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Arab Board Oncology Part 1 study materials
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Arab Board Oncology Part 1 practice questions

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Question 1Cancer Biology, Carcinogenesis and Molecular Genetics

A proto-oncogene is converted into an oncogene by a mutation that produces which effect?

  1. Gain of function in the encoded growth-promoting protein Correct answer.
  2. Silencing of the promoter by DNA methylation
  3. Deletion of the entire coding region
  4. Loss of both alleles at the locus

Explanation

Proto-oncogenes encode proteins that promote proliferation or survival, and a single activating alteration is enough to drive growth. Such gain-of-function mutations behave dominantly at the cellular level. Losses, deletions and promoter silencing are instead mechanisms of tumour suppressor inactivation.

Question 2Cancer Biology, Carcinogenesis and Molecular Genetics

Knudson's two-hit model of tumourigenesis is classically illustrated by germline mutation of which gene?

  1. RB1 Correct answer.
  2. KRAS
  3. BCR-ABL1
  4. MYCN

Explanation

Retinoblastoma requires inactivation of both RB1 alleles; in hereditary cases one hit is germline, so a single somatic hit in a retinal cell is sufficient and disease presents early and bilaterally. KRAS, MYCN and BCR-ABL1 are activated dominantly and do not follow a two-hit recessive pattern.

Question 3Cancer Biology, Carcinogenesis and Molecular Genetics

The p53 protein is best described as which of the following?

  1. A mismatch repair enzyme
  2. A receptor tyrosine kinase
  3. A transcription factor that induces cell-cycle arrest or apoptosis after DNA damage Correct answer.
  4. A cyclin-dependent kinase

Explanation

p53 is a transcription factor stabilised after DNA damage or oncogenic stress, and it transactivates targets such as p21 and PUMA that arrest the cycle or trigger apoptosis. This response prevents propagation of damaged genomes. It has no kinase or mismatch repair catalytic activity.

Question 4Cancer Biology, Carcinogenesis and Molecular Genetics

The Philadelphia chromosome t(9;22) generates which fusion gene?

  1. PAX3-FOXO1
  2. TMPRSS2-ERG
  3. BCR-ABL1 Correct answer.
  4. EWS-FLI1

Explanation

The t(9;22) translocation joins BCR on chromosome 22 to ABL1 on chromosome 9, producing a constitutively active tyrosine kinase that drives chronic myeloid leukaemia. EWS-FLI1, PAX3-FOXO1 and TMPRSS2-ERG arise from different translocations in other tumour types.

Question 5Cancer Biology, Carcinogenesis and Molecular Genetics

Which carcinogen requires metabolic activation by cytochrome P450 to form DNA-reactive epoxides?

  1. Ionizing radiation
  2. Epstein-Barr virus
  3. Ultraviolet B radiation
  4. Polycyclic aromatic hydrocarbons such as benzo[a]pyrene Correct answer.

Explanation

Polycyclic aromatic hydrocarbons are indirect carcinogens: cytochrome P450 enzymes oxidise them to epoxides that bind DNA and form bulky adducts. Ionizing and ultraviolet radiation act physically, and Epstein-Barr virus is a biological carcinogen.

Question 6Cancer Biology, Carcinogenesis and Molecular Genetics

Which virus is causally linked to the development of cervical carcinoma?

  1. Human T-cell lymphotropic virus type 1
  2. Human papillomavirus Correct answer.
  3. Epstein-Barr virus
  4. Hepatitis B virus

Explanation

High-risk human papillomavirus types, particularly 16 and 18, encode E6 and E7 proteins that inactivate p53 and RB respectively. Persistent infection with these types is the principal cause of cervical carcinoma.

Question 7Cancer Biology, Carcinogenesis and Molecular Genetics

Aflatoxin B1 exposure is most strongly associated with which malignancy?

  1. Hepatocellular carcinoma Correct answer.
  2. Nasopharyngeal carcinoma
  3. Burkitt lymphoma
  4. Cervical carcinoma

Explanation

Aflatoxin B1 is metabolised to a reactive epoxide that forms DNA adducts and favours the characteristic TP53 codon 249 mutation, contributing to hepatocellular carcinoma. The risk is amplified in people with chronic hepatitis B infection.

