Hereditary Cancer Syndromes — MCQs
A patient presents with headaches, palpitations, hypertension, and urine VMA positivity. The biopsy findings are shown in the image. Which of the following statements is correct?
Which of the following is not a premalignant condition?
BRCA1 gene lies on chromosome
A patient has a cerebellar mass, renal tumor, and a family history of similar conditions. Which of the following mutations is most likely present in the family?
Which of the following genes is least likely to be involved in the development of carcinoma of the colon?
Familial retinoblastoma is characterized by which of the following statements?
Which of the following cancers is least associated with BRCA2 mutations?
Which of the following statements are true about familial adenomatous polyposis? 1. It is autosomal recessive 2. If not treated, 100% of the cases progress to adenocarcinoma colon. 3. It is associated with a gene mutation in KRAS 4. It is associated with congenital hypertrophy of the retinal pigment epithelium.
Which of the following statements about Von-Hippel Lindau syndrome is true:
HNPCC has defect in which
Hereditary Cancer Syndromes Indian Medical PG Practice Questions and MCQs
Question 1: A patient presents with headaches, palpitations, hypertension, and urine VMA positivity. The biopsy findings are shown in the image. Which of the following statements is correct?
- A. Mostly malignant
- B. Mostly in children
- C. Mostly bilateral
- D. Associated with MEN 2A (Correct Answer)
Explanation: ***Associated with MEN 2A*** - The clinical presentation (headaches, palpitations, hypertension) and positive **urine VMA (vanillylmandelic acid)** strongly suggest a **pheochromocytoma**. - Pheochromocytomas are tumors of the adrenal medulla that secrete catecholamines and are frequently associated with **Multiple Endocrine Neoplasia Type 2A (MEN 2A)**, along with medullary thyroid carcinoma and primary hyperparathyroidism. *Mostly malignant* - Pheochromocytomas are generally benign, with approximately **10% being malignant** ("rule of 10s"). - Malignancy is difficult to predict based on histology alone and is usually defined by the presence of **metastases**. *Mostly in children* - While pheochromocytomas can occur at any age, they are **more common in adults**, typically between 30 and 50 years old. - When they do occur in children, they are more often bilateral, extra-adrenal, or associated with genetic syndromes. *Mostly bilateral* - The majority of pheochromocytomas (approximately **90%**) are **unilateral**. - Bilateral pheochromocytomas are often seen in genetic syndromes such as **MEN 2**, von Hippel-Lindau disease, and neurofibromatosis type 1.
Question 2: Which of the following is not a premalignant condition?
- A. Bloom's syndrome
- B. Down's syndrome
- C. Fragile X syndrome (Correct Answer)
- D. Fanconi anemia
Explanation: ***Fragile X syndrome*** - This is a genetic condition causing **intellectual disability** and developmental problems, primarily due to an **FRM1 gene mutation** leading to a fragile site on the X chromosome [1]. - It is **not associated with an increased risk of malignancy** and is therefore not considered a premalignant condition. *Bloom's syndrome* - This is a rare genetic disorder characterized by **growth deficiency**, a **photosensitive rash**, and a significantly **increased risk of various cancers**, including leukemias, lymphomas, and solid tumors. - It is associated with a mutation in the **BLM gene**, which plays a role in DNA repair and replication, leading to chromosomal instability. *Down's syndrome* - Individuals with Down's syndrome (trisomy 21) have a **20-fold increased risk of acute lymphoblastic leukemia (ALL)** and a 10-fold increased risk of acute myeloid leukemia (AML), particularly transient myeloproliferative disorder in infancy. - While it is a developmental disorder, the increased incidence of specific cancers classifies it as a **premalignant condition**. *Fanconi anemia* - This is a rare genetic disorder characterized by **bone marrow failure**, physical abnormalities, and an extraordinarily high risk of developing **acute myeloid leukemia (AML)** and myelodysplastic syndrome (MDS). - It is caused by mutations in genes involved in **DNA repair**, making cells highly susceptible to DNA damage and cancer.
