Molecular Pathology Practice Questions

Q: Which of the following is considered a good prognostic factor for neuroblastoma?

Trk-A expression present. ***Trk-A expression present*** - **High TrkA (NTRK1) expression** is a well-established **favorable prognostic marker** in neuroblastoma - Associated with younger age, lower stage disease, and better differentiation - Tumors with high TrkA expression tend to be less aggressive and may undergo **spontaneous regression** [1] - Reflects activation of neurotrophin signaling pathways that promote differentiation rather than proliferation *Presence of 1p deletion* - **1p deletion** is a **poor prognostic factor** in neuroblastoma - Associated with aggressive disease and worse outcomes - The **absence** (not presence) of 1p deletion would be favorable *MYCN amplification* - **MYCN amplification** is the **strongest adverse prognostic factor** in neuroblastoma [1] - Found in approximately 20-25% of cases - Associated with rapid tumor progression, advanced stage, and poor survival - Patients with MYCN amplification are classified as high-risk regardless of other factors *Age greater than 18 months at diagnosis* - **Age > 18 months** is a **poor prognostic factor** - Younger children (especially < 12-18 months) have significantly better outcomes - Age is a key component of neuroblastoma risk stratification systems - Older children tend to present with more advanced disease and have worse response to therapy **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Diseases of Infancy and Childhood, pp. 483-487.

Q: Which of the following are examples of trinucleotide repeat mutations?

All of the options. ***All of the options*** - **Fragile X syndrome**, **Friedreich ataxia**, and **Huntington's chorea** are all well-known examples of genetic disorders caused by trinucleotide repeat expansions [1]. - The mutations involve an abnormal increase in the number of repetitions of a specific three-nucleotide sequence in the DNA [1]. *Fragile X syndrome* - This condition is caused by an expansion of the **CGG repeat** in the **FMR1 gene** on the X chromosome [1]. - The expansion leads to hypermethylation and silencing of the gene, impairing the production of fragile X mental retardation protein [1]. *Friedreich ataxia* - This is an autosomal recessive neurodegenerative disorder caused by an expansion of the **GAA repeat** in an intron of the **frataxin gene (FXN)**. - The repeat expansion interferes with transcription, leading to reduced frataxin protein levels. *Huntington's chorea* - This is an autosomal dominant neurodegenerative disorder caused by an expansion of the **CAG repeat** in the **huntingtin gene (HTT)**. - The expanded polyglutamine tract in the huntingtin protein leads to protein misfolding and neuronal damage, particularly in the striatum [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 177-181.

Q: Li–Fraumeni syndrome is associated with mutations in which of the following genes?

Gene TP53. ***Gene TP53*** - Li-Fraumeni syndrome is a rare, inherited cancer susceptibility syndrome associated with germline mutations in the **TP53 tumor suppressor gene**. - The **TP53 gene** encodes the p53 protein, which plays a critical role in cell cycle arrest, DNA repair, and initiation of apoptosis in response to cellular stress, thus preventing tumor formation. *Gene P21* - The **p21 gene** (CDKN1A) is a cyclin-dependent kinase inhibitor that acts downstream of p53, mediating p53-induced cell cycle arrest. - While p21 is involved in the p53 pathway, mutations in p21 itself are not the primary cause of Li-Fraumeni syndrome. *Gene RB1* - The **RB1 gene** encodes the retinoblastoma protein, a tumor suppressor involved in cell cycle regulation, particularly in controlling passage from G1 to S phase. - Mutations in **RB1** are primarily associated with hereditary retinoblastoma and osteosarcoma, not Li-Fraumeni syndrome. *Gene BRCA1* - The **BRCA1 gene** is a tumor suppressor gene involved in DNA repair, especially homologous recombination. - Germline mutations in **BRCA1** are strongly associated with hereditary breast and ovarian cancer syndrome, not Li-Fraumeni syndrome.

