Hedgehog signaling pathway — MCQs

10 questions

A 33-year-old woman comes to the physician 1 week after noticing a lump in her right breast. Fifteen years ago, she was diagnosed with osteosarcoma of her left distal femur. Her father died of an adrenocortical carcinoma at the age of 41 years. Examination shows a 2-cm, firm, immobile mass in the lower outer quadrant of the right breast. A core needle biopsy of the mass shows adenocarcinoma. Genetic analysis in this patient is most likely to show a defect in which of the following genes?

During the third week of development, the blastocyst undergoes a variety of differentiation processes responsible for the formation of the gastrula and, eventually, the embryo. This differentiation creates cell lineages that eventually become a variety of body systems. What cell lineage, present at this date, is responsible for the formation of the liver?

A laboratory physician investigates the chromosomes of a fetus with a suspected chromosomal anomaly. She processes a cell culture obtained by amniocentesis. Prior to staining and microscopic examination of the fetal chromosomes, a drug that blocks cell division is added to the cell culture. In order to arrest chromosomes in metaphase, the physician most likely added a drug that is also used for the treatment of which of the following conditions?

A 13-year-old girl presents to an orthopedic surgeon for evaluation of a spinal curvature that was discovered during a school screening. She has otherwise been healthy and does not take any medications. On presentation, she is found to have significant asymmetry of her back and is sent for a spine radiograph. The radiograph reveals a unilateral rib attached to the left transverse process of the C7 vertebrae. Abnormal expression of which of the following genes is most likely responsible for this finding?

A 62-year-old woman presents to her oncologist to discuss the chemotherapy options for her newly diagnosed breast cancer. During the meeting, they discuss a drug that inhibits the breakdown of mitotic spindles in cells. Her oncologist explains that this will be more toxic to cancer cells because those cells are dividing more rapidly. Which of the following side effects is closely associated with the use of this chemotherapeutic agent?

An investigator is studying the mechanism regulating pigment production in the skin. She has isolated a hormone produced by the anterior and intermediate lobe of the pituitary gland that stimulates neural crest-derived cells to produce pigments through the oxidation and polymerization of the amino acid tyrosine. This hormone is most likely cosecreted with a substance that acts on which of the following receptors?

A 55-year-old man with a history of sun exposure presents with a slowly growing, pearly nodule with telangiectasias on his nose. The lesion occasionally bleeds when traumatized. Biopsy shows basaloid cells arranged in palisading patterns. Which of the following mutations is most likely involved in the pathogenesis?

A 55-year-old woman has a total thyroidectomy for papillary thyroid carcinoma. She complains of tingling around the mouth 11 hours after the operation. Her condition rapidly deteriorates with difficulty breathing and chest tightness. Which of the following best represent the signaling pathway of the deficient hormone responsible for this patient’s symptoms?

A 62-year-old man comes to the physician because of progressive fatigue and dyspnea on exertion for 3 months. During this time, he has also had increased straining during defecation and a 10-kg (22-lb) weight loss. He has no personal or family history of serious medical illness. Physical examination shows conjunctival pallor. Laboratory studies show microcytic anemia. Test of the stool for occult blood is positive. Colonoscopy shows an exophytic mass in the ascending colon. Pathologic examination of the mass shows a well-differentiated adenocarcinoma. A gain-of-function mutation in which of the following genes is most likely involved in the pathogenesis of this patient's condition?

Q10

Antigen presentation of extracellular pathogens by antigen presenting cells requires endocytosis of the antigen, followed by the degradation in the acidic environment of the formed phagolysosome. Should the phagolysosome become unable to lower its pH, what is the most likely consequence?

Hedgehog signaling pathway US Medical PG Practice Questions and MCQs

Question 1: A 33-year-old woman comes to the physician 1 week after noticing a lump in her right breast. Fifteen years ago, she was diagnosed with osteosarcoma of her left distal femur. Her father died of an adrenocortical carcinoma at the age of 41 years. Examination shows a 2-cm, firm, immobile mass in the lower outer quadrant of the right breast. A core needle biopsy of the mass shows adenocarcinoma. Genetic analysis in this patient is most likely to show a defect in which of the following genes?

