Molecular Pathology — MCQs

Molecular Pathology Indian Medical PG Practice Questions and MCQs

Question 221: In the context of molecular diagnostics, which method is the best for detecting chromosomal translocations?

A. Array CGH
B. Karyotyping
C. FISH (Correct Answer)
D. Sanger Sequencing

Explanation: ***FISH*** - FISH (Fluorescence In Situ Hybridization) uses **fluorescently labeled probes** that bind to specific DNA sequences on chromosomes, enabling the **direct visualization of chromosomal translocations** under a microscope [2]. - This method is particularly effective for identifying **known or suspected translocations** where specific probes can be designed for the breakpoint regions [1]. - **Superior to karyotyping** for detecting cryptic translocations and providing precise breakpoint identification, making it the **gold standard for translocation detection** in clinical practice (e.g., BCR-ABL in CML, PML-RARA in APL) [2]. *Array CGH* - Array Comparative Genomic Hybridization (aCGH) is used to detect **copy number variations (CNVs)**, such as deletions or duplications, across the genome [1]. - While it can indirectly detect some translocation events that result in CNVs, it is **not the primary method for directly visualizing or characterizing balanced translocations**, which do not involve gain or loss of genetic material [1]. *Karyotyping* - Karyotyping provides a **visual representation of a cell's chromosomes**, arranged by size and centromere position [3]. - It can detect **large chromosomal translocations** (typically >5-10 Mb), but its resolution is limited, meaning small or cryptic translocations may be missed [3]. - **Less sensitive and specific** compared to FISH for detecting and characterizing specific translocations. *Sanger Sequencing* - Sanger sequencing is a method for **determining the precise order of nucleotides** within a DNA fragment. - It is best suited for detecting **single-nucleotide variants (SNVs)**, small insertions, or deletions, and is **not designed to detect large-scale chromosomal abnormalities** like translocations across different chromosomes. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187. [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. 225-226. [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. 54-55.

Question 222: What is the consequence of defects in DNA repair enzymes on genomic stability in cancer development?

A. Enhanced DNA repair mechanisms.
B. Increased cell survival.
C. Increased cellular differentiation.
D. Increased mutation rate due to genomic instability. (Correct Answer)

Explanation: ***Increased mutation rate due to genomic instability*** - Defects in **DNA repair enzymes** lead to an inability to correct DNA damage, resulting in the accumulation of mutations [1]. - This accumulation of mutations increases **genomic instability**, which is a hallmark of cancer development, as critical genes controlling cell growth and division are more likely to be affected [1], [2]. *Enhanced DNA repair mechanisms* - This statement is contrary to the premise; defects in DNA repair enzymes mean that the mechanisms are **compromised**, not enhanced. - Enhanced DNA repair would typically lead to **decreased mutation rates** and contribute to genomic stability, thereby reducing cancer risk [1]. *Increased cell survival* - While some mutations might lead to increased cell survival in the context of cancer, the direct consequence of **defective DNA repair** is often **apoptosis** or cell cycle arrest to prevent the proliferation of damaged cells [3]. - Unrepaired DNA damage typically triggers cellular responses aimed at **eliminating damaged cells** rather than promoting their survival [1]. *Increased cellular differentiation* - **Cellular differentiation** is a process where cells become more specialized, which is generally a mechanism to control cell growth and maintain tissue homeostasis. - Defects in DNA repair are more directly linked to **uncontrolled cell proliferation** and **dedifferentiation** (loss of specialized features) observed in many cancers, rather than increased differentiation [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 288-290. [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. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 332-333.

Question 223: Which one of the following is an autosomal recessive disorder?

A. Albinism (Correct Answer)
B. Marfan’s syndrome
C. Neurofibromatosis-1
D. Huntington's disease

Explanation: ***Albinism*** - **Albinism** is an **autosomal recessive disorder** characterized by a partial or complete lack of melanin pigment in the skin, hair, and eyes [1], [2]. - This condition is inherited when an individual receives **two copies of the defective gene**, one from each parent [1]. *Huntington's disease* - **Huntington's disease** is an **autosomal dominant disorder**, meaning only one copy of the mutated gene is sufficient to cause the disease. - It is characterized by progressive neurodegeneration, leading to uncontrolled movements, cognitive decline, and psychiatric problems. *Marfan's syndrome* - **Marfan's syndrome** is an **autosomal dominant disorder** affecting connective tissue, primarily impacting the skeletal, ocular, and cardiovascular systems. - It results from a mutation in the **FBN1 gene** which encodes for fibrillin-1, a component of elastic fibers. *Neurofibromatosis-1* - **Neurofibromatosis type 1 (NF1)** is an **autosomal dominant disorder** caused by a mutation in the NF1 gene, leading to the growth of tumors along nerves. - Clinical features include **café-au-lait spots**, neurofibromas, and Lisch nodules. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 150-151. [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. 119-120.

Question 224: Which of the following is the most common mutation in Ewing's sarcoma?

