, forming adherens junctions that are critical for maintaining epithelial tissue integrity. Its loss disrupts cell cohesion, leading to the characteristic single-file or 'Indian file' infiltration pattern.
13. In this classic progression model for colorectal cancer, the initiating genetic event is most often a mutation in which of the following genes?
    Answer: APC The classic adenoma-carcinoma sequence, described by Vogelstein, begins with a loss-of-function mutation in the APC tumor suppressor gene. This is the 'first hit' that leads to the formation of an early adenoma. Subsequent mutations, such as an activating mutation in KRAS and a loss-of-function mutation in TP53, drive the progression from adenoma to carcinoma.
14. The mutated gene in this patient's cancer encodes a protein that is a key component of which of the following signaling pathways?
    Answer: MAPK/ERK The V600E mutation is a specific activating mutation in the BRAF gene, found in about 50% of melanomas. BRAF is a serine/threonine kinase that acts downstream of Ras and upstream of MEK in the mitogen-activated protein kinase (MAPK/ERK) signaling pathway. The mutation leads to constitutive activation of this pathway, promoting cell proliferation and survival.
15. The mutated gene in this patient's syndrome normally targets which of the following proteins for proteasomal degradation?
    Answer: Hypoxia-inducible factor 1-α (HIF-1α) This patient's presentation is characteristic of von Hippel-Lindau (VHL) disease. The VHL protein is part of a ubiquitin ligase complex that, under normoxic conditions, binds to and targets hypoxia-inducible factor 1-α (HIF-1α) for degradation. Loss of VHL function leads to stabilization of HIF-1α, which then promotes the transcription of pro-angiogenic factors like VEGF, driving tumor growth.
16. The predisposition to cancer in this patient is due to an inherited defect in which of the following cellular processes?
    Answer: Nucleotide excision repair Xeroderma pigmentosum (XP) is an autosomal recessive disorder caused by defects in the nucleotide excision repair (NER) pathway. This pathway is responsible for removing bulky DNA lesions, such as pyrimidine dimers formed by exposure to ultraviolet (UV) radiation. The inability to repair this UV-induced DNA damage leads to a high mutation rate and a dramatically increased risk of developing skin cancers.
17. This patient's constellation of findings (WAGR syndrome) is associated with a deletion of a gene that functions as which of the following?
    Answer: A transcription factor crucial for renal development WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and intellectual disability [Retardation]) is caused by a contiguous gene deletion on chromosome 11, which includes the WT1 and PAX6 genes. The WT1 gene encodes a zinc-finger transcription factor that is essential for the normal development of the kidney and gonads. Loss of WT1 function disrupts this development and predisposes to Wilms tumor.
18. The molecular pathogenesis of this patient's disease involves a genetic alteration that creates a fusion protein with what type of enzymatic activity?
    Answer: Tyrosine kinase This patient has chronic myeloid leukemia (CML), which is characterized by the Philadelphia chromosome, a result of the t(9;22) translocation. This translocation creates the BCR-ABL fusion gene. The resulting BCR-ABL protein is a constitutively active tyrosine kinase that drives the proliferation of myeloid progenitor cells and is the target of specific inhibitors like imatinib.
19. This environmental carcinogen is known to cause a specific G:C to T:A transversion mutation that frequently inactivates which of the following tumor suppressor genes?
    Answer: TP53 Aflatoxin B1 is a potent hepatocarcinogen. After being metabolized by cytochrome P450 enzymes in the liver, it forms a reactive epoxide that binds to DNA. This adduct preferentially causes a specific mutation at codon 249 of the TP53 gene, leading to a G to T transversion. This inactivating mutation in the p53 tumor suppressor is a molecular hallmark of aflatoxin-induced hepatocellular carcinoma.
20. The resulting fusion protein promotes oncogenesis primarily through which of the following mechanisms?
    Answer: Constitutive activation of a tyrosine kinase domain The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase. The EML4-ALK fusion oncogene, found in a subset of non-small cell lung cancers, results in a chimeric protein. The EML4 portion causes ligand-independent dimerization, leading to constitutive activation of the ALK tyrosine kinase domain. This drives downstream signaling pathways, such as MAPK and PI3K/AKT, promoting cell proliferation and survival.

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