A. BRCA1
B. KRAS
C. TP53 (Correct Answer)
D. Rb
E. PTEN

Explanation: ***TP53*** - This patient's presentation with **early-onset breast cancer**, a history of **osteosarcoma** at a young age, and a father's death from **adrenocortical carcinoma** at 41 years strongly suggests **Li-Fraumeni syndrome**. - Li-Fraumeni syndrome is an autosomal dominant disorder caused by a germline mutation in the **tumor suppressor gene TP53**, increasing the risk for multiple primary cancers at a young age. *BRCA1* - While **BRCA1 mutations** are associated with an increased risk of breast and ovarian cancer, they are not typically linked to osteosarcoma or adrenocortical carcinoma. - The constellation of cancers in this patient is more indicative of Li-Fraumeni syndrome than solely a BRCA1-related cancer syndrome. *KRAS* - **KRAS** is an oncogene commonly mutated in several cancers, including pancreatic, colorectal, and lung cancer, but is not primarily associated with either Li-Fraumeni syndrome or the specific tumors seen in this family history. - Mutations in KRAS are typically somatic mutations acquired during a person's lifetime, not germline mutations causing inherited cancer syndromes like the one suggested here. *Rb* - Mutations in the **retinoblastoma (Rb) gene** are associated with retinoblastoma and an increased risk of osteosarcoma, but not typically with adrenocortical carcinoma or breast cancer as part of a classic inherited syndrome. - The combination of breast cancer, osteosarcoma, and adrenocortical carcinoma points more specifically to TP53. *PTEN* - **PTEN mutations** are associated with Cowden syndrome, which increases the risk for breast cancer, thyroid cancer, and endometrial cancer, along with benign growths. - However, Cowden syndrome does not typically include osteosarcoma or adrenocortical carcinoma as prominent features, making PTEN less likely than TP53 for this specific family history.

Question 2: During the third week of development, the blastocyst undergoes a variety of differentiation processes responsible for the formation of the gastrula and, eventually, the embryo. This differentiation creates cell lineages that eventually become a variety of body systems. What cell lineage, present at this date, is responsible for the formation of the liver?

A. Neuroectoderm
B. Syncytiotrophoblasts
C. Ectoderm
D. Endoderm (Correct Answer)
E. Mesoderm

Explanation: ***Endoderm*** - The **endoderm** is one of the three primary germ layers that develops during gastrulation and is responsible for forming the lining of the **gastrointestinal tract** and associated organs, including the **liver** and pancreas. - Liver development begins from an outgrowth of the **foregut endoderm**, which differentiates into hepatocytes and bile duct cells, forming the hepatic parenchyma. *Neuroectoderm* - **Neuroectoderm** is a specialized part of the ectoderm that gives rise to the entire **nervous system**, including the brain, spinal cord, and peripheral nerves. - It does not contribute to the formation of visceral organs like the liver. *Syncytiotrophoblasts* - **Syncytiotrophoblasts** are a layer of the **trophoblast** that form part of the placenta, specifically involved in hormone production and nutrient exchange between the mother and fetus. - They are part of the supporting structures for pregnancy and do not contribute to the embryonic germ layers or organ formation within the embryo itself. *Ectoderm* - The **ectoderm** is the outermost germ layer and gives rise to the **epidermis of the skin**, hair, nails, nervous system, and sensory organs. - While it forms the outer coverings and nervous system, it does not directly form internal organs like the liver. *Mesoderm* - The **mesoderm** is the middle germ layer, responsible for forming **muscle**, **bone**, connective tissue, the circulatory system, kidneys, and gonads. - While mesoderm contributes supporting structures to the liver (blood vessels, connective tissue, hematopoietic cells), the **hepatic parenchyma** (hepatocytes and bile ducts) is derived from the endoderm, making endoderm the primary cell lineage responsible for liver formation.

Question 3: A laboratory physician investigates the chromosomes of a fetus with a suspected chromosomal anomaly. She processes a cell culture obtained by amniocentesis. Prior to staining and microscopic examination of the fetal chromosomes, a drug that blocks cell division is added to the cell culture. In order to arrest chromosomes in metaphase, the physician most likely added a drug that is also used for the treatment of which of the following conditions?