Question 8Cancer Biology, Carcinogenesis and Molecular Genetics

Hereditary non-polyposis colorectal cancer (Lynch syndrome) is caused by a defect in which DNA repair pathway?

  1. Mismatch repair Correct answer.
  2. Homologous recombination
  3. Base excision repair
  4. Nucleotide excision repair

Explanation

Lynch syndrome results from germline loss of mismatch repair genes such as MLH1, MSH2, MSH6 or PMS2, producing microsatellite instability and a high mutational burden. Nucleotide excision repair and homologous recombination defects underlie different hereditary cancer syndromes.

Question 9Cancer Biology, Carcinogenesis and Molecular Genetics

A breast tumour shows strong membranous HER2 overexpression on immunohistochemistry. Which agent is most directly indicated by this finding?

  1. Trastuzumab Correct answer.
  2. Imatinib
  3. Rituximab
  4. Tamoxifen

Explanation

HER2 overexpression or amplification identifies tumours that depend on HER2 signalling and respond to HER2-directed antibodies such as trastuzumab. Imatinib targets BCR-ABL1, tamoxifen requires oestrogen receptor expression and rituximab targets CD20.

Question 10Cancer Biology, Carcinogenesis and Molecular Genetics

A patient with chronic myeloid leukaemia is treated with imatinib. Which kinase is the principal target of this drug?

  1. BRAF V600E kinase
  2. Anaplastic lymphoma kinase
  3. BCR-ABL1 tyrosine kinase Correct answer.
  4. Epidermal growth factor receptor

Explanation

Imatinib binds the ATP pocket of the ABL kinase domain and inhibits the constitutively active BCR-ABL1 fusion protein that defines chronic myeloid leukaemia. This is the paradigm of oncogene-addiction therapy. EGFR, ALK and BRAF are targets of other inhibitors.

Question 11Cancer Biology, Carcinogenesis and Molecular Genetics

In the absence of functional APC, beta-catenin accumulates because APC normally does which of the following?

  1. Phosphorylates beta-catenin at the plasma membrane
  2. Blocks beta-catenin entry into the nucleus
  3. Participates in the destruction complex that targets beta-catenin for proteasomal degradation Correct answer.
  4. Acts directly as an E3 ubiquitin ligase for beta-catenin

Explanation

APC is a scaffold of the destruction complex containing axin, GSK3-beta and CK1, which phosphorylates beta-catenin and permits its ubiquitination and proteasomal degradation. Loss of APC stabilises beta-catenin, allowing it to enter the nucleus and activate TCF/LEF targets such as MYC and cyclin D1. APC is neither a kinase nor an E3 ligase.

Question 12Cancer Biology, Carcinogenesis and Molecular Genetics

Release of cytochrome c from mitochondria during intrinsic apoptosis leads directly to activation of which protease?

  1. XIAP
  2. Bcl-2
  3. Bcl-xL
  4. Caspase-9 Correct answer.

Explanation

Cytochrome c binds Apaf-1 to form the apoptosome, which recruits and activates caspase-9, the initiator caspase of the intrinsic pathway. Bcl-2 and Bcl-xL are anti-apoptotic regulators upstream of cytochrome c release, while XIAP inhibits caspases.

Question 13Cancer Biology, Carcinogenesis and Molecular Genetics

Hypoxia within a growing tumour stabilises HIF-1-alpha, which increases transcription of which factor?

  1. p53
  2. Vascular endothelial growth factor Correct answer.
  3. E-cadherin
  4. PTEN

Explanation

Under low oxygen tension HIF-1-alpha escapes degradation and partners with HIF-1-beta to transactivate genes including VEGF, GLUT1 and erythropoietin, promoting angiogenesis and glycolytic metabolism. p53, E-cadherin and PTEN are not HIF-1 targets in this context.

Question 14Cancer Biology, Carcinogenesis and Molecular Genetics

A woman carries a germline BRCA1 mutation and develops breast cancer. Which event best explains loss of heterozygosity at the BRCA1 locus in her tumour?

  1. Promoter hypomethylation of the wild-type allele
  2. A reciprocal chromosomal translocation
  3. Amplification of the mutant allele
  4. Somatic deletion of the remaining wild-type allele Correct answer.

