Pharmacogenomics in Oncology — MCQs
Which of the following is not considered a pharmacogenetic condition?
Which among the following drugs is the new FDA approved immune checkpoint inhibitor for endometrial carcinoma?
Prader-Willi syndrome and Angelman syndrome are examples of what genetic phenomenon?
Which of the following is the platinum-based chemotherapeutic agent used as first-line treatment for ovarian carcinoma?
Molecular genetic testing is used to detect all of the following except?
Resistance to Methotrexate develops due to?
A 55-year-old woman with non-small cell lung cancer is found to have an ALK gene rearrangement. How should this finding influence her treatment?
All are true regarding Sunitinib except which of the following?
Which of the following techniques is used for the detection of variations in DNA sequence and gene expression?
What is the primary indication for the use of Erlotinib?
Pharmacogenomics in Oncology Indian Medical PG Practice Questions and MCQs
Question 1: Which of the following is not considered a pharmacogenetic condition?
- A. Adenosine deaminase deficiency (Correct Answer)
- B. Coumarin insensitivity
- C. G6PD deficiency
- D. Malignant hyperthermia
Explanation: ***Adenosine deaminase deficiency*** - **Adenosine deaminase deficiency** (ADA deficiency) is an **autosomal recessive** metabolic disorder causing severe immunodeficiency, primarily affecting gene function rather than drug response. - While it can be treated with enzyme replacement therapies or gene therapy, it is not primarily characterized by an altered response to standard therapeutic drugs. *Coumarin insensitivity* - **Coumarin insensitivity** refers to an individual's reduced response to **warfarin (a coumarin derivative)**, requiring higher doses to achieve effective anticoagulation. - This is a well-documented **pharmacogenetic condition**, often linked to variations in genes like *CYP2C9* and *VKORC1*. *G6PD deficiency* - **Glucose-6-phosphate dehydrogenase (G6PD) deficiency** is an X-linked genetic disorder that can lead to **hemolytic anemia** upon exposure to certain drugs (e.g., antimalarials, sulfonamides, aspirin) and fava beans [1]. - It is a classic example of a **pharmacogenetic condition** where genetic variations dictate drug-induced adverse reactions [1]. *Malignant hyperthermia* - **Malignant hyperthermia** is a life-threatening, inherited disorder triggered by certain **inhalation anesthetics** (e.g., halothane, isoflurane) and the **depolarizing muscle relaxant succinylcholine**. - This condition is caused by mutations in genes involved in calcium regulation in muscle cells (e.g., *RYR1*) and is a critical **pharmacogenetic response**.
Question 2: Which among the following drugs is the new FDA approved immune checkpoint inhibitor for endometrial carcinoma?
- A. Ipilimumab
- B. Pembrolizumab (Correct Answer)
- C. Trastuzumab
- D. Nivolumab
Explanation: **Pembrolizumab** * **Pembrolizumab** (Keytruda), a **PD-1 inhibitor**, received accelerated FDA approval for patients with **advanced endometrial carcinoma** that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H), and has progressed following prior systemic therapy or is not a candidate for curative surgery or radiation. * This approval was based on data from the KEYNOTE-158 study, demonstrating **durable responses** in these specific subsets of endometrial cancer, highlighting its role in precision oncology. *Ipilimumab* * **Ipilimumab** (Yervoy) is a **CTLA-4 inhibitor** primarily approved for the treatment of **melanoma** and renal cell carcinoma, often in combination with nivolumab. * While it is an immune checkpoint inhibitor, its primary indications and specific FDA approvals do not include **endometrial carcinoma**. *Trastuzumab* * **Trastuzumab** (Herceptin) is a **monoclonal antibody** that targets the **HER2 protein**, commonly used in the treatment of **HER2-positive breast cancer** and certain types of gastric cancer. * It is not an immune checkpoint inhibitor and its mechanism of action is distinct from blocking immune checkpoints like PD-1 or CTLA-4. *Nivolumab* * **Nivolumab** (Opdivo) is a **PD-1 inhibitor** with broad FDA approvals for various cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and others. * While a potent immune checkpoint inhibitor, **pembrolizumab** received the specific accelerated approval for advanced endometrial carcinoma in the context described, making it the most direct answer for the "new FDA approved" status in this specific indication.