A. Trichomonas vaginitis
B. Testicular cancer
C. Herpes zoster
D. Polycythemia vera
E. Acute gouty arthritis (Correct Answer)

Explanation: ***Acute gouty arthritis*** - The drug used to arrest chromosomes in metaphase is likely **colchicine**, which inhibits **microtubule polymerization** and spindle formation, thus arresting cells in metaphase. - **Colchicine** is a well-established treatment for **acute gouty arthritis** due to its anti-inflammatory properties, primarily through disrupting neutrophil functions. *Trichomonas vaginitis* - This condition is typically treated with **metronidazole** or **tinidazole**, which are antibiotics targeting protozoa and anaerobic bacteria. - These drugs do not inhibit microtubule assembly or arrest cells in metaphase. *Testicular cancer* - Testicular cancer is primarily treated with **BEP regimen** (bleomycin, etoposide, cisplatin), which does not include microtubule-inhibiting agents. - While vinca alkaloids (vincristine, vinblastine) do arrest cells in metaphase via microtubule inhibition similar to colchicine, they are not standard first-line agents for testicular cancer. - The question specifically asks about the primary clinical use of colchicine, which is gout, not cancer chemotherapy. *Herpes zoster* - Herpes zoster (shingles) is a viral infection treated with **antiviral medications** like acyclovir, valacyclovir, or famciclovir. - These antivirals work by interfering with viral DNA replication and do not target microtubule formation or cell division. *Polycythemia vera* - Polycythemia vera is a myeloproliferative neoplasm often managed with **phlebotomy**, **hydroxyurea**, or ruxolitinib. - These treatments aim to reduce blood cell counts or inhibit specific signaling pathways, none of which primarily involve arresting cells in metaphase by disrupting microtubules.

Question 4: A 13-year-old girl presents to an orthopedic surgeon for evaluation of a spinal curvature that was discovered during a school screening. She has otherwise been healthy and does not take any medications. On presentation, she is found to have significant asymmetry of her back and is sent for a spine radiograph. The radiograph reveals a unilateral rib attached to the left transverse process of the C7 vertebrae. Abnormal expression of which of the following genes is most likely responsible for this finding?

A. WNT7
B. FGF
C. Homeobox (Correct Answer)
D. PAX
E. Sonic hedgehog

Explanation: ***Homeobox*** - **Homeobox genes (HOX genes)** play a crucial role in specifying the identity of vertebral segments along the **craniocaudal axis** during embryonic development. - An abnormal expression of these genes can lead to **skeletal malformations**, such as the formation of a **cervical rib**, by altering the segmental identity of the C7 vertebra. *WNT7* - **WNT7 genes** are involved in limb patterning and have a role in the formation of the **dorsoventral axis** of the limb and kidney development. - They are not primarily associated with vertebral segmentation or the formation of cervical ribs. *FGF* - **Fibroblast growth factor (FGF) genes** are essential for various processes, including limb development, neurogenesis, and angiogenesis. - While they are involved in numerous developmental pathways, they are not the primary genes responsible for specifying vertebral identity and thus cervical rib formation. *PAX* - **PAX genes** are a family of transcription factors critical for organ development, especially of the eye, brain, and kidney. - While important for development, they are not directly implicated in the specification of vertebral segments or the pathogenesis of cervical ribs. *Sonic hedgehog* - **Sonic hedgehog (SHH)** signaling is a key pathway in embryonic development, particularly for pattern formation in the neural tube, limbs, and facial structures. - While crucial for body axis development and segmentation, **HOX genes** have a more direct role in determining the specific identity of vertebral segments and causing cervical ribs.

Question 5: A 62-year-old woman presents to her oncologist to discuss the chemotherapy options for her newly diagnosed breast cancer. During the meeting, they discuss a drug that inhibits the breakdown of mitotic spindles in cells. Her oncologist explains that this will be more toxic to cancer cells because those cells are dividing more rapidly. Which of the following side effects is closely associated with the use of this chemotherapeutic agent?