Question 3: BRCA1 gene lies on chromosome
- A. 18
- B. 21
- C. 20
- D. 17 (Correct Answer)
Explanation: ***Correct: 17*** - The **BRCA1 gene** is located on the long arm (q arm) of **chromosome 17** at position 21 (17q21). - This gene is a **tumor suppressor gene** involved in DNA repair, and mutations are strongly associated with increased risk of breast and ovarian cancers. *Incorrect: 18* - Chromosome 18 is associated with different genetic conditions, such as **Edwards syndrome** (trisomy 18), but not directly with BRCA1. - No major tumor suppressor genes like BRCA1 are primarily located on chromosome 18. *Incorrect: 21* - Chromosome 21 is known for being related to **Down syndrome** (trisomy 21). - It does not house the BRCA1 gene. *Incorrect: 20* - While chromosome 20 contains genes involved in various functions, it is **not the location of the BRCA1 gene**. - No significant link between BRCA1 and chromosome 20 has been identified.
Question 4: A patient has a cerebellar mass, renal tumor, and a family history of similar conditions. Which of the following mutations is most likely present in the family?
- A. VHL (Correct Answer)
- B. Neurofibromatosis (NF1)
- C. Tuberous Sclerosis Complex (TSC)
- D. Li-Fraumeni syndrome
Explanation: ***VHL*** - **Von Hippel-Lindau (VHL) disease** is an inherited disorder characterized by the development of tumors and cysts in various parts of the body, including **hemangioblastomas** in the cerebellum and retina, **renal cell carcinomas**, and pheochromocytomas [1]. - The combination of a **cerebellar mass**, renal tumor, and a family history strongly points to VHL disease, which is caused by a germline mutation in the **VHL tumor suppressor gene** [1]. *Neurofibromatosis (NF1)* - **Neurofibromatosis type 1 (NF1)** typically presents with multiple neurofibromas, **café-au-lait spots**, optic pathway gliomas, and Lisch nodules in the iris. - While NF1 can cause tumors, the specific combination of a cerebellar mass and renal tumor is not typical of NF1, and the characteristic skin findings are not mentioned. *Tuberous Sclerosis Complex (TSC)* - **Tuberous Sclerosis Complex (TSC)** is characterized by the growth of benign tumors in the brain (e.g., **subependymal giant cell astrocytomas**), kidneys (e.g., **angiomyolipomas**), heart, lungs, and skin (e.g., facial angiofibromas) [2]. - While TSC can involve brain and kidney tumors, the typical brain tumors are different (astrocytomas vs. hemangioblastomas), and hemangioblastomas are not a common feature of TSC [2]. *Li-Fraumeni syndrome* - **Li-Fraumeni syndrome** is a rare inherited cancer predisposition syndrome characterized by a high risk of developing various cancers, including **sarcomas**, breast cancer, brain tumors (often astrocytomas or medulloblastomas), and adrenocortical carcinoma. - While brain tumors are part of Li-Fraumeni syndrome, renal cell carcinoma is not a primary feature, and the classic cerebellar hemangioblastoma is not typical for this syndrome. **References:** [1] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Manifestations Of Central And Peripheral Nervous System Disease, pp. 724-727. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Central Nervous System, pp. 1318-1319.
Question 5: Which of the following genes is least likely to be involved in the development of carcinoma of the colon?
