Molecular Pathology Practice Questions

Q: 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?

CDH1 mutation. ***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.

Q: 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?

BRCA1. **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.

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

Marfan syndrome. ***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.

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

Inability to repair UV-induced DNA damage. ***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.

Q: Which gene is responsible for Marfan syndrome?

FBN1 gene, leading to defective fibrillin-1. ***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.

Q: 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?

Fluorescence In Situ Hybridization (FISH). ***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.

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

FISH. ***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 1

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?

Accepted Answer

CDH1 mutation

Answer

BRCA1 mutation

Answer

KRAS mutation

Answer

APC mutation

Question 2

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?

Accepted Answer

BRCA1

Answer

TP53

Answer

HER2

Answer

KRAS

Question 3

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

Accepted Answer

FISH

Answer

NGS

Answer

Sanger Sequencing

Answer

Southern Blot

Question 4

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

Accepted Answer

Marfan syndrome

Answer

Cystic fibrosis

Answer

Sickle cell anemia

Answer

Tay-Sachs disease

Question 5

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

Accepted Answer

Inability to repair UV-induced DNA damage

Answer

Increased oxidative damage

Answer

Impaired mismatch repair

Answer

Defective base excision repair

Question 6

Which gene is responsible for Marfan syndrome?

Accepted Answer

FBN1 gene, leading to defective fibrillin-1

Answer

CFTR gene, leading to defective chloride channels

Answer

HBB gene, leading to abnormal hemoglobin

Answer

GAA gene, leading to defective acid alpha-glucosidase

Question 7

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?

Accepted Answer

KRAS mutation analysis

Answer

TP53 mutation analysis

Answer

CA 19-9 serum levels

Answer

BRCA1/2 mutation testing

Question 8

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?

Accepted Answer

Fluorescence In Situ Hybridization (FISH)

Answer

Polymerase Chain Reaction (PCR)

Answer

Micro-array

Answer

Next-Generation Sequencing (NGS)

Question 9

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

Accepted Answer

FISH

Answer

NGS

Answer

Micro-array

Answer

PCR

Question 10

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

Accepted Answer

Decreased replication fidelity; increased cancer risk

Answer

Increased replication fidelity; decreased cancer risk

Answer

No effect on replication fidelity; unchanged cancer risk

Answer

Increased DNA repair efficiency; reduced cancer risk

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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