A. Translocation X : 18
B. Translocation 11; 22 (Correct Answer)
C. Missense mutation in EXT1
D. Activating mutation of cell surface protein

Explanation: **Translocation 11; 22** - The most common and characteristic genetic alteration in **Ewing's sarcoma** is a **balanced chromosomal translocation** between chromosomes 11 and 22, specifically **t(11;22)(q24;q12)**. - This translocation results in the fusion of the **EWS gene** (on chromosome 22) with the **FLI1 gene** (on chromosome 11), creating a novel **fusion oncogene (EWS-FLI1)** that drives tumor development. *Translocation X : 18* - This translocation, **t(X;18)(p11.2;q11.2)**, is characteristic of **synovial sarcoma**, a distinct soft tissue tumor, not Ewing's sarcoma. - It leads to the fusion of the **SS18 gene** with one of several **SSX genes** (SSX1, SSX2, or SSX4). *Activating mutation of cell surface protein* - While activating mutations in various genes can occur in cancers, a general statement about an "activating mutation of a cell surface protein" is not the specific, most common genetic hallmark for **Ewing's sarcoma**. - Ewing's sarcoma is defined by its characteristic **fusion oncogene**. *Missense mutation in EXTI* - A **missense mutation in EXTI** (exostosin glycosyltransferase 1) is associated with **hereditary multiple exostoses** (also known as multiple osteochondromas), a different genetic disorder. - This mutation is not a defining characteristic or common mutation found in **Ewing's sarcoma**.

Question 225: Which of the following statements about FISH (Fluorescence In Situ Hybridization) is false?

A. Used to detect copy number variations
B. Used to detect balanced translocations
C. Requires DNA polymerase (Correct Answer)
D. Requires fluorescent probes

Explanation: ***Requires DNA polymerase*** - **FISH (Fluorescence In Situ Hybridization)** is a cytogenetic technique used to detect and localize specific DNA sequences on chromosomes [1]. - It does not involve DNA synthesis or amplification, therefore, it does **not require DNA polymerase**. - FISH is purely a **hybridization technique** where labeled probes bind directly to target sequences. *Used to detect copy number variations* - **FISH** is commonly used to identify **aneuploidies** (e.g., trisomy 21) or deletions/duplications of specific chromosomal regions, which are forms of **copy number variations** [2]. - This is achieved by using probes that bind to specific unique sequences or whole chromosomes, allowing for quantification of chromosome or gene copies [2]. *Used to detect balanced translocations* - **FISH** can detect balanced translocations, especially when using **dual-color break-apart probes** that span known breakpoints or fusion probes for specific translocations. - While some subtle balanced translocations without known breakpoints may be missed, FISH is a standard method for detecting many clinically relevant translocations (e.g., BCR-ABL, PML-RARA). *Requires fluorescent probes* - **FISH** by definition uses **fluorescently labeled DNA probes** that hybridize to complementary sequences on chromosomes [1]. - These probes can be short oligonucleotides or larger DNA fragments (BAC clones, cosmids), all tagged with fluorescent dyes for visualization under fluorescence microscopy [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187. [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. 256-257.

Question 226: Li-Fraumeni syndrome occurs due to mutation in which gene?

A. TP53 (Correct Answer)
B. CDKN2A
C. PTEN
D. MDM2

Explanation: ***Correct Answer: TP53*** - Li-Fraumeni syndrome is an autosomal dominant hereditary cancer syndrome linked to germline mutations in the **TP53 tumor suppressor gene**. - The TP53 gene encodes the **p53 protein**, a critical regulator of the cell cycle and apoptosis, often called the "guardian of the genome." *Incorrect: CDKN2A* - Mutations in the **CDKN2A gene** are primarily associated with familial melanoma and pancreatic cancer. - This gene encodes two tumor suppressor proteins, **p16INK4a** and **p14ARF**, which regulate the cell cycle. *Incorrect: PTEN* - The **PTEN gene** is associated with Cowden syndrome, which increases the risk of benign and malignant tumors in various tissues, including breast, thyroid, and endometrium. - PTEN is a tumor suppressor gene involved in cell growth, proliferation, and apoptosis. *Incorrect: MDM2* - The **MDM2 gene** is an oncogene that inactivates the p53 tumor suppressor protein. - While it interacts with p53, MDM2 mutations or overexpression are not the primary cause of Li-Fraumeni syndrome; rather, they contribute to cancer development by inhibiting p53 function.

Question 227: What is the chromosomal defect associated with Prader-Willi syndrome?

A. Chromosome 15 (Correct Answer)
B. Chromosome 5
C. Chromosome 10
D. Chromosome 21

Explanation: ***Chromosome 15*** - **Prader-Willi syndrome** is characterized by a deletion or other abnormality on the **paternal copy** of **chromosome 15q11-q13** [1]. - This specific region contains genes critical for normal development and function, whose altered expression due to the paternal origin causes the syndrome [1]. *Chromosome 5* - Abnormalities of chromosome 5 are associated with conditions like **Cri-du-chat syndrome**, which involves a deletion on the short arm (5p). - This is not linked to the characteristic symptoms of Prader-Willi syndrome. *Chromosome 10* - Defects on chromosome 10 are associated with various other genetic disorders, such as **multiple endocrine neoplasia type 2 (MEN 2)** or **Cowden syndrome**. - There is no established direct link between chromosome 10 abnormalities and Prader-Willi syndrome. *Chromosome 21* - **Trisomy 21** is the genetic defect responsible for **Down syndrome** (presence of an extra copy of chromosome 21) [2]. - While a common chromosomal abnormality, it presents with a distinct set of clinical features different from Prader-Willi syndrome [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 182-183. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 171-172.