Explanation

BRCA1 is a tumour suppressor, so the inherited mutant allele is accompanied by a second somatic hit, commonly deletion or mutation of the wild-type allele, that removes residual function. This fits the two-hit model. Amplification, translocation and hypomethylation would not eliminate the wild-type allele.

Question 15Cancer Biology, Carcinogenesis and Molecular Genetics

Cyclin D-CDK4/6 complexes promote cell-cycle progression through which checkpoint?

  1. The metaphase-to-anaphase transition
  2. The G2/M checkpoint
  3. The spindle assembly checkpoint
  4. The G1/S restriction point Correct answer.

Explanation

Cyclin D-CDK4/6 phosphorylates RB, releasing E2F and allowing transition through the G1/S restriction point. CDK inhibitors such as p16 restrain this step, and their loss contributes to unchecked G1 progression. G2/M and mitotic checkpoints are controlled by different cyclin-CDK pairs and regulatory kinases.

Question 16Cancer Biology, Carcinogenesis and Molecular Genetics

Hypermethylation of CpG islands in the promoter of a tumour suppressor gene most commonly produces which effect?

  1. Transcriptional silencing Correct answer.
  2. An activating point mutation
  3. Increased mRNA translation
  4. Gene amplification

Explanation

Promoter CpG island hypermethylation recruits methyl-binding proteins and histone deacetylases, condensing chromatin and silencing transcription without changing the DNA sequence. This epigenetic mechanism inactivates tumour suppressors such as MLH1 and CDKN2A. It does not amplify the gene or create an activating mutation.

Question 17Cancer Biology, Carcinogenesis and Molecular Genetics

The Warburg effect refers to which metabolic behaviour of cancer cells?

  1. Increased aerobic glycolysis even when oxygen is available Correct answer.
  2. Exclusive dependence on fatty acid beta-oxidation
  3. Increased reliance on oxidative phosphorylation
  4. Decreased glucose uptake across the cell membrane

Explanation

Cancer cells frequently convert glucose to lactate by glycolysis despite adequate oxygen, a phenomenon termed aerobic glycolysis or the Warburg effect. This supports biosynthetic precursor production and is exploited clinically by FDG-PET imaging. It does not mean oxidative phosphorylation is absent or that glucose uptake falls.

Question 18Cancer Biology, Carcinogenesis and Molecular Genetics

Epithelial-mesenchymal transition during tumour invasion is characterised by which change?

  1. Reduced secretion of matrix metalloproteinases
  2. Increased cytokeratin expression
  3. Increased E-cadherin expression
  4. Loss of E-cadherin with gain of vimentin expression Correct answer.

Explanation

EMT involves downregulation of the epithelial adhesion molecule E-cadherin and upregulation of mesenchymal markers such as vimentin, increasing motility and invasiveness. Transcription factors including Snail, Slug and Twist mediate this switch. Matrix metalloproteinases are generally increased, not reduced.

Question 19Cancer Biology, Carcinogenesis and Molecular Genetics

Li-Fraumeni syndrome is caused by a germline mutation in which gene?

  1. BRCA2
  2. TP53 Correct answer.
  3. APC
  4. RB1

Explanation

Li-Fraumeni syndrome results from a germline TP53 mutation and predisposes to sarcomas, breast cancer, brain tumours, adrenocortical carcinoma and leukaemia, often at young ages. RB1, BRCA2 and APC germline mutations cause different hereditary cancer syndromes.

Question 20Cancer Biology, Carcinogenesis and Molecular Genetics

A lung adenocarcinoma contains an EGFR exon 19 deletion. Which systemic agent is most appropriate based on this finding?

  1. Trastuzumab
  2. Vemurafenib
  3. Erlotinib Correct answer.
  4. Crizotinib

Explanation

Exon 19 deletions activate EGFR and confer sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib and osimertinib. Crizotinib targets ALK, vemurafenib targets BRAF V600E and trastuzumab targets HER2, none of which fits this genotype.

Question 21Cancer Biology, Carcinogenesis and Molecular Genetics

Loss of PTEN function in a tumour cell leads to constitutive activation of which signalling pathway?