- A. K-ras
- B. Beta-Catenin (Correct Answer)
- C. APC
- D. Mismatch Repair Genes
Explanation: ***Beta-Catenin*** - While **beta-catenin protein accumulation** is critical in colorectal cancer pathogenesis (primarily through APC mutations), direct mutations in the **CTNNB1 gene** (encoding beta-catenin) are **rare in colorectal cancer** (~5% of cases) [1]. - Most colorectal cancers achieve beta-catenin activation indirectly through **APC inactivation**, making beta-catenin gene mutations the least likely mechanism among the listed options [1]. - This contrasts with other cancers (e.g., hepatocellular carcinoma, endometrial cancer) where direct CTNNB1 mutations are more common. *APC* - The **adenomatous polyposis coli (APC) gene** is mutated in approximately **80% of sporadic colorectal cancers**, representing the earliest and most common genetic alteration in the **adenoma-carcinoma sequence** [1]. - APC loss leads to beta-catenin accumulation and constitutive **Wnt pathway activation**, driving uncontrolled cell proliferation [2]. - Germline APC mutations cause **familial adenomatous polyposis (FAP)** [5]. *K-ras* - **K-ras oncogene** mutations occur in **30-50% of colorectal cancers**, typically as an intermediate event in the adenoma-carcinoma progression [1]. - These activating mutations lead to constitutive signaling through the **MAPK pathway**, promoting cell proliferation and survival independent of growth factor signals. *Mismatch Repair Genes* - **Mismatch repair (MMR) genes** (MLH1, MSH2, MSH6, PMS2) are involved in **15-20% of all colorectal cancers** [4]. - Germline mutations cause **Lynch syndrome (HNPCC)** (~3% of CRCs) [5]. - Sporadic **MLH1 promoter hypermethylation** accounts for 12-15% of colorectal cancers, leading to **microsatellite instability (MSI-high)** tumors [3]. - MMR deficiency represents an alternative, well-established pathway of colorectal carcinogenesis. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 819. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 304-305. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, pp. 819-821. [4] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Problems From Alimentary System Disease, pp. 373-374. [5] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, pp. 821-822.
Question 6: Familial retinoblastoma is characterized by which of the following statements?
- A. Due to mutations in the RB1 gene
- B. Less common than sporadic retinoblastoma
- C. More commonly bilateral
- D. Has autosomal dominant inheritance (Correct Answer)
Explanation: ***Has autosomal dominant inheritance*** - Familial retinoblastoma is inherited in an **autosomal dominant pattern** with approximately **90% penetrance**, meaning a child who inherits the mutated RB1 gene has a 90% chance of developing the tumor [1]. - This is the **defining characteristic** that distinguishes familial from sporadic retinoblastoma - it represents a **germline mutation** present in all cells of the body from conception [2]. - The inheritance pattern allows the condition to be passed through generations, with each affected parent having a 50% chance of passing the mutation to their offspring. *Due to mutations in the RB1 gene* - While this statement is **medically accurate**, mutations in the RB1 tumor suppressor gene occur in **both familial and sporadic** forms of retinoblastoma [3]. - This does not **characterize** or distinguish familial retinoblastoma specifically, as the same gene is involved in all retinoblastoma cases [1]. - The key difference is that familial cases involve **germline** RB1 mutations, while sporadic cases typically involve **somatic** mutations [2]. *More commonly bilateral* - This statement is **factually correct** - familial retinoblastoma presents bilaterally in approximately **60-75%** of cases, compared to only 25-30% of sporadic cases. - However, bilaterality is a **clinical consequence** of having a germline mutation (multiple retinal cells at risk) rather than the primary defining characteristic [2]. - Bilateral presentation is better viewed as a **manifestation** of the inherited genetic defect rather than the characteristic itself. *Less common than sporadic retinoblastoma* - This is an **accurate epidemiological fact** - familial cases account for approximately **25-30%** of all retinoblastoma cases, with sporadic cases comprising the majority (~70-75%) [3]. - However, this describes the **relative frequency** rather than characterizing the nature or mechanism of familial retinoblastoma. - Prevalence data doesn't define what makes familial retinoblastoma unique from a genetic or clinical standpoint. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 298-300. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, p. 300. [3] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Manifestations Of Central And Peripheral Nervous System Disease, pp. 737-738.
Question 7: Which of the following cancers is least associated with BRCA2 mutations?
- A. Breast cancer
- B. Prostate cancer
- C. Ovarian cancer
- D. Vulval cancer (Correct Answer)
Explanation: ***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 8: Which of the following statements are true about familial adenomatous polyposis? 1. It is autosomal recessive 2. If not treated, 100% of the cases progress to adenocarcinoma colon. 3. It is associated with a gene mutation in KRAS 4. It is associated with congenital hypertrophy of the retinal pigment epithelium.
