Molecular Pathology — MCQs

Molecular Pathology Indian Medical PG Practice Questions and MCQs

Question 211: A 65-year-old man presents with severe weight loss and a palpable mass in the epigastrium. Endoscopy reveals a gastric ulcer with heaped-up margins, and a biopsy confirms adenocarcinoma. Which genetic mutation is most strongly associated with hereditary predisposition to this condition?

A. CDH1 mutation (Correct Answer)
B. BRCA1 mutation
C. KRAS mutation
D. APC mutation

Explanation: ***CDH1 mutation*** - The **CDH1 gene** mutation is associated with hereditary diffuse gastric cancer, which can lead to gastric adenocarcinoma, especially in individuals with a family history of cancer. - This mutation increases the risk of developing **signet-ring cell type** gastric cancer, which may present with **poorly differentiated histology** and a palpable mass [1]. *KRAS mutation* - The **KRAS gene** mutation is commonly associated with **pancreatic** and other cancers, but not specifically with gastric adenocarcinoma. - It is often found in tumors arising from the **pancreas** and **colorectal** cancers, rather than in the context of gastric cancer. *BRCA1 mutation* - The **BRCA1 mutation** is primarily associated with **breast** and **ovarian cancers**, and does not directly link to gastric cancer. - While it may have a broader cancer risk, it does not specifically increase the likelihood of developing gastric adenocarcinoma. *APC mutation* - The **APC gene** mutation is primarily linked to **Familial Adenomatous Polyposis (FAP)**, which leads to colorectal cancer, not gastric cancer. - Though it can be associated with some **extraintestinal manifestations**, it does not have a direct correlation with gastric adenocarcinoma. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 779.

Question 212: A 34-year-old female with a family history of breast and ovarian cancer presents for genetic counseling. Which gene mutation increases her risk for both types of cancer?

A. BRCA1 (Correct Answer)
B. TP53
C. HER2
D. KRAS

Explanation: **Correct: BRCA1** - **BRCA1** (and **BRCA2**) mutations are most strongly associated with an increased risk for both **hereditary breast cancer** and **ovarian cancer**, known as hereditary breast and ovarian cancer syndrome (HBOC) [1]. - These genes play a crucial role in **DNA repair** via homologous recombination, and their dysfunction leads to genomic instability and increased cancer susceptibility. - **BRCA1** mutation carriers have a **50-85% lifetime risk of breast cancer** and a **40-60% risk of ovarian cancer** [1]. *Incorrect: TP53* - The **TP53 gene** is a tumor suppressor gene linked to **Li-Fraumeni syndrome**, which increases the risk for various cancers, including breast cancer, sarcomas, brain tumors, and adrenocortical carcinoma. - While it increases breast cancer risk, ovarian cancer is not a prominent feature, and it is not the primary gene for **both breast and ovarian cancer** predisposition. *Incorrect: HER2* - **HER2** is an oncogene whose **amplification or overexpression** is associated with an aggressive subtype of breast cancer (HER2-positive breast cancer). - It is a **somatic alteration** (not germline), serving as a **prognostic and predictive biomarker** for targeted therapy (trastuzumab), not an inherited predisposition gene. *Incorrect: KRAS* - **KRAS** is an oncogene frequently mutated in **colorectal cancer**, pancreatic cancer, and lung cancer [2]. - It is involved in cell signaling pathways, but mutations in **KRAS are not associated with hereditary breast and ovarian cancer syndrome**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Breast, pp. 1058-1059. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Pancreas, pp. 898-899.

Question 213: Which molecular technique is used to detect chromosomal translocations in cancers such as chronic myelogenous leukemia?