Question 3: Prader-Willi syndrome and Angelman syndrome are examples of what genetic phenomenon?
- A. Gene Knockout
- B. Impaired DNA repair
- C. Genomic Imprinting (Correct Answer)
- D. RNA interference
Explanation: ***Genomic Imprinting*** - **Genomic imprinting** is an epigenetic phenomenon where certain genes are expressed in a **parent-of-origin-specific manner**. - In Prader-Willi syndrome, the disease results from the loss of function of specific genes on chromosome 15 (15q11-q13) inherited from the father, while Angelman syndrome results from the loss of function of a different gene (UBE3A) in the same region, but inherited from the mother. *RNA interference* - **RNA interference** is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules. - This process is not directly responsible for the parent-of-origin-specific expression patterns observed in these syndromes. *Gene Knockout* - A **gene knockout** is a genetic technique in which an organism's genes are made inoperative. - While it involves modifying gene function, it does not explain the differential expression based on parental origin. *Impaired DNA repair* - **Impaired DNA repair** refers to defects in the mechanisms that correct DNA damage. - This can lead to increased mutations and conditions like cancer, but it is not the underlying mechanism for Prader-Willi or Angelman syndromes.
Question 4: Which of the following is the platinum-based chemotherapeutic agent used as first-line treatment for ovarian carcinoma?
- A. Cyclophosphamide
- B. Methotrexate
- C. Cisplatin (Correct Answer)
- D. Dacarbazine
Explanation: ***Cisplatin*** - **Cisplatin** is a platinum-based chemotherapy drug that forms **DNA cross-links**, inhibiting DNA synthesis and leading to the death of rapidly dividing cells, making it highly effective against **ovarian carcinoma**. - It is a cornerstone of chemotherapy regimens for ovarian cancer, often used in combination with other agents such as paclitaxel. *Methotrexate* - **Methotrexate** is an **antimetabolite** that inhibits dihydrofolate reductase, thereby interfering with DNA synthesis. - While it is used in various cancers like leukemia, lymphoma, and some solid tumors (e.g., breast cancer, gestational trophoblastic disease), it is **not a primary recommended drug for ovarian carcinoma**. *Cyclophosphamide* - **Cyclophosphamide** is an **alkylating agent** that causes DNA damage, leading to cell death. - It is used in many cancers, including lymphoma, breast cancer, and some leukemias, but it is **not a first-line or primary agent for ovarian carcinoma** in contemporary treatment guidelines. *Dacarbazine* - **Dacarbazine** is an **alkylating agent** primarily used in the treatment of **malignant melanoma** and Hodgkin lymphoma. - It is **not indicated for the treatment of ovarian carcinoma**.
Question 5: Molecular genetic testing is used to detect all of the following except?
- A. Deletion
- B. Translocation (Correct Answer)
- C. Amplification
- D. Point mutation
Explanation: ***Translocation*** - **Translocations** are chromosomal rearrangements that were historically detected primarily by **cytogenetic methods** (karyotyping, conventional FISH), rather than by traditional molecular genetic testing methods focused on DNA sequencing [3]. - While modern molecular techniques like **RT-PCR for fusion transcripts** (e.g., BCR-ABL), **NGS-based fusion detection**, and **targeted breakpoint sequencing** can now detect translocations, the classic distinction is that translocations involve large-scale structural chromosomal changes better visualized by cytogenetics [2], [3]. - In the traditional classification, molecular genetic testing referred primarily to **sequence-based methods** (PCR, Sanger sequencing) that detect smaller-scale DNA changes rather than gross chromosomal rearrangements. *Deletion* - **Deletions** are readily detected by molecular genetic testing using PCR, Sanger sequencing, MLPA (Multiplex Ligation-dependent Probe Amplification), and NGS [5]. - These techniques identify missing DNA sequences by analyzing changes in fragment size, read depth, or absence of expected amplification products [2], [5]. *Amplification* - **Amplification** (increased gene copy number) is detected by molecular methods including **quantitative PCR (qPCR)**, **digital PCR**, and **NGS-based copy number analysis** [4]. - These techniques quantify gene copy numbers to identify amplifications like HER2 amplification in breast cancer. *Point mutation* - **Point mutations** are the primary target of classic molecular genetic testing [1]. - Detected by **Sanger sequencing**, **allele-specific PCR**, **NGS panels**, and other sequence-based methods that identify single nucleotide changes in DNA [1], [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 185. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 185-186. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 342-343. [4] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, p. 344. [5] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 183-184.