  1. PI3K-AKT Correct answer.
  2. RAS-MAPK
  3. JAK-STAT
  4. Wnt/beta-catenin

Explanation

PTEN is a lipid phosphatase that removes the 3-phosphate from PIP3, opposing PI3K activity. Loss of PTEN allows PIP3 accumulation, AKT activation and downstream mTOR signalling, promoting growth and survival. RAS-MAPK, JAK-STAT and Wnt pathways are regulated by different lesions.

Question 22Cancer Biology, Carcinogenesis and Molecular Genetics

Which finding most directly supports the cancer stem cell model?

  1. All cells within a tumour form colonies with equal efficiency in soft agar
  2. Only a small subpopulation defined by surface markers can serially transplant tumours that reproduce the original heterogeneity Correct answer.
  3. Chemotherapy selects pre-existing resistant mutations
  4. All tumours arise from a single transformed clone

Explanation

The cancer stem cell model predicts a hierarchical organisation in which a minority of cells can self-renew, regenerate a heterogeneous tumour in serial xenografts and resist therapy. Equal clonogenicity of all cells or monoclonality would not distinguish this from the stochastic model. Drug selection explains resistance but not tumour-initiating hierarchy.

Question 23Cancer Biology, Carcinogenesis and Molecular Genetics

Tumours with BRCA1 or BRCA2 loss are sensitive to PARP inhibitors because of which mechanism?

  1. PARP inhibitors increase homologous recombination activity
  2. Blocked single-strand break repair generates double-strand breaks that homologous recombination cannot repair Correct answer.
  3. PARP inhibitors restore BRCA1/2 protein function
  4. BRCA-deficient cells cannot perform base excision repair

Explanation

PARP inhibition traps repair intermediates and converts single-strand lesions into double-strand breaks during replication. BRCA-deficient cells cannot repair these by homologous recombination, so the combined defect is synthetically lethal. PARP inhibitors do not restore BRCA function or increase recombination.

Question 24Cancer Biology, Carcinogenesis and Molecular Genetics

Amplification of MYCN in a neuroblastoma is associated with which clinical feature?

  1. Favourable histology
  2. Advanced stage and poor outcome Correct answer.
  3. Spontaneous regression
  4. Localised stage I disease

Explanation

MYCN amplification is a well-established adverse prognostic marker in neuroblastoma, correlating with advanced disease, rapid progression and inferior survival, and it intensifies therapy in risk stratification. Favourable biology, in contrast, is seen in infants with localised disease that may regress spontaneously.

Question 25Cancer Biology, Carcinogenesis and Molecular Genetics

Which statement about telomerase in human cancer is most accurate?

  1. Telomerase shortens telomeres with each round of replication
  2. Telomerase replicates mitochondrial DNA
  3. Most normal somatic cells express little telomerase, whereas most carcinomas reactivate it Correct answer.
  4. Telomerase activity is lost during malignant transformation

Explanation

Normal somatic cells generally have low telomerase activity and gradually lose telomeric DNA, whereas most carcinomas reactivate telomerase to maintain telomere length and permit replicative immortality. Telomerase extends telomeres using an RNA template and is not a mitochondrial polymerase.

Question 26Cancer Biology, Carcinogenesis and Molecular Genetics

A gain-of-function mutation that constitutively activates a growth-promoting signalling protein is characteristic of which gene class?

  1. Apoptosis executor gene
  2. DNA mismatch repair gene
  3. Proto-oncogene Correct answer.
  4. Tumour suppressor gene

Explanation

Proto-oncogenes encode proteins that normally promote proliferation or survival, and gain-of-function changes convert them into oncogenes. Such mutations are usually dominant at the cellular level because one altered allele can produce a constitutively active signal. Tumour suppressor genes, by contrast, typically require loss of function.

Question 27Cancer Biology, Carcinogenesis and Molecular Genetics

Which cancer is most strongly associated with Epstein-Barr virus infection?

  1. Nasopharyngeal carcinoma Correct answer.
  2. Cervical carcinoma
  3. Hepatocellular carcinoma
  4. Kaposi sarcoma

Explanation

Epstein-Barr virus establishes latent infection in B cells and epithelial cells and is strongly linked to nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. Hepatocellular carcinoma is linked mainly to hepatitis B and C, Kaposi sarcoma to human herpesvirus 8, and cervical carcinoma to human papillomavirus.

