A patient presents to his primary care physician with complaints of regular headaches and upper abdominal pain. On physical examination, his spleen and liver seem enlarged, and his face is plethoric. Gastroendoscopy reveals several gastric ulcers ranging from 3–5 mm in greatest dimension. A bone marrow aspirate shows hypercellularity with fibrosis and serum erythropoietin is low. The patient is informed about a new treatment with ruxolitinib for the main cause of his symptoms. Which of the conditions below can develop due to the same mutation that is causing this patient's symptoms?
Q2
An investigator is studying the function of the endoplasmic reticulum in genetically modified lymphocytes. A gene is removed that facilitates the binding of ribosomes to the endoplasmic reticulum. Which of the following processes is most likely to be impaired as a result of this genetic modification?
Q3
A 59-year-old man is brought to the physician by his wife for a psychiatric evaluation. Over the past 12 months, his behavior has become increasingly disruptive. His wife no longer brings him along shopping because he has attempted to grope a female cashier on 2 occasions. He has begun to address the mail carrier using a racial epithet. Three years later, the patient dies. Light microscopy of sections of the frontal and temporal lobes shows intracellular inclusions of transactive response DNA binding protein (TDP-43). These proteins are bound to a regulatory molecule that usually marks them for degradation. The regulatory molecule in question is most likely which of the following?
Q4
A group of scientists is studying the mechanism of action of various pancreatic hormones in rats. The scientists studied hormone A, which is secreted by the β-cells of the pancreas, and found that hormone A binds to a complex dimeric receptor on the cell membrane and exerts its effects via phosphorylation and subsequent downstream signaling that includes dephosphorylation of different intracellular proteins. Now they are studying hormone B, which is secreted by the α-cells and antagonizes the actions of hormone A. Which 2nd messenger system would hormone B utilize to exert its cellular effects?
Q5
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?
Q6
A newborn is brought to the pediatric clinic by his mother because she has noticed a swelling in the belly while dressing her baby. On physical examination, the newborn is found to have a non-tender upper abdominal mass. The clinician also noticed absent irises and undescended testes in this baby. A magnetic resonance image (MRI) scan of the abdomen shows a mass of intra-renal origin. Which 1 of the following genetic disorders is most probably the cause of this neonate’s symptoms and signs?
Q7
An 11-year-old girl presents to her primary care physician because she has been having difficulty hearing her teachers at school. She says that the difficulty hearing started about a year ago, and it has slowly been getting worse. Her past medical history is significant for multiple fractures in both her upper and lower extremities. She also recently had a growth spurt and says that her friends say she is tall and lanky. A mutation in which of the following genes is most likely associated with this patient's condition?
Q8
A 78-year-old man receives chemotherapy for advanced hepatocellular carcinoma. Despite appropriate therapy, he dies 4 months later. Histopathological examination of the cancer cells shows the presence of a transmembrane efflux pump protein that is known to cause decreased intracellular concentrations of chemotherapeutic drugs. Which of the following best describes this membrane protein?
Q9
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?
Q10
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?
Notch signaling pathway US Medical PG Practice Questions and MCQs
Question 1: A patient presents to his primary care physician with complaints of regular headaches and upper abdominal pain. On physical examination, his spleen and liver seem enlarged, and his face is plethoric. Gastroendoscopy reveals several gastric ulcers ranging from 3–5 mm in greatest dimension. A bone marrow aspirate shows hypercellularity with fibrosis and serum