USMLE Step 1 Quiz
Practice Cancer Genetics in USMLE Step 1 with focused quiz questions that help you check what you know, review explanations, and build confidence with test-style prompts.
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A researcher observes that many cancer cells have developed mechanisms to evade apoptosis. One such mechanism involves the inactivation of the p53 tumor suppressor protein, which normally induces apoptosis in response to cellular stress.
p53 carries out its pro-apoptotic function primarily by acting as a transcription factor for which of the following target genes?
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.
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.
A researcher observes that many cancer cells have developed mechanisms to evade apoptosis. One such mechanism involves the inactivation of the p53 tumor suppressor protein, which normally induces apoptosis in response to cellular stress.
p53 carries out its pro-apoptotic function primarily by acting as a transcription factor for which of the following target genes?
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.
A 65-year-old man with a 40-pack-year smoking history presents with a 3-month history of painless jaundice, weight loss, and pruritus. An abdominal CT scan shows a 3-cm mass in the head of the pancreas. Molecular analysis of a tumor biopsy is performed.
This analysis is most likely to reveal an activating mutation in a gene that encodes a protein with which of the following functions?
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.
A 68-year-old man is diagnosed with mantle cell lymphoma. Cytogenetic analysis of the malignant B-cells reveals a characteristic t(11;14) translocation.
This chromosomal translocation leads to the overexpression of a protein that directly promotes which of the following cellular processes?
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.
A 33-year-old man presents with intermittent headaches, palpitations, and sweating. His blood pressure is 180/110 mm Hg. An MRI of the abdomen reveals bilateral adrenal masses, consistent with pheochromocytomas. Further imaging shows a cerebellar hemangioblastoma and multiple renal cysts suspicious for renal cell carcinoma.
The mutated gene in this patient's syndrome normally targets which of the following proteins for proteasomal degradation?
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.
A 25-year-old man undergoes a screening colonoscopy because his father was diagnosed with colon cancer at age 30. The procedure reveals more than 500 adenomatous polyps carpeting his colon and rectum. He is diagnosed with familial adenomatous polyposis (FAP).
The protein product of the gene mutated in this patient's condition normally functions to promote the degradation of which of the following signaling molecules?
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.
A 55-year-old woman is diagnosed with invasive ductal carcinoma of the breast. Fluorescence in situ hybridization (FISH) analysis of the tumor tissue reveals multiple copies of the ERBB2 gene.
The genetic mechanism responsible for this finding is best described as which of the following?
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.
A patient with sporadic colon cancer has a tumor that displays microsatellite instability. Immunohistochemistry shows a complete loss of MLH1 protein expression. However, direct sequencing of the MLH1 gene's coding region and splice sites reveals no mutations.
Which of the following epigenetic mechanisms is the most likely cause for the silencing of the MLH1 gene in this tumor?
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.
A 2-year-old boy is brought to the ophthalmologist for evaluation of a "white pupil" in his right eye, first noticed in a photograph. Fundoscopic examination reveals a white mass in the posterior globe. The patient's father had an eye enucleated in childhood for a similar condition. The boy is diagnosed with retinoblastoma.
This patient's condition is most likely caused by a mutation in a gene whose protein product normally functions to do which of the following?
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.
A 32-year-old woman is diagnosed with breast cancer. Her medical history is remarkable for a soft tissue sarcoma she developed at age 15. A detailed family history reveals her father died of a brain tumor at age 40, and a paternal aunt was diagnosed with an adrenocortical carcinoma.
This patient's personal and family history is most characteristic of an inherited mutation in which of the following genes?
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.
A 45-year-old woman is diagnosed with triple-negative breast cancer. Due to a strong family history of breast and ovarian cancer, she undergoes genetic testing and is found to have a germline mutation in the BRCA1 gene.
The protein encoded by this gene is most directly involved in which of the following cellular processes?
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.
A 10-year-old boy is evaluated for multiple light-brown macules on his trunk and axillary freckling. A slit-lamp examination reveals pigmented hamartomas of the iris (Lisch nodules). His clinical picture is consistent with neurofibromatosis type 1 (NF1).
The protein affected in this patient's disorder normally functions to negatively regulate which of the following signaling proteins?
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.
An 8-year-old boy from equatorial Africa is brought to a clinic with a rapidly enlarging, nontender mass on his jaw. A biopsy of the mass is performed, and histopathology shows a diffuse infiltrate of intermediate-sized lymphoid cells interspersed with benign macrophages, creating a 'starry sky' appearance. Cytogenetic analysis confirms a t(8;14) translocation.
This genetic translocation leads to the overexpression of a protein that primarily functions as which of the following?
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.
A 52-year-old man presents with a 6-month history of fatigue, early satiety, and night sweats. Physical examination reveals marked splenomegaly. His complete blood count shows a white blood cell count of 180,000/μL with a predominance of neutrophils, myelocytes, and metamyelocytes. The Philadelphia chromosome is detected on karyotyping.
The molecular pathogenesis of this patient's disease involves a genetic alteration that creates a fusion protein with what type of enzymatic activity?
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.
A 25-year-old woman undergoes a prophylactic thyroidectomy based on genetic testing. Her father and older brother both developed medullary thyroid carcinoma and pheochromocytomas before the age of 30. Genetic analysis confirmed a germline point mutation in the RET gene.
The protein encoded by the proto-oncogene mutated in this patient's condition is best classified as which of the following?
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.
A 58-year-old man with a history of significant sun exposure is diagnosed with metastatic melanoma. Molecular testing of his tumor identifies a V600E mutation, making him a candidate for targeted therapy.
The mutated gene in this patient's cancer encodes a protein that is a key component of which of the following signaling pathways?
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.
A 72-year-old man undergoes a colonoscopy for screening, which reveals a large, ulcerated mass in the sigmoid colon. Biopsy confirms adenocarcinoma. A pathologist explains that the development of this cancer likely involved a stepwise accumulation of mutations over many years, a process known as the adenoma-carcinoma sequence.
In this classic progression model for colorectal cancer, the initiating genetic event is most often a mutation in which of the following genes?
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.
A 46-year-old woman is diagnosed with colorectal cancer. Her family history is notable for her mother having endometrial cancer at age 48 and a maternal uncle having colon cancer at age 45. Tumor analysis shows high levels of microsatellite instability.
The underlying genetic defect in this patient's hereditary cancer syndrome most likely involves a gene responsible for which of the following cellular functions?
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.
A 60-year-old woman is diagnosed with invasive lobular carcinoma of the breast. Histologic examination shows cords of single-file tumor cells infiltrating the stroma, a pattern attributed to a loss of cell-cell adhesion.
Loss-of-function mutations in the gene encoding which of the following proteins is most characteristically responsible for this histologic appearance?
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.
A 55-year-old man from a rural province in China presents with right upper quadrant pain and is diagnosed with hepatocellular carcinoma. His region is known for high rates of dietary contamination with aflatoxin B1, a mycotoxin from Aspergillus species.
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?
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.
A 3-year-old girl is diagnosed with bilateral retinoblastoma. Her father had unilateral retinoblastoma as a child.
Which of the following statements best describes the genetic events leading to her cancer, according to Knudson's two-hit hypothesis?
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.