Q: Sex chromosome pattern in Klinefelter's syndrome is:

XXY. ***XXY*** - Klinefelter's syndrome is a **chromosomal disorder** that affects males, resulting from the presence of an extra X chromosome [2]. - The typical sex chromosome pattern is **XXY**, leading to a total of 47 chromosomes (47, XXY) [2]. - Clinical features include **tall stature**, **gynecomastia**, **small firm testes**, **infertility**, and **decreased testosterone** levels [2]. *XO* - This chromosomal pattern (45, XO) is characteristic of **Turner syndrome**, which affects females [1]. - Individuals with Turner syndrome typically present with **short stature**, **ovarian dysgenesis**, and a **webbed neck** [1]. *XX* - This is the normal sex chromosome pattern for a **female** (46, XX). - Females with this pattern typically develop normal **secondary sexual characteristics** and reproductive functions. *XY* - This is the normal sex chromosome pattern for a **male** (46, XY). - Males with this pattern typically develop normal **secondary sexual characteristics** and reproductive functions. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 173-174. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 174-175.

Q: Which malformation is associated with mutations in the HOX gene?

Polysyndactyly. ***Polysyndactyly*** - The **HOX gene** plays a critical role in limb development and is associated with the malformation of **polysyndactyly**, which is characterized by extra fingers or toes [1]. - This condition is due to the disruption of the normal **patterning** during limb formation, directly involving the action of HOX genes [1]. *Gorlin syndrome* - Gorlin syndrome is primarily caused by mutations in the **PTCH1 gene**, linked to **basal cell carcinoma** and other abnormalities. - It does not involve HOX gene mutations, hence is **not** related to limb malformations. *Holoprosencephaly* - Holoprosencephaly is a developmental condition often linked to **chromosomal anomalies** and abnormal embryonic development, **not specifically** HOX gene mutations. - It refers to the incomplete separation of the forebrain, distinct from the **limb malformations** associated with HOX genes. *Mayer Rokitansky syndrome* - Mayer-Rokitansky syndrome involves **agenesis** or **hypoplasia** of the uterus and upper two-thirds of the vagina, which is due to other genetic factors. - This condition is not related to the functions of the **HOX genes** in limb or skeletal development. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Bones, Joints, and Soft Tissue Tumors, p. 1186.

Q: Which tumor is not associated with von Hippel-Lindau disease?

Cholangiocarcinoma. ***Cholangiocarcinoma*** - Cholangiocarcinoma is a **bile duct cancer** that is not typically associated with **von Hippel-Lindau (VHL) disease**. - While VHL disease affects various organs through abnormal blood vessel growth, the **bile ducts** are not common sites for VHL-related tumors. *Hemangioblastoma of Cerebellum* - **Hemangioblastomas**, particularly in the **cerebellum**, are characteristic benign tumors strongly associated with **VHL disease**. - These tumors are highly vascular and linked to mutations in the **VHL tumor suppressor gene** [2]. *Renal Cell Carcinoma* - **Clear cell renal cell carcinoma** is a major manifestation of VHL disease due to a mutated **VHL gene**, which affects oxygen sensing and leads to tumor formation [1]. - Patients with VHL disease have a significantly increased risk of developing **renal cysts** and these specific kidney cancers. *Pheochromocytoma* - **Pheochromocytomas**, which are neuroendocrine tumors of the **adrenal medulla**, are a well-documented feature of VHL disease. - They produce **catecholamines** and can lead to hypertension and other symptoms related to hormonal excess. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Kidney, pp. 958-959. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 306-307.

Q: Which of the following is a characteristic feature of Down syndrome?

Trisomy 21. ***Trisomy 21*** - **Down syndrome** is the most common autosomal chromosome abnormality and is characterized by the presence of an extra copy of chromosome 21 [1, 2]. - This extra genetic material leads to the characteristic physical features, intellectual disability, and medical conditions associated with the syndrome [1, 2]. *Trisomy 18* - **Trisomy 18**, also known as **Edwards syndrome**, is a serious chromosomal disorder distinct from Down syndrome [2]. - It is characterized by severe developmental problems, including **heart defects**, **kidney malformations**, and **severe intellectual disability**, with generally a much shorter life expectancy [2, 3]. *Robertsonian translocation involving chromosome 21* - A **Robertsonian translocation** involving chromosome 21 is a cause of Down syndrome, but it is not the characteristic feature itself; rather, it is a specific **chromosomal rearrangement** that can lead to an extra copy of chromosome 21 material [1, 2]. - This specific type of translocation accounts for only a small percentage (2-3%) of all Down syndrome cases, while **Trisomy 21** (nondisjunction) is the most common cause [1, 2]. *Trisomy 13* - **Trisomy 13**, also known as **Patau syndrome**, is a distinct chromosomal disorder characterized by the presence of an extra copy of chromosome 13 [2]. - It is associated with severe birth defects, including **cleft lip/palate**, **polydactyly**, and severe neurological problems, and is usually fatal within the first year of life [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 170-171. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 171-172. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 168-169.