A. Photosensitivity
B. Peripheral neuropathy (Correct Answer)
C. Paralytic ileus
D. Hemorrhagic cystitis
E. Pulmonary fibrosis

Explanation: ***Peripheral neuropathy*** - Drugs that inhibit the breakdown of **mitotic spindles** are **microtubule-targeting agents** (e.g., **taxanes** like paclitaxel/docetaxel, **vinca alkaloids** like vincristine/vinblastine). - These agents interfere with **microtubule function** in neurons, leading to **axonal damage** and **peripheral neuropathy**. - This is the **most characteristic and common dose-limiting toxicity** of microtubule inhibitors, affecting sensory and motor nerves (numbness, tingling, weakness in extremities). *Photosensitivity* - **Photosensitivity** is a common adverse effect associated with certain chemotherapeutic agents like **fluorouracil** (5-FU) or **methotrexate**, but is not linked to microtubule inhibitors. - It involves an increased sensitivity to UV light, often manifesting as a rash or exaggerated sunburn. *Paralytic ileus* - **Paralytic ileus** can occur with **vinca alkaloids** (especially vincristine) due to autonomic neuropathy affecting the **enteric nervous system**. - However, this is **less common** than peripheral neuropathy and occurs more specifically with vincristine rather than taxanes. - **Peripheral neuropathy** is the more pervasive, dose-limiting, and universally characteristic side effect across all microtubule inhibitors. *Hemorrhagic cystitis* - **Hemorrhagic cystitis** is a classic side effect of **alkylating agents** like **cyclophosphamide** and **ifosfamide**, which produce the toxic metabolite **acrolein**. - It is prevented/managed with **mesna**, which inactivates acrolein. - Not associated with microtubule inhibitors. *Pulmonary fibrosis* - **Pulmonary fibrosis** is a known side effect of certain chemotherapeutic drugs, most notably **bleomycin** and **busulfan**. - This adverse effect is not associated with agents that target **mitotic spindle breakdown**.

Question 6: An investigator is studying the mechanism regulating pigment production in the skin. She has isolated a hormone produced by the anterior and intermediate lobe of the pituitary gland that stimulates neural crest-derived cells to produce pigments through the oxidation and polymerization of the amino acid tyrosine. This hormone is most likely cosecreted with a substance that acts on which of the following receptors?

A. TSH receptor
B. Glucocorticoid receptor
C. Vasopressin receptor
D. Dopamine receptor
E. Mu receptor (Correct Answer)

Explanation: ***Mu receptor*** - The hormone described, which stimulates pigment production in neural crest-derived cells, is **melanocyte-stimulating hormone (MSH)**. - **MSH** is derived from the pro-opiomelanocortin (POMC) precursor, which also gives rise to **β-endorphin**, a potent opioid peptide that acts on **mu opioid receptors**. *TSH receptor* - The **TSH receptor** binds thyroid-stimulating hormone (TSH), which primarily regulates thyroid hormone production and is not directly related to pigment production or opioid co-secretion from POMC. - TSH is produced by the anterior pituitary but from a different lineage than POMC-derived hormones. *Glucocorticoid receptor* - The **glucocorticoid receptor** binds cortisol and other glucocorticoids, which are involved in stress response and metabolism. - While ACTH (also derived from POMC) can stimulate adrenal glucocorticoid release, the question specifically refers to a substance *cosecreted* with MSH, not one that is *regulated* by MSH or its derivatives. *Vasopressin receptor* - **Vasopressin receptors** bind antidiuretic hormone (ADH), which regulates water balance and blood pressure. - ADH is produced by the posterior pituitary (though synthesized in the hypothalamus) and is not cosecreted with MSH from the anterior/intermediate pituitary. *Dopamine receptor* - **Dopamine receptors** bind dopamine, a neurotransmitter involved in various functions, including the inhibition of prolactin release from the pituitary. - While dopamine can influence pituitary function, it is not cosecreted with MSH in the manner described, nor is it a direct product of POMC cleavage.

Question 7: A 55-year-old man with a history of sun exposure presents with a slowly growing, pearly nodule with telangiectasias on his nose. The lesion occasionally bleeds when traumatized. Biopsy shows basaloid cells arranged in palisading patterns. Which of the following mutations is most likely involved in the pathogenesis?