- A. 2 and 4 (Correct Answer)
- B. None of the options
- C. 1 and 4
- D. 2 and 3
Explanation: ***2 and 4*** - Without treatment, **familial adenomatous polyposis (FAP)** leads to colorectal **adenocarcinoma** in 100% of cases, due to the accumulation of numerous adenomatous polyps throughout the colon. - FAP is strongly associated with **congenital hypertrophy of the retinal pigment epithelium (CHRPE)**, which can be an early diagnostic marker [1]. *None of the options* - This statement is incorrect because FAP does indeed involve the progression to adenocarcinoma and is associated with CHRPE. - The combination of these two true statements makes this option invalid. *1 and 4* - FAP is inherited in an **autosomal dominant** manner, not autosomal recessive [1]. - While statement 4 (association with CHRPE) is true, statement 1 being false makes this option incorrect. *2 and 3* - Although statement 2 (100% progression to adenocarcinoma) is true, statement 3 is incorrect. - FAP is primarily caused by mutations in the **APC gene**, not the KRAS gene [1]. KRAS is more commonly associated with sporadic colorectal cancer progression rather than FAP.
Question 9: Which of the following statements about Von-Hippel Lindau syndrome is true:
- A. Supratentorial lesions are uncommon
- B. Tumors of Schwann cells are common
- C. Hemangioblastomas seen in craniospinal axis (Correct Answer)
- D. Predominantly supratentorial hemangioblastomas
Explanation: ***Hemangioblastomas seen in craniospinal axis*** - **Von Hippel-Lindau (VHL) syndrome** is characterized by the development of **hemangioblastomas**, which are the hallmark tumor of this condition [1]. - These tumors typically occur in the **retina**, **cerebellum**, and **spinal cord** (craniospinal axis), making this the most defining feature of VHL syndrome [1]. - Hemangioblastomas are **highly vascular** tumors that can cause symptoms due to mass effect or hemorrhage [1]. *Supratentorial lesions are uncommon* - This statement is **true** - hemangioblastomas in VHL predominantly occur **infratentorially** (cerebellum and brainstem) rather than supratentorially [1]. - While supratentorial hemangioblastomas can rarely occur, they are much less common than infratentorial lesions. - However, this is a less specific feature compared to the presence of hemangioblastomas in the craniospinal axis, which is the hallmark finding. *Predominantly supratentorial hemangioblastomas* - This is **incorrect** - hemangioblastomas in VHL are characteristically **infratentorial** (below the tentorium cerebelli), not supratentorial [1]. - The cerebellum is the most common site, followed by the spinal cord and retina [1]. - This directly contradicts the typical distribution pattern of VHL-associated tumors. *Tumors of Schwann cells are common* - **Schwann cell tumors**, such as **vestibular schwannomas** (acoustic neuromas), are characteristic of **Neurofibromatosis type 2 (NF2)**, not Von Hippel-Lindau syndrome [2]. - VHL is associated with hemangioblastomas, clear cell renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors - not schwannomas [1]. **References:** [1] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Manifestations Of Central And Peripheral Nervous System Disease, pp. 724-727. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Manifestations Of Central And Peripheral Nervous System Disease, pp. 727-728.
Question 10: HNPCC has defect in which
- A. Mismatch repair gene (Correct Answer)
- B. Base excision repair
- C. Point mutation
- D. Nucleotide excision repair
Explanation: ***Mismatch repair gene*** - **HNPCC (hereditary non-polyposis colorectal cancer)**, also known as Lynch syndrome, is caused by inherited mutations in genes responsible for **DNA mismatch repair** [1]. - These genes, such as **MLH1, MSH2, MSH6, and PMS2**, normally correct errors that occur during DNA replication, preventing the accumulation of mutations. *Base pair excision* - **Base excision repair** is a distinct DNA repair pathway that primarily fixes small base lesions, such as damaged or modified bases. - This mechanism is not primarily implicated in the development of HNPCC. *Point mutation* - A **point mutation** refers to a single nucleotide change in a DNA sequence, which can be the *result* of a defective repair mechanism but is not the defect itself. - While mismatch repair defects lead to an increased rate of point mutations, the underlying *defect* in HNPCC is in the repair system, not in the mutation type. *Nucleotide excision* - **Nucleotide excision repair** is a major pathway for removing bulky, helix-distorting DNA lesions, such as those caused by UV radiation. - Defects in this pathway are associated with conditions like **xeroderma pigmentosum**, not HNPCC. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 817.
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