Question 28Cancer Biology, Carcinogenesis and Molecular Genetics

Follicular lymphoma often carries t(14;18), which places BCL2 under immunoglobulin heavy-chain enhancer control. Which effect best explains the survival advantage of the lymphoma cells?

  1. Enhanced cytochrome c release
  2. Reduced programmed cell death Correct answer.
  3. Increased DNA repair
  4. Accelerated cell-cycle entry

Explanation

BCL2 inhibits the intrinsic apoptotic pathway by opposing Bax/Bak-mediated mitochondrial permeabilization and cytochrome c release. Enhancer-driven overexpression therefore allows B cells to survive despite lacking normal survival signals. The translocation does not directly accelerate cell-cycle entry or increase DNA repair.

Question 29Cancer Biology, Carcinogenesis and Molecular Genetics

A child with extreme sun sensitivity develops freckling and multiple skin cancers on sun-exposed skin. A defect in which repair process is most likely?

  1. Nucleotide excision repair Correct answer.
  2. DNA mismatch repair
  3. Base excision repair
  4. Homologous recombination repair

Explanation

Xeroderma pigmentosum results from defective nucleotide excision repair, the pathway that removes ultraviolet-induced pyrimidine dimers. Unrepaired damage causes mutations and markedly increases skin cancer risk. Mismatch repair, base excision repair, and homologous recombination repair address other classes of DNA damage.

Question 30Cancer Biology, Carcinogenesis and Molecular Genetics

A pancreatic adenocarcinoma carries a KRAS codon 12 mutation. Which molecular consequence most directly promotes proliferation?

  1. Loss of receptor tyrosine kinase dimerization
  2. Impaired RAS attachment to the plasma membrane
  3. Failure of RAS GTP hydrolysis Correct answer.
  4. Constitutive nuclear translocation of beta-catenin

Explanation

Codons 12, 13, and 61 of KRAS encode residues critical for intrinsic GTPase activity. Mutation impairs GTP hydrolysis, locking RAS in the active GTP-bound state and sustaining downstream RAF-MEK-ERK and PI3K signalling. Membrane attachment is required for RAS function but is not the direct effect of the codon 12 mutation.

Question 31Cancer Biology, Carcinogenesis and Molecular Genetics

Tumour cells expressing PD-L1 can escape T-cell killing by engaging which receptor on activated T cells?

  1. CD28
  2. T-cell receptor
  3. PD-1 Correct answer.
  4. CTLA-4

Explanation

PD-L1 on tumour or stromal cells binds PD-1 on activated T cells and delivers an inhibitory signal that limits effector function and promotes exhaustion. Blocking this interaction is the rationale for PD-1 or PD-L1 checkpoint inhibitors. CTLA-4 and CD28 bind different ligands and serve distinct costimulatory or inhibitory roles.

Question 32Cancer Biology, Carcinogenesis and Molecular Genetics

A patient with metastatic melanoma responds initially to a BRAF inhibitor and then relapses. Rebiopsy shows expansion of a subclone with BRAF amplification and reactivated MAPK signalling. Which concept best explains this outcome?

  1. Synthetic lethality
  2. Clonal selection Correct answer.
  3. Field cancerization
  4. Knudson two-hit hypothesis

Explanation

Tumours contain genetically heterogeneous subpopulations, and a targeted drug can eliminate sensitive cells while allowing pre-existing resistant subclones to expand. This is clonal selection under therapeutic pressure. Field cancerization describes widespread altered epithelium, synthetic lethality describes paired genetic dependencies, and the two-hit hypothesis describes sequential inactivation of both alleles of a tumour suppressor.

Question 33Cancer Immunology and Principles of Immunotherapy

MHC class I molecules display peptides derived from cytosolic proteins to which cell population?

  1. Natural killer cells via Fc gamma receptors
  2. CD4-positive helper T cells
  3. B lymphocytes through surface immunoglobulin
  4. CD8-positive cytotoxic T cells Correct answer.

