ABPath - American Board of Pathology Molecular Genetic Pathology Questions and Answers 1 — Questions and Answers
Question 1: A 52-year-old male with metastatic melanoma undergoes molecular testing of his tumor tissue to determine eligibility for targeted therapy. The results reveal a mutation that renders the tumor susceptible to treatment with dabrafenib, a BRAF inhibitor. Which of the following is the most likely mutation identified?
- KRAS G12D
- EGFR L858R
- BRAF V600E (Correct answer)
- KIT D816V
Correct answer: BRAF V600E
The BRAF V600E mutation is the most common activating mutation in melanoma, found in about half of cases. This specific mutation leads to constitutive activation of the MAPK signaling pathway, promoting cell proliferation. Dabrafenib is a potent inhibitor of the mutated BRAF kinase and is a standard of care, often in combination with a MEK inhibitor, for patients with BRAF V600E-mutant metastatic melanoma.
Question 2: A 60-year-old patient presents with erythrocytosis, leukocytosis, and splenomegaly. A bone marrow biopsy is consistent with a myeloproliferative neoplasm (MPN). Molecular testing for the JAK2 V617F mutation is ordered. This mutation is most prevalent, occurring in over 95% of cases, in which of the following MPNs?
- Essential thrombocythemia (ET)
- Primary myelofibrosis (PMF)
- Chronic myeloid leukemia (CML)
- Polycythemia vera (PV) (Correct answer)
Correct answer: Polycythemia vera (PV)
The JAK2 V617F mutation is a hallmark of Philadelphia-negative MPNs. While it is found in approximately 50-60% of patients with ET and PMF, it is present in over 95% of patients with polycythemia vera (PV) and is a major diagnostic criterion for this disorder. CML is characterized by the BCR-ABL1 fusion gene.
Question 3: The most common mutation causing cystic fibrosis is F508del in the CFTR gene. This genetic alteration leads to the production of a misfolded protein that is retained in the endoplasmic reticulum and targeted for degradation, preventing its transport to the cell membrane. According to the functional classification system, this type of defect is categorized as a:
- Class II mutation (defective protein processing and trafficking) (Correct answer)
- Class I mutation (defective protein production)
- Class IV mutation (defective chloride conductance)
- Class III mutation (defective channel regulation or gating)
Correct answer: Class II mutation (defective protein processing and trafficking)
CFTR mutations are classified based on their functional consequences. The F508del mutation is the archetypal Class II mutation, where the synthesized protein is misfolded and does not traffic correctly to the cell surface, leading to a severe loss of function. Class I mutations result in no protein production, Class III mutations result in a protein that reaches the membrane but has defective gating, and Class IV mutations result in a protein with reduced ion flow.
Question 4: A pathologist is selecting a molecular testing strategy for a newly diagnosed non-small cell lung cancer patient to identify multiple potential targetable driver mutations. Given that the biopsy sample is small, which of the following is the primary advantage of using a Next-Generation Sequencing (NGS) panel over performing several individual single-gene assays?
- Lower cost for analyzing a single hotspot mutation
- Faster turnaround time for one specific gene
- Simultaneous analysis of numerous genes from a limited sample (Correct answer)
- Superior detection of large chromosomal translocations
Correct answer: Simultaneous analysis of numerous genes from a limited sample
The main advantage of NGS in this context is its ability to perform massively parallel sequencing, allowing for the simultaneous assessment of multiple genes from a single, often limited, tissue sample. This is highly efficient and tissue-sparing compared to ordering multiple separate tests (like PCR or Sanger sequencing) for individual genes such as EGFR, ALK, ROS1, and BRAF, which are all relevant in lung cancer.
Question 5: A 68-year-old patient is diagnosed with metastatic colorectal cancer. Immunohistochemistry for mismatch repair (MMR) proteins shows loss of MLH1 and PMS2 expression, and subsequent PCR analysis confirms high-level microsatellite instability (MSI-H). This molecular finding is a strong predictive biomarker for a favorable response to which class of therapeutic agents?
- EGFR inhibitors (e.g., cetuximab)
- PARP inhibitors (e.g., olaparib)
- Anti-angiogenic agents (e.g., bevacizumab)
- Immune checkpoint inhibitors (e.g., pembrolizumab) (Correct answer)
Correct answer: Immune checkpoint inhibitors (e.g., pembrolizumab)
Tumors with high-level microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) accumulate a very high number of somatic mutations. This high tumor mutational burden leads to the production of numerous neoantigens, which makes the tumor highly visible to the immune system. Immune checkpoint inhibitors, such as the anti-PD-1 antibody pembrolizumab, work by blocking the inhibitory signals that cancer cells use to evade T-cells, thereby restoring the anti-tumor immune response. This has proven to be a highly effective therapy for patients with MSI-H tumors across various cancer types.
Question 6: A 70-year-old patient requiring anticoagulation for atrial fibrillation is started on warfarin. Pharmacogenetic testing is performed to help guide dosing and minimize bleeding risk. Genetic variants in which of the following two genes have the most significant and well-established impact on warfarin metabolism and sensitivity?
- TPMT and NUDT15
- CYP2C9 and VKORC1 (Correct answer)
- SLCO1B1 and UGT1A1
- CYP2D6 and OPRM1
Correct answer: CYP2C9 and VKORC1
Warfarin dosing is significantly influenced by genetic variants in two key genes. CYP2C9 is the primary enzyme responsible for metabolizing the active S-enantiomer of warfarin; variants can lead to decreased metabolism and require lower doses. VKORC1 encodes the vitamin K epoxide reductase complex, which is the molecular target of warfarin; variants can alter sensitivity to the drug. Together, polymorphisms in these two genes account for a large portion of the inter-individual variability in warfarin dose requirements.
ABPath - American Board of Pathology Molecular Genetic Pathology Questions and Answers 1
A 52-year-old male with metastatic melanoma undergoes molecular testing of his tumor tissue to determine eligibility for targeted therapy.
The results reveal a mutation that renders the tumor susceptible to treatment with dabrafenib, a BRAF inhibitor.
Which of the following is the most likely mutation identified?