A. P53 mutation
B. PTCH1 gene mutation (Correct Answer)
C. EGFR mutation
D. KIT mutation

Explanation: **PTCH1 gene mutation** - The clinical presentation of a **pearly nodule with telangiectasias** on the **nose**, history of **sun exposure**, and **basaloid cells arranged in palisading patterns** on biopsy are classic for **basal cell carcinoma (BCC)** [1]. - Mutations in the **PTCH1 gene**, a tumor suppressor gene involved in the **Hedgehog signaling pathway**, are found in the majority of sporadic BCCs and are central to its pathogenesis [2,3]. *P53 mutation* - While **P53 mutations** are common in many cancers, including **squamous cell carcinoma** [3], they are not the primary driver mutation for basal cell carcinoma in the way PTCH1 mutations are. - Loss of P53 function typically leads to uncontrolled cell growth and reduced apoptosis, but it's a general cancer mechanism rather than a specific one for BCC. *EGFR mutation* - **EGFR mutations** are primarily associated with certain types of **lung adenocarcinoma** and **glioblastoma**, not basal cell carcinoma. - These mutations lead to constitutive activation of the **epidermal growth factor receptor** signaling pathway, promoting cell proliferation and survival in those specific cancers. *KIT mutation* - **KIT mutations** are most commonly found in **gastrointestinal stromal tumors (GIST)** and certain types of **melanoma**. - The KIT receptor tyrosine kinase plays a role in cell growth and differentiation in specific cell lineages, distinct from the epidermal cells involved in BCC. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Skin, pp. 1158-1162. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 306-307. [3] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Disorders Involving Inflammatory And Haemopoietic Cells, pp. 643-644.

Question 8: A 55-year-old woman has a total thyroidectomy for papillary thyroid carcinoma. She complains of tingling around the mouth 11 hours after the operation. Her condition rapidly deteriorates with difficulty breathing and chest tightness. Which of the following best represent the signaling pathway of the deficient hormone responsible for this patient’s symptoms?

A. Cyclic guanosine monophosphate (cGMP)
B. Cyclic adenosine monophosphate (cAMP) (Correct Answer)
C. Intracellular receptors
D. Receptor tyrosine kinase
E. Inositol trisphosphate (IP3)

Explanation: ***Cyclic adenosine monophosphate (cAMP)*** - The patient's symptoms of perioral tingling, difficulty breathing, and chest tightness after total thyroidectomy suggest **hypocalcemia**, likely due to accidental removal or damage to the **parathyroid glands** during surgery. - The deficient **parathyroid hormone (PTH)** acts primarily through the **cAMP second messenger system** to increase serum calcium levels. *Cyclic guanosine monophosphate (cGMP)* - **cGMP** is a second messenger system primarily involved in mediating the effects of hormones like **atrial natriuretic peptide (ANP)** and **nitric oxide**, which are unrelated to calcium homeostasis and parathyroid function. - This pathway is not the primary mechanism of action for **PTH**. *Intracellular receptors* - **Intracellular receptors** are typically used by **steroid hormones** (e.g., cortisol, estrogen) and **thyroid hormones**, which are lipid-soluble and can cross the cell membrane. - **PTH** is a peptide hormone and acts on cell surface receptors. *Receptor tyrosine kinase* - **Receptor tyrosine kinases (RTKs)** are transmembrane receptors involved in signaling pathways for hormones like **insulin** and **growth factors**, promoting cell growth, differentiation, and metabolism. - This is not the primary signaling pathway for **PTH**. *Inositol trisphosphate (IP3)* - The **IP3/DAG (diacylglycerol)** pathway is another common second messenger system used by various hormones (e.g., **vasopressin, oxytocin, TRH**), leading to the release of intracellular calcium. - While it involves calcium signaling, it is not the primary or most characteristic pathway for **PTH** action, which predominantly utilizes **cAMP**.

Question 9: A 62-year-old man comes to the physician because of progressive fatigue and dyspnea on exertion for 3 months. During this time, he has also had increased straining during defecation and a 10-kg (22-lb) weight loss. He has no personal or family history of serious medical illness. Physical examination shows conjunctival pallor. Laboratory studies show microcytic anemia. Test of the stool for occult blood is positive. Colonoscopy shows an exophytic mass in the ascending colon. Pathologic examination of the mass shows a well-differentiated adenocarcinoma. A gain-of-function mutation in which of the following genes is most likely involved in the pathogenesis of this patient's condition?