Explanation

MHC class I is expressed on nearly all nucleated cells and presents endogenously synthesised peptides to CD8-positive cytotoxic T lymphocytes, which then can kill the presenting cell. MHC class II instead presents exogenously acquired peptides to CD4-positive helper T cells. This division of labour is central to how tumours become visible to the adaptive immune system.

Question 34Cancer Immunology and Principles of Immunotherapy

Which agent is administered at high dose to selected patients with metastatic melanoma or renal cell carcinoma in order to expand effector lymphocytes?

  1. Interleukin-2 Correct answer.
  2. Erythropoietin
  3. Granulocyte colony-stimulating factor
  4. Interferon gamma

Explanation

High-dose interleukin-2 drives expansion of effector T cells and natural killer cells and can produce durable complete responses in a minority of patients with metastatic melanoma or renal cell carcinoma. Its use is limited by capillary leak syndrome and multi-organ toxicity, so patients require intensive care support.

Question 35Cancer Immunology and Principles of Immunotherapy

Intravesical bacillus Calmette-Guerin is standard adjuvant therapy for high-risk non-muscle-invasive bladder cancer. Its antitumour effect depends mainly on which process?

  1. Inhibition of the mammalian target of rapamycin
  2. Blockade of vascular endothelial growth factor
  3. Induction of local granulomatous inflammation Correct answer.
  4. Direct alkylation of tumour DNA

Explanation

Bacillus Calmette-Guerin attaches to the urothelium and triggers a Th1-weighted granulomatous inflammatory response that recruits neutrophils and lymphocytes capable of clearing residual tumour cells. The effect is immunologically mediated, so patients on immunosuppression respond poorly and are at risk of disseminated infection.

Question 36Cancer Immunology and Principles of Immunotherapy

Which cell population is the principal mediator of antibody-dependent cellular cytotoxicity against tumour cells coated with immunoglobulin G?

  1. Natural killer cells Correct answer.
  2. CD4-positive helper T cells
  3. Dendritic cells
  4. Cytotoxic T lymphocytes

Explanation

Natural killer cells express the activating receptor Fc gamma RIII (CD16) and kill immunoglobulin G-opsonised targets without prior sensitisation or MHC restriction. This is one mechanism by which antibodies such as trastuzumab and rituximab recruit immune effector function.

Question 37Cancer Immunology and Principles of Immunotherapy

Tumour-specific neoantigens that drive effective antitumour T-cell responses arise most commonly from which source?

  1. Somatic mutations in tumour DNA Correct answer.
  2. Germline polymorphisms in HLA genes
  3. Physiological expression of tissue antigens
  4. Post-translational modification of histones

Explanation

Neoantigens are encoded by somatically mutated genes and are therefore absent from normal tissues, so central tolerance has not deleted the reactive T-cell clones. Because they are truly tumour-specific, they are attractive targets for vaccines and adoptive cell therapy. A higher mutational burden, as in melanoma or mismatch repair-deficient tumours, increases the chance that such antigens exist.

Question 38Cancer Immunology and Principles of Immunotherapy

A patient receiving pembrolizumab for melanoma develops grade 2 immune-mediated colitis with six watery stools per day and mild abdominal pain. What is the most appropriate initial management?

  1. Reduce the dose and give prophylactic antibiotics
  2. Discontinue permanently and give infliximab
  3. Continue therapy and add loperamide
  4. Hold immunotherapy and start corticosteroids Correct answer.

Explanation

Grade 2 immune-mediated colitis is managed by withholding the checkpoint inhibitor and starting systemic corticosteroids, typically prednisone 0.5 to 1 mg per kg daily, with taper once symptoms resolve. Grade 3 or 4 toxicity requires high-dose intravenous methylprednisolone and infliximab or vedolizumab if steroid-refractory. Anti-CTLA-4 agents cause this toxicity more often and more severely than anti-PD-1 agents.

Question 39Cancer Immunology and Principles of Immunotherapy

In a second-generation chimeric antigen receptor, which element confers antigen specificity?