A. FISH (Correct Answer)
B. NGS
C. Sanger Sequencing
D. Southern Blot

Explanation: ***FISH*** - **Fluorescence In Situ Hybridization (FISH)** uses fluorescently labeled probes that bind specifically to target DNA sequences on chromosomes, making it ideal for visualizing **chromosomal translocations**, such as the **BCR-ABL fusion** in CML [3]. - Its ability to directly visualize chromosomal abnormalities makes it a powerful diagnostic tool for a variety of genetic conditions and cancers [3]. *NGS* - **Next-Generation Sequencing (NGS)** provides high-throughput sequencing of entire genomes or specific regions, useful for detecting a broad range of **genomic alterations** including point mutations, small indels, and some structural variants [3]. - While NGS can detect translocations, FISH is often preferred for rapid and targeted detection of known translocations due to its direct visualization and cost-effectiveness for specific aberrations. *Sanger Sequencing* - **Sanger sequencing** is a method for determining the precise order of nucleotides within a DNA molecule, primarily used for sequencing individual DNA fragments up to 1000 base pairs. - It is highly accurate for detecting **point mutations** and small insertions/deletions within specific genes, but it is not suitable for detecting large chromosomal rearrangements like translocations across different chromosomes [1]. *Southern Blot* - **Southern blot** is a laboratory technique used to detect specific DNA sequences in DNA samples and involves DNA electrophoresis, transfer to a membrane, and hybridization with a labeled probe. - While it can detect large DNA rearrangements, it is less sensitive, more time-consuming, and requires larger amounts of DNA compared to FISH, especially for identifying a specific translocation [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 185-186. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187. [3] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 225-226.

Question 214: Which genetic disorder is characterized by a mutation in the FBN1 gene?

A. Marfan syndrome (Correct Answer)
B. Cystic fibrosis
C. Sickle cell anemia
D. Tay-Sachs disease

Explanation: ***Marfan syndrome*** - This connective tissue disorder is caused by a **mutation in the FBN1 gene**, which encodes for **fibrillin-1** [1]. - Fibrillin-1 is a crucial component of **elastic fibers**, affecting the skeletal, ocular, and cardiovascular systems [1]. *Cystic fibrosis* - This genetic disorder is caused by mutations in the **CFTR (cystic fibrosis transmembrane conductance regulator) gene** [2]. - It primarily affects the lungs and digestive system by impairing **chloride transport** [2]. *Sickle cell anemia* - This is a **hemoglobinopathy** resulting from a point mutation in the **HBB gene** that leads to production of abnormal beta-globin [2]. - This mutation causes red blood cells to deform into a **sickle shape** under low oxygen conditions. *Tay-Sachs disease* - This is a lysosomal storage disorder caused by mutations in the **HEXA gene**, leading to a deficiency of the **hexosaminidase A enzyme**. - The deficiency results in the harmful accumulation of **gangliosides** in nerve cells, particularly in the brain. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 153-154. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 147.

Question 215: Which gene is responsible for Marfan syndrome?

A. FBN1 gene, leading to defective fibrillin-1 (Correct Answer)
B. CFTR gene, leading to defective chloride channels
C. HBB gene, leading to abnormal hemoglobin
D. GAA gene, leading to defective acid alpha-glucosidase

Explanation: ***FBN1 gene, leading to defective fibrillin-1*** - Marfan syndrome is an autosomal dominant disorder caused by a mutation in the **FBN1 gene** on chromosome 15 [1]. - This gene encodes **fibrillin-1**, a glycoprotein essential for the formation of elastic fibers found in connective tissue [1]. *CFTR gene, leading to defective chloride channels* - The **CFTR gene** is responsible for **cystic fibrosis**, a disorder characterized by abnormal fluid transport across epithelial cells due to defective chloride channels [2]. - Patients with cystic fibrosis often have respiratory, digestive, and reproductive system issues, which are distinct from the features of Marfan syndrome. *HBB gene, leading to abnormal hemoglobin* - The **HBB gene** encodes the beta-globin chain of hemoglobin; mutations in this gene cause **sickle cell anemia** and **beta-thalassemia** [3]. - These conditions primarily affect red blood cell function and lead to anemia and related complications, not connective tissue abnormalities. *GAA gene, leading to defective acid alpha-glucosidase* - The **GAA gene** is responsible for **Pompe disease** (glycogen storage disease type II), which involves a deficiency of acid alpha-glucosidase. - This enzyme deficiency leads to the accumulation of glycogen in lysosomes, causing muscle weakness and organ damage, symptoms unrelated to Marfan syndrome. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 153-154. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 147. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death, pp. 50-51.

Question 216: How does a nucleotide excision repair (NER) defect lead to an increased risk of skin cancer?