Question 228: Diagnose the disorder by looking at the karyotype.

A. Down syndrome. (Correct Answer)
B. Patau syndrome.
C. Turner syndrome.
D. Klinefelter syndrome.

Explanation: ***Down syndrome*** - The **karyotype** shows an extra copy of chromosome 21 (trisomy 21), characteristic of Down syndrome (47, XX or XY, +21) [1]. - This is the **most common chromosomal abnormality**, occurring in approximately 1 in 700 live births [1] [2]. - Clinical features include **intellectual disability**, **characteristic facial features** (flat nasal bridge, upslanting palpebral fissures), **single palmar crease**, **congenital heart defects**, and **increased risk of leukemia** [1]. *Turner syndrome* - Turner syndrome is caused by **monosomy X** (45,X), meaning there's only one X chromosome and no second sex chromosome. - The presented karyotype does not show a missing sex chromosome; instead, it shows an extra autosomal chromosome (chromosome 21). *Patau syndrome* - Patau syndrome is characterized by **trisomy 13**, meaning an extra copy of chromosome 13 [1]. - The karyotype does not exhibit trisomy 13; it shows trisomy 21. - Patau syndrome presents with severe abnormalities including **holoprosencephaly**, **cleft lip/palate**, and **polydactyly**. *Klinefelter syndrome* - Klinefelter syndrome is characterized by the presence of an **extra X chromosome in males** (47,XXY) [2]. - The provided karyotype shows trisomy 21, not a sex chromosome aneuploidy. - Klinefelter syndrome presents with **tall stature**, **small testes**, **gynecomastia**, and **infertility**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 170-172. [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. 92-93.

Question 229: Which of the following genes primarily promotes apoptosis (programmed cell death)?

A. Bax (Correct Answer)
B. Bclx
C. Mcl
D. Bcl2

Explanation: ***Bax*** - **Bax** is a **pro-apoptotic gene** that actively promotes programmed cell death by forming channels in the mitochondrial outer membrane, leading to cytochrome c release and activation of caspases [1]. - It is a key member of the Bcl-2 family and plays a critical role in the **intrinsic apoptotic pathway** [2]. - Unlike the other options, Bax **promotes** rather than inhibits apoptosis [1]. *Bclx* - **Bcl-xL** is an **anti-apoptotic** gene that **inhibits** cell death by preventing the activation of pro-apoptotic proteins like Bax [1]. - It maintains mitochondrial membrane integrity, thereby **blocking** apoptosis [1]. *Mcl* - **Mcl-1** (Myeloid cell leukemia sequence 1) is an **anti-apoptotic** gene belonging to the Bcl-2 family [1]. - Its primary role is to **inhibit** apoptosis and promote cell survival by sequestering pro-apoptotic proteins [1]. *Bcl2* - **Bcl-2** (B-cell lymphoma 2) is the prototype **anti-apoptotic** gene that **prevents** programmed cell death [3]. - It functions by binding to and inhibiting pro-apoptotic members of the Bcl-2 family, thus maintaining cell viability and **opposing** apoptosis [3]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, p. 310. [2] 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. 64-67. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 310-311.

Question 230: Which gene is primarily associated with Cowden syndrome?

A. PTEN (Correct Answer)
B. RB1
C. KRAS
D. TP53

Explanation: ***PTEN*** - Cowden syndrome is an **autosomal dominant** inherited disorder caused by germline mutations in the **PTEN (phosphatase and tensin homolog) tumor suppressor gene**. - The PTEN gene plays a crucial role in cell growth, proliferation, and apoptosis, and its dysfunction leads to uncontrolled cell growth and the development of multiple **hamartomas** and increased cancer risk. *TP53* - Mutations in the **TP53 gene** are primarily associated with Li-Fraumeni syndrome, a different inherited cancer predisposition syndrome characterized by a high risk of various cancers including sarcomas, breast cancer, and adrenocortical carcinoma. - While both inherited cancer syndromes involve tumor suppressor gene mutations, the specific gene affected and the clinical presentation differ significantly. *RB1* - The **RB1 gene** is a tumor suppressor gene primarily associated with **retinoblastoma**, a rare childhood eye cancer, and an increased risk of other cancers like osteosarcoma. - It plays a critical role in cell cycle regulation, and its mutation leads to uncontrolled cell division in the retina and other tissues. *KRAS* - The **KRAS gene** is an oncogene, not a tumor suppressor gene, and its mutations are frequently found in various sporadic cancers, particularly **colorectal cancer**, pancreatic cancer, and lung cancer. - KRAS mutations lead to constitutive activation of signaling pathways that promote cell growth and survival, but they are not the primary genetic cause of inherited Cowden syndrome.

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