  1. The intracellular CD3-zeta signalling domain
  2. The transmembrane hinge region of the receptor
  3. A single-chain variable fragment Correct answer.
  4. A costimulatory domain derived from 4-1BB

Explanation

The single-chain variable fragment is assembled from the variable heavy and light chains of a monoclonal antibody and binds surface antigen in an MHC-independent manner. The CD3-zeta domain supplies activation signal one, while a costimulatory domain such as 4-1BB or CD28 supports proliferation and persistence. Antigen loss, as with CD19 escape, is therefore a major mechanism of resistance.

Question 40Cancer Immunology and Principles of Immunotherapy

Anti-CTLA-4 antibodies act predominantly during T-cell priming in lymphoid tissue. Which statement best explains this effect?

  1. It frees B7 ligands so CD28 can provide signal 2 Correct answer.
  2. It directly blocks PD-L1 on tumour cell membranes
  3. It increases MHC class I expression on tumour cells
  4. It kills regulatory T cells through complement fixation

Explanation

CTLA-4 competes with CD28 for the shared B7 ligands and raises the threshold for T-cell activation; antibody blockade frees B7 so that CD28 costimulation can proceed. Because this competition occurs during priming in draining lymph nodes, the effect broadens the reactive repertoire rather than being tumour-antigen specific.

Question 41Cancer Immunology and Principles of Immunotherapy

Eight weeks after starting nivolumab, a patient with metastatic melanoma has new pulmonary nodules and an enlarging index lesion. Which finding on later assessment would most support pseudoprogression rather than true progression?

  1. Rising lactate dehydrogenase with each cycle
  2. A steady rise in tumour marker levels
  3. New lesions that shrink on subsequent scans Correct answer.
  4. Early decline in performance status

Explanation

Pseudoprogression reflects transient tumour swelling from immune infiltration, and response criteria for immunotherapy require confirmation of progression on a repeat scan four to eight weeks later. Regression of the new lesions on that confirmatory scan supports the diagnosis and justifies continuing treatment.

Question 42Cancer Immunology and Principles of Immunotherapy

Sipuleucel-T is an autologous cellular immunotherapy for metastatic castration-resistant prostate cancer. Which construct is used to load the antigen-presenting cells during manufacture?

  1. Prostatic acid phosphatase linked to GM-CSF Correct answer.
  2. CD19 linked to the CD3-zeta chain
  3. NY-ESO-1 linked to interferon alfa-2b
  4. Prostate-specific antigen linked to interleukin-2

Explanation

Autologous peripheral blood mononuclear cells are pulsed ex vivo with PA2024, a fusion protein combining prostatic acid phosphatase with granulocyte-macrophage colony-stimulating factor. The GM-CSF moiety delivers activation signals through its receptor while the antigen is processed for presentation. The reinfused cells are intended to prime T cells against prostatic acid phosphatase.

Question 43Cancer Immunology and Principles of Immunotherapy

Why is the incidence of severe immune-related toxicity lower with PD-1 or PD-L1 blockade than with CTLA-4 blockade?

  1. PD-1 acts mainly at the effector phase in tissues Correct answer.
  2. PD-L1 blockade spares peripheral tolerance entirely
  3. Anti-PD-L1 antibodies are cleared very rapidly
  4. PD-1 is expressed only on tumour-infiltrating cells

Explanation

CTLA-4 restrains the breadth of the T-cell repertoire during priming in lymph nodes, so its blockade expands autoreactive clones broadly. PD-1 predominantly regulates already-activated effector cells within peripheral tissues, which narrows the scope of collateral autoimmunity. This difference in the phase at which the checkpoint operates partly explains the distinct toxicity profiles.

Question 44Cancer Immunology and Principles of Immunotherapy

Which biomarker has supported tissue-agnostic regulatory approval of pembrolizumab irrespective of the primary tumour site?

  1. High circulating tumour cell count
  2. Mismatch repair deficiency Correct answer.
  3. High tumour PD-L1 expression
  4. Presence of tumour-infiltrating neutrophils

Explanation

Mismatch repair deficiency and the resulting high microsatellite instability produce a large neoantigen load and high response rates to PD-1 blockade across many histologies, including colorectal, endometrial and small bowel cancers. PD-L1 scoring is used to select patients within specific tumour types rather than as a site-independent criterion.