A. Increased oxidative damage
B. Impaired mismatch repair
C. Defective base excision repair
D. Inability to repair UV-induced DNA damage (Correct Answer)

Explanation: ***Inability to repair UV-induced DNA damage.*** - Nucleotide excision repair (NER) is the primary pathway for removing **bulky DNA adducts**, such as **pyrimidine dimers** caused by ultraviolet (UV) radiation [1]. - A defect in NER means these **mutagenic lesions** accumulate, leading to **genomic instability** and an increased likelihood of oncogenic mutations in skin cells [1]. *Increased oxidative damage* - While oxidative damage can contribute to cancer, it is primarily repaired by **base excision repair (BER)**, not nucleotide excision repair (NER). - NER plays a minor role in addressing **oxidative DNA lesions**, which are typically smaller than the bulky adducts targeted by NER. *Impaired mismatch repair* - Mismatch repair (MMR) is a correction system that fixes errors made during **DNA replication**, such as incorrect base pairing or small insertions/deletions. - Defects in MMR are associated with hereditary nonpolyposis colorectal cancer (HNPCC), rather than the increased skin cancer risk seen with NER defects. *Defective base excision repair* - Base excision repair (BER) is responsible for removing **small, non-bulky DNA lesions**, such as modified bases, abasic sites, and single-strand breaks. - While critical for genome integrity, its defect does not directly explain the heightened **UV-induced skin cancer risk**, which is characteristic of NER impairment. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 322-333.

Question 217: A 40-year-old man with chronic pancreatitis develops jaundice. Imaging reveals a mass in the pancreas. Which molecular test is most relevant for diagnosing pancreatic adenocarcinoma?

A. TP53 mutation analysis
B. CA 19-9 serum levels
C. BRCA1/2 mutation testing
D. KRAS mutation analysis (Correct Answer)

Explanation: ***KRAS mutation analysis*** - **KRAS mutations** are present in approximately **90% of pancreatic adenocarcinomas**, making it the most commonly mutated gene in this malignancy [1]. - As a true **molecular test**, KRAS mutation analysis is performed on **tissue biopsy specimens** to confirm the diagnosis and guide therapeutic decisions. - Detection of KRAS mutations in pancreatic tissue strongly supports the diagnosis of adenocarcinoma and has prognostic implications [1]. - This is the most relevant **molecular test** among the options for diagnosing pancreatic cancer. *CA 19-9 serum levels* - **CA 19-9** is a **tumor marker** (not a molecular test) commonly elevated in pancreatic adenocarcinoma. - While clinically useful for monitoring and prognosis, it is a **serological biomarker** measured by immunoassay, not a molecular diagnostic test. - Can be elevated in benign conditions like cholestasis and chronic pancreatitis, limiting its diagnostic specificity. - Additionally, 10-15% of the population (Lewis antigen-negative individuals) cannot synthesize CA 19-9. *TP53 mutation analysis* - **TP53 mutations** occur in 50-75% of pancreatic adenocarcinomas but are found in many other cancers as well [1]. - While it is a molecular test, it lacks specificity for pancreatic cancer and is not routinely used as a primary diagnostic test. - Its role is more in prognosis and research rather than initial diagnosis. *BRCA1/2 mutation testing* - **BRCA1/2 mutations** confer increased risk for pancreatic cancer, especially in families with hereditary breast-ovarian cancer syndrome [2]. - This is a **germline genetic test** for assessing predisposition and guiding targeted therapy (PARP inhibitors), not a diagnostic test for an existing pancreatic mass [2]. - Performed on blood samples to identify hereditary cancer risk, not for diagnosing current malignancy. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Pancreas, pp. 897-898. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Pancreas, p. 899.

Question 218: A 45-year-old female is suspected of having a specific balanced translocation based on clinical presentation. Which of the following tests would be most appropriate for rapid confirmation and detailed analysis of the suspected chromosomal rearrangement?