Q: Which of the following cancers is least associated with BRCA2 mutations?

Vulval cancer. ***Vulval cancer*** - While there may be some rare, sporadic cases, **vulval cancer** is generally not considered a primary cancer with a strong, well-established association with **BRCA2 mutations**. - Its etiology is more commonly linked to **HPV infection** and other risk factors not directly related to hereditary breast and ovarian cancer syndromes. *Breast cancer* - **BRCA2 mutations** are strongly associated with an increased lifetime risk of developing **breast cancer**, particularly for **male breast cancer**. - These mutations impair DNA repair mechanisms, leading to genomic instability that can result in cancerous transformation of breast tissue. *Prostate cancer* - Men with **BRCA2 mutations** have a significantly elevated risk of developing **prostate cancer**, often at an earlier age and with a more aggressive phenotype. - This association is well-documented, making BRCA2 testing relevant in high-risk prostate cancer populations. *Ovarian cancer* - **BRCA2 mutations** are a significant risk factor for **ovarian cancer**, particularly **high-grade serous ovarian cancer**. - The risk is substantial, though generally lower than that conferred by BRCA1 mutations for ovarian cancer in particular.

Question 1

Which of the following is considered a good prognostic factor for neuroblastoma?

Accepted Answer

Trk-A expression present

Answer

MYCN amplification

Answer

Age greater than 18 months at diagnosis

Answer

Presence of 1p deletion

Question 2

Which of the following are examples of trinucleotide repeat mutations?

Accepted Answer

All of the options

Answer

Friedreich ataxia

Answer

Fragile X syndrome

Answer

Huntington's chorea

Question 3

Li–Fraumeni syndrome is associated with mutations in which of the following genes?

Accepted Answer

Gene TP53

Answer

Gene RB1

Answer

Gene BRCA1

Answer

Gene P21

Question 4

Which investigation is the gold standard for diagnosing Edwards syndrome?

Accepted Answer

Karyotype

Answer

MLPA

Answer

Microarray

Answer

FISH

Question 5

Which syndrome is characterized by oro-cutaneous hamartomatous tumors, gastrointestinal polyps, and abnormalities of the breast, thyroid gland, and genitourinary system?

Accepted Answer

Cowden's syndrome - a genetic disorder involving multiple hamartomas and systemic abnormalities, including breast, thyroid, and genitourinary systems.

Answer

Juvenile polyposis - involves juvenile polyps in the gastrointestinal tract, without systemic hamartomas.

Answer

Peutz-Jeghers syndrome - features pigmented lesions and gastrointestinal hamartomas, without systemic involvement.

Answer

Familial adenomatous polyposis (FAP) - involves multiple adenomatous polyps and a high risk of colorectal cancer.

Question 6

Sex chromosome pattern in Klinefelter's syndrome is:

Accepted Answer

XXY

Answer

XO

Answer

XX

Answer

XY

Question 7

Which malformation is associated with mutations in the HOX gene?

Accepted Answer

Polysyndactyly

Answer

Holoprosencephaly

Answer

Mayer Rokitansky syndrome

Answer

Gorlin syndrome

Question 8

Which tumor is not associated with von Hippel-Lindau disease?

Accepted Answer

Cholangiocarcinoma

Answer

Renal Cell Carcinoma

Answer

Pheochromocytoma

Answer

Hemangioblastoma of Cerebellum

Question 9

Which of the following is a characteristic feature of Down syndrome?

Accepted Answer

Trisomy 21

Answer

Trisomy 18

Answer

Robertsonian translocation involving chromosome 21

Answer

Trisomy 13

Question 10

Which of the following cancers is least associated with BRCA2 mutations?

Accepted Answer

Vulval cancer

Answer

Breast cancer

Answer

Prostate cancer

Answer

Ovarian cancer

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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