USMLE Step 1 Quiz: Cancer Genetics

What this quiz covers

This quiz focuses on Cancer Genetics, giving you a quick way to practice the rules, question types, and explanations that matter most for USMLE Step 1.

How to use this quiz

Try each quiz question before looking at the correct answer. Use the explanations to review missed ideas, then come back to similar questions until the pattern feels familiar.

Question 1

1. BCL2
2. BAX (correct answer)
3. MYC
4. RAS

Explanation: 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.

Question 2

1. GTP-binding signal transducer (correct answer)
2. DNA damage checkpoint sensor
3. Cell-cell adhesion molecule
4. DNA mismatch repair enzyme

Explanation: 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.

Question 3

1. Apoptosis
2. G1 to S phase transition of the cell cycle (correct answer)
3. DNA mismatch repair
4. Signal transduction from the B-cell receptor

Explanation: 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.

Question 4

1. Hypoxia-inducible factor 1-α (HIF-1α) (correct answer)
2. β-catenin
3. p53
4. E2F

Explanation: 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.

Question 5

1. Ras
2. β-catenin (correct answer)
3. SMAD4
4. p21

Explanation: Familial adenomatous polyposis (FAP) is caused by an inherited mutation in the APC tumor suppressor gene. The APC protein is a key component of the destruction complex that phosphorylates β-catenin, targeting it for ubiquitination and degradation. Loss of APC function leads to the accumulation of β-catenin, which then translocates to the nucleus and activates transcription of pro-proliferative genes.

Question 6

1. Gene amplification (correct answer)
2. Chromosomal translocation
3. Activating point mutation
4. Loss of heterozygosity

Explanation: 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.

Question 7

1. Histone deacetylation
2. Hypermethylation of the promoter region (correct answer)
3. A nonsense-mediated decay pathway
4. Inhibition by a microRNA

Explanation: In sporadic colorectal cancers with microsatellite instability, the most common cause of MLH1 silencing is not a mutation but an epigenetic event. Specifically, hypermethylation of CpG islands in the promoter region of the MLH1 gene leads to transcriptional inactivation, resulting in the loss of MLH1 protein expression and a deficient mismatch repair system.

Question 8

1. Inhibit the E2F transcription factor (correct answer)
2. Activate signal transduction via GTP binding
3. Promote angiogenesis via HIF-1α stabilization
4. Repair double-stranded DNA breaks

Explanation: This patient has hereditary retinoblastoma, caused by a germline mutation in the RB1 tumor suppressor gene. The RB protein, when hypophosphorylated, binds to and inactivates the E2F transcription factor, thereby halting the cell cycle at the G1/S checkpoint. Loss of RB function leads to unregulated E2F activity and uncontrolled cell proliferation.

Question 9

1. BRCA1
2. APC
3. TP53 (correct answer)
4. NF2

Explanation: 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.

Question 10

1. Mismatch repair of DNA replication errors
2. Homologous recombination repair of double-strand DNA breaks (correct answer)
3. Nucleotide excision repair of pyrimidine dimers
4. Regulation of the G1/S cell cycle checkpoint

Explanation: 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.

Question 11

1. ABL
2. MYC
3. JAK2
4. Ras (correct answer)

Explanation: 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.

Question 12

1. A receptor tyrosine kinase
2. A DNA repair enzyme
3. A transcription factor (correct answer)
4. A signal-transducing G-protein

Explanation: 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.

Question 13

1. Serine/threonine kinase
2. GTPase-activating protein
3. Tyrosine kinase (correct answer)
4. DNA helicase

Explanation: 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.

Question 14

1. A DNA-binding transcription factor
2. A receptor tyrosine kinase (correct answer)
3. A cytoplasmic G-protein
4. A nuclear hormone receptor

Explanation: 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.

Question 15

1. Wnt/β-catenin
2. MAPK/ERK (correct answer)
3. PI3K/AKT/mTOR
4. JAK/STAT

Explanation: 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.

Question 16

1. KRAS
2. TP53
3. SMAD4
4. APC (correct answer)

Explanation: 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.

Question 17

1. DNA mismatch repair (correct answer)
2. Repair of double-stranded DNA breaks
3. Base excision repair
4. Cell cycle checkpoint control

Explanation: This clinical scenario is highly suggestive of Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer), the most common cause of inherited colorectal cancer. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes, most commonly MLH1, MSH2, MSH6, and PMS2. Defective MMR leads to microsatellite instability and an increased mutation rate, predisposing individuals to colorectal, endometrial, ovarian, and other cancers.

Question 18

1. Integrin
2. Fibronectin
3. E-cadherin (correct answer)
4. Vimentin

Explanation: 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.

Question 19

1. APC
2. RB1
3. NF1
4. TP53 (correct answer)

Explanation: 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.

Question 20

1. She inherited one mutated allele and acquired a second somatic mutation in a retinal cell. (correct answer)
2. She acquired two separate somatic mutations in a single retinal cell after birth.
3. She inherited two mutated alleles, one from each parent, which is incompatible with life.
4. She inherited a mutated oncogene that requires only one activating event.

Explanation: 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.