Question 45Cancer Immunology and Principles of Immunotherapy

Tocilizumab is used to treat severe cytokine release syndrome after chimeric antigen receptor T-cell therapy. It acts by blocking the receptor for which cytokine?

  1. Interleukin-1 beta
  2. Interferon gamma
  3. Interleukin-6 Correct answer.
  4. Tumour necrosis factor alpha

Explanation

Cytokine release syndrome is driven largely by interleukin-6 released from activated macrophages and the infused T cells, producing fever, hypotension and hypoxia. Tocilizumab is an anti-interleukin-6 receptor antibody that does not penetrate the central nervous system well, so corticosteroids are often added when neurotoxicity coexists.

Question 46Cancer Immunology and Principles of Immunotherapy

Loss of beta-2-microglobulin expression is a recognised mechanism of acquired resistance to checkpoint blockade. What is its direct functional consequence?

  1. Increased PD-L1 expression on tumour cells
  2. Failure to present peptides to CD8-positive T cells Correct answer.
  3. Recruitment of regulatory T cells into the stroma
  4. Increased secretion of vascular endothelial growth factor

Explanation

Beta-2-microglobulin is the invariant light chain required for folding and surface expression of MHC class I, so its loss abolishes presentation of any peptide to CD8-positive T cells. Such clones escape even when checkpoint blockade successfully activates tumour-reactive T cells. They may be partly controlled by natural killer cells through missing-self recognition but can expand under therapeutic pressure.

Question 47Cancer Immunology and Principles of Immunotherapy

In combined nivolumab and ipilimumab regimens for advanced melanoma, ipilimumab is given at 1 mg per kg rather than the 3 mg per kg used as monotherapy. What is the main rationale?

  1. Low-dose ipilimumab cannot bind CTLA-4
  2. Efficacy is preserved while toxicity is reduced Correct answer.
  3. It prevents competitive binding to PD-1
  4. Nivolumab accelerates the clearance of ipilimumab

Explanation

Randomised comparison showed that low-dose ipilimumab combined with nivolumab maintained response rates while substantially reducing grade 3 and 4 immune-related adverse events compared with the standard-dose combination. The efficacy of the doublet reflects blockade of two non-redundant checkpoints acting at different phases of the immune response.

Question 48Cancer Immunology and Principles of Immunotherapy

Interferon gamma released by tumour-infiltrating T cells induces PD-L1 on tumour cells, which then engage PD-1 and dampen the same T cells. Which term best describes this process?

  1. Adaptive immune resistance Correct answer.
  2. Innate immune escape through complement inhibition
  3. Antigenic mimicry by tumour cells
  4. Oncogene addiction of the tumour clone

Explanation

Adaptive immune resistance describes a tumour adapting to an active T-cell infiltrate by upregulating inhibitory ligands such as PD-L1 in response to inflammatory cytokines. It explains why PD-L1 positivity often marks tumours that are already immunologically engaged and therefore more likely to respond to checkpoint blockade. The same principle underlies IDO1 and HLA-E upregulation in resistant tumours.

Question 49Medical Oncology Pharmacology and Principles of Systemic Therapy

Which mechanism best describes the cytotoxic action of cyclophosphamide and other classical alkylating agents?

  1. Formation of covalent DNA cross-links Correct answer.
  2. Stabilization of microtubule polymers
  3. Inhibition of topoisomerase I
  4. Incorporation into RNA as a false pyrimidine

Explanation

Alkylating agents transfer alkyl groups to nucleophilic sites, chiefly the N7 position of guanine, producing interstrand and intrastrand cross-links that block DNA replication. This damage is not limited to a single cell-cycle phase.

Question 50Medical Oncology Pharmacology and Principles of Systemic Therapy

A patient receives high-dose methotrexate. Leucovorin is given 24 hours later primarily to:

  1. Block methotrexate entry into tumor cells
  2. Restore reduced folate pools without dihydrofolate reductase Correct answer.
  3. Alkalinize the urine and prevent crystallization
  4. Increase renal excretion of methotrexate

Explanation

Methotrexate inhibits dihydrofolate reductase and depletes tetrahydrofolate cofactors. Leucovorin is already a reduced folate, so it repletes normal-tissue pools without requiring the blocked enzyme.