A. APC
B. TP53
C. MLH1
D. KRAS (Correct Answer)
E. DCC

Explanation: ***KRAS*** - A **gain-of-function mutation** in **KRAS** is a common early event in the development of colorectal adenocarcinoma, driving uncontrolled cell growth and proliferation. - This mutation is frequently found in **sporadic colorectal cancers**, particularly in the advanced stages of adenoma to carcinoma progression. *APC* - **APC** is a **tumor suppressor gene**, and mutations in it are typically **loss-of-function**, not gain-of-function. - While APC mutations are crucial early steps in the adenoma-carcinoma sequence, they lead to inactivation of the gene, not increased function. *TP53* - **TP53** is a **tumor suppressor gene** which, when mutated, usually involves **loss-of-function** or dominant-negative effects, impairing its ability to induce apoptosis or cell cycle arrest. - Mutations in TP53 are typically associated with **later stages** of colorectal cancer progression and tend to be loss-of-function, not gain-of-function. *MLH1* - **MLH1** is involved in **DNA mismatch repair**, and mutations here lead to **microsatellite instability** and are characteristic of hereditary nonpolyposis colorectal cancer (Lynch syndrome). - These are typically **loss-of-function mutations** that impair DNA repair, not gain-of-function mutations promoting oncogenesis directly through signaling pathways. *DCC* - **DCC** (**Deleted in Colorectal Carcinoma**) is a **tumor suppressor gene**, and its inactivation or loss is associated with colorectal cancer progression, particularly the transition from adenoma to carcinoma. - Mutations or deletions in DCC result in a **loss-of-function**, not a gain-of-function, contributing to tumor growth by failing to regulate cell differentiation and apoptosis.

Question 10: Antigen presentation of extracellular pathogens by antigen presenting cells requires endocytosis of the antigen, followed by the degradation in the acidic environment of the formed phagolysosome. Should the phagolysosome become unable to lower its pH, what is the most likely consequence?

A. Deficient presentation of pathogens to CD4 T-cells (Correct Answer)
B. Deficient cell extravasation
C. Deficient presentation of pathogens to CD8 T-cells
D. Deficient NK cell activation
E. Deficient expression of B7

Explanation: ***Deficient presentation of pathogens to CD4 T-cells*** - The acidic environment of the **phagolysosome** is crucial for optimal **antigen degradation** and processing into peptides that can bind to **MHC class II molecules**. - Without proper acidification, peptide loading onto **MHC class II** is impaired, leading to deficient presentation of extracellular pathogens to **CD4 T-cells**. *Deficient cell extravasation* - **Cell extravasation** involves events like rolling, adhesion, and transendothelial migration, which are primarily regulated by **adhesion molecules** and **chemokines**, not phagolysosomal pH. - A defect in phagolysosomal pH would not directly impede the ability of cells to exit the vasculature. *Deficient presentation of pathogens to CD8 T-cells* - **CD8 T-cell** activation primarily involves the presentation of **intracellular antigens** via **MHC class I molecules**, which typically occurs through degradation in the **cytosol** via proteasomes. - While some cross-presentation pathways exist, the primary mechanism of CD8 T-cell antigen presentation is not dependent on the acidification of phagolysosomes for extracellular pathogens. *Deficient NK cell activation* - **Natural Killer (NK) cells** recognize and kill target cells based on the presence or absence of **MHC class I molecules** and activating ligands, not on the processing of extracellular antigens within phagolysosomes. - Their activation depends on cytokine environments and surface receptor interactions, not directly on phagolysosomal pH. *Deficient expression of B7* - **B7 molecules (CD80/CD86)** are **co-stimulatory molecules** expressed by antigen-presenting cells that are crucial for full T-cell activation. While antigen processing can influence APC activation, a specific defect in phagolysosomal pH would primarily affect the *presentation* of peptides, not the *expression* of co-stimulatory molecules. - The expression of B7 is more broadly regulated by inflammatory signals and toll-like receptor (TLR) engagement, rather than being solely dependent on proper phagolysosomal acidification.

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