Question 6: Resistance to Methotrexate develops due to?
- A. Rapid proliferation of cancer cells
- B. Thymidylate kinase deficiency
- C. Thymidylate synthetase deficiency
- D. Increased production of dihydrofolate reductase (DHFR) (Correct Answer)
Explanation: ***Increased production of dihydrofolate reductase (DHFR)*** - Methotrexate acts by inhibiting **dihydrofolate reductase (DHFR)**, an enzyme essential for **folate metabolism** and DNA synthesis. - An **increased production of DHFR** (through gene amplification or overexpression) by cancer cells allows them to bypass the drug's inhibitory effects, leading to resistance. - This is the **most common mechanism** of methotrexate resistance. *Rapid proliferation of cancer cells* - While **rapid cell proliferation** is a characteristic of cancer, it doesn't directly explain resistance to methotrexate. - Methotrexate targets fast-dividing cells (S-phase specific), so rapid proliferation often makes them **more susceptible**, not resistant, as long as the drug's mechanism is effective. *Thymidylate kinase deficiency* - **Thymidylate kinase** is involved in the phosphorylation of **thymidine** to produce **dTMP** (deoxythymidine monophosphate). - A deficiency in this enzyme would likely hinder DNA synthesis, potentially increasing sensitivity to DNA-targeting agents, rather than causing resistance to methotrexate. *Thymidylate synthetase deficiency* - **Thymidylate synthetase** converts dUMP to dTMP using **5,10-methylene-THF** as a cofactor. - Methotrexate **indirectly inhibits** thymidylate synthetase by depleting tetrahydrofolate cofactor pools through DHFR inhibition. - A **deficiency** of this enzyme would not cause resistance; rather, **increased thymidylate synthetase** expression can be an alternative resistance mechanism, though less common than DHFR overexpression.
Question 7: A 55-year-old woman with non-small cell lung cancer is found to have an ALK gene rearrangement. How should this finding influence her treatment?
- A. Refer for surgical resection, if appropriate
- B. Switch to crizotinib, a targeted ALK inhibitor (Correct Answer)
- C. Consider radiation therapy, if indicated
- D. Continue standard chemotherapy, if appropriate for the patient's condition
Explanation: ***Switch to crizotinib, a targeted ALK inhibitor*** - The presence of an **ALK gene rearrangement** in **non-small cell lung cancer (NSCLC)** is a strong indicator for **targeted therapy** with an **ALK inhibitor** like crizotinib. - These drugs specifically block the aberrant activity of the ALK fusion protein, leading to **superior response rates** and **progression-free survival** compared to standard chemotherapy in ALK-positive patients. *Refer for surgical resection, if appropriate* - **Surgical resection** is primarily considered for **early-stage NSCLC** without evidence of metastatic disease [1]. - While surgery can be curative, the presence of specific gene rearrangements like ALK typically prompts consideration of **neoadjuvant or adjuvant targeted therapy** or systemic therapy for advanced disease. *Consider radiation therapy, if indicated* - **Radiation therapy** for NSCLC is usually employed for **local control**, either in curative intent for early stages or for **palliative management** of symptoms in advanced disease [2]. - It does not directly address the underlying **genetic driver** (ALK rearrangement) and would not be the primary systemic treatment. *Continue standard chemotherapy, if appropriate for the patient's condition* - While **standard chemotherapy** is a treatment option for NSCLC, the identification of a **driver mutation** like an ALK rearrangement makes **targeted therapy** a significantly more effective and preferred first-line approach. - Continuing chemotherapy without considering targeted therapy would be **suboptimal** for a patient with an ALK rearrangement due to the availability of more effective treatments.