A. Fluorescence In Situ Hybridization (FISH) (Correct Answer)
B. Polymerase Chain Reaction (PCR)
C. Micro-array
D. Next-Generation Sequencing (NGS)

Explanation: ***Fluorescence In Situ Hybridization (FISH)*** - **FISH** is commonly used for detecting **specific chromosomal rearrangements**, such as balanced translocations, deletions, and duplications [1]. - It uses **fluorescently labeled probes** that bind to specific regions of chromosomes, allowing for rapid visualization and confirmation under a microscope [1]. *Polymerase Chain Reaction (PCR)* - **PCR** is primarily used for **amplifying specific DNA sequences** and detecting sequence variations, not for visualizing chromosomal structural changes. - While it can detect small deletions or insertions if primers are designed appropriately, it cannot visualize or analyze a **balanced translocation**. *Micro-array* - **Microarray analysis** (e.g., Array Comparative Genomic Hybridization, aCGH) is excellent for detecting **unbalanced chromosomal abnormalities** (gains or losses of genetic material) [1]. - However, it cannot detect **balanced translocations** because there is no net gain or loss of genetic material, only a rearrangement [1]. *Next-Generation Sequencing (NGS)* - **NGS** can detect various genetic alterations, including single nucleotide variants, small insertions/deletions, and **copy number variations**. - While advances are being made, routine NGS for comprehensive detection of complex **chromosomal rearrangements**, especially balanced ones, can be challenging and often requires specialized bioinformatics pipelines. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187.

Question 219: Which molecular test is preferred for detecting HER2/neu amplification in breast cancer?

A. FISH (Correct Answer)
B. NGS
C. Micro-array
D. PCR

Explanation: ***FISH*** - **Fluorescence in situ hybridization (FISH)** is the gold standard for detecting HER2/neu amplification in breast cancer [1,2]. - It provides accurate analysis of **HER2 gene copy number** and is essential for determining eligibility for HER2-targeted therapies [1,2]. *PCR* - Polymerase chain reaction (PCR) detects **DNA sequences**, but it does not provide information on gene copy number or amplification status. - It is more suited for **qualitative or quantitative DNA analysis**, rather than for evaluating specific gene amplifications like HER2. *NGS* - Next-generation sequencing (NGS) is a high-throughput method that sequences DNA but may not reliably quantify HER2 copy number directly. - It offers comprehensive genomic profiling, making it less appropriate for focused HER2 amplification testing compared to **FISH**. *Micro-array* - Micro-array involves analyzing multiple genes simultaneously, but it lacks the specificity and sensitivity needed for **HER2 amplification detection**. - It is not typically used for clinical HER2 testing due to complexity and the need for more refined techniques like **FISH**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Breast, p. 1066. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 256-259.

Question 220: What is the effect of defective mismatch repair genes in Lynch syndrome on DNA replication fidelity and cancer risk?

A. Increased replication fidelity; decreased cancer risk
B. No effect on replication fidelity; unchanged cancer risk
C. Increased DNA repair efficiency; reduced cancer risk
D. Decreased replication fidelity; increased cancer risk (Correct Answer)

Explanation: ***Decreased replication fidelity; increased cancer risk*** - Defective **mismatch repair (MMR)** genes in Lynch syndrome lead to reduced ability to correct errors during DNA replication, resulting in **decreased replication fidelity** [1]. - This accumulation of uncorrected errors, particularly in **microsatellites**, increases the rate of mutations and genomic instability, significantly elevating the **cancer risk** [2]. *Increased replication fidelity; decreased cancer risk* - This option is incorrect because defective MMR genes lead to a *decrease* in the accuracy of DNA replication, not an increase. - Reduced fidelity results in a *higher* cancer risk due to accumulating mutations. *No effect on replication fidelity; unchanged cancer risk* - This is incorrect as the primary role of MMR genes is to maintain **replication fidelity**; their defect directly impacts this process. - The direct consequence of defective MMR is a significant *increase* in cancer risk, predominantly **colorectal cancer** [1]. *Increased DNA repair efficiency; reduced cancer risk* - This option incorrectly suggests an improvement in DNA repair efficiency, which is the opposite of what occurs with defective MMR genes. - A reduction in DNA repair efficiency is what leads to an *increased* cancer risk. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 817. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 226-227.

Practice by Chapter

Principles of Molecular Pathology

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DNA and RNA Analysis Techniques

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Cytogenetics

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Polymerase Chain Reaction Applications

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Next-Generation Sequencing

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Molecular Diagnosis of Infectious Diseases

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Molecular Oncology

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Pharmacogenomics

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Genetic Counseling and Risk Assessment

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Molecular Diagnostics Quality Control

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