Question 8: All are true regarding Sunitinib except which of the following?
- A. It inhibits tyrosine kinase receptors
- B. It is excreted primarily in urine (Correct Answer)
- C. It is used for the treatment of GIST
- D. It is used for renal cell carcinoma
Explanation: ***It is excreted primarily in urine*** - **Sunitinib** is predominantly metabolized in the **liver** by CYP3A4 and primarily excreted in the **feces**, not urine. - Its major active metabolite, N-desethyl sunitinib, is also primarily eliminated via the fecal route. *It inhibits tyrosine kinase receptors* - **Sunitinib** is a **multitargeted receptor tyrosine kinase (RTK) inhibitor**. - It blocks several RTKs involved in tumor growth, angiogenesis, and metastatic progression, such as **VEGFR, PDGFR, KIT, and FLT3**. *It is used for the treatment of GIST* - **Sunitinib** is approved for the treatment of **imatinib-refractory** or **imatinib-intolerant gastrointestinal stromal tumors (GIST)**. - Its mechanism in GIST involves inhibiting KIT and PDGFR, which are often mutated and constitutively active in this cancer. *It is used for renal cell carcinoma* - **Sunitinib** is a standard first-line treatment for **advanced renal cell carcinoma (RCC)**. - Its efficacy in RCC is primarily due to its inhibition of VEGFR, which targets the high vascularity characteristic of kidney tumors.
Question 9: Which of the following techniques is used for the detection of variations in DNA sequence and gene expression?
- A. Southern blot
- B. Western blot
- C. Microarray (Correct Answer)
- D. Northern blot
Explanation: ***Microarray*** - **Microarrays** are designed to detect thousands of DNA or RNA sequences simultaneously, making them ideal for analyzing **gene expression profiles** and identifying **sequence variations** like SNPs. - They involve hybridizing labeled sample DNA/RNA to probes fixed on a solid surface, with the intensity of hybridization indicating the presence or abundance of specific sequences. *Northern blot* - The **Northern blot** technique is primarily used to study **gene expression** by detecting specific **RNA sequences** in a sample. - It does not directly analyze DNA sequence variations. *Southern blot* - The **Southern blot** is a molecular biology method used to detect specific **DNA sequences** in DNA samples. - While it can identify large-scale DNA rearrangements or deletions, it is not optimized for simultaneous detection of multiple gene expression levels or subtle sequence variations. *Western blot* - The **Western blot** is used to detect specific **proteins** in a sample. - It analyzes protein expression levels and modifications and is not designed for the detection of DNA sequence variations or gene expression at the RNA level.
Question 10: What is the primary indication for the use of Erlotinib?
- A. Colon cancer
- B. Gall bladder cancer
- C. Pancreatic cancer
- D. NSCLC (Correct Answer)
Explanation: ***NSCLC (Non-Small Cell Lung Cancer)*** - **Erlotinib** is primarily indicated for patients with advanced **non-small cell lung cancer (NSCLC)**, particularly those with activating mutations in the **epidermal growth factor receptor (EGFR)**. - It functions as an **EGFR tyrosine kinase inhibitor**, blocking the signaling pathways essential for cancer cell growth and survival. - This is the **FDA-approved primary indication** and where Erlotinib shows the most significant clinical benefit. *Pancreatic cancer* - While Erlotinib has been used in combination with gemcitabine for **locally advanced, unresectable or metastatic pancreatic cancer**, it is not its primary or most prominent indication. - Its efficacy in pancreatic cancer is generally modest and overshadowed by its dramatic impact in EGFR-mutated NSCLC. *Colon cancer* - **Erlotinib** is **not a primary treatment** for **colon cancer**. - Other targeted therapies (such as anti-EGFR monoclonal antibodies like cetuximab) or chemotherapy regimens are typically used for colorectal cancer. *Gall bladder cancer* - **Erlotinib** is generally **not indicated** for the treatment of **gallbladder cancer**. - Treatment often involves surgery, chemotherapy, or radiation, with targeted therapies being less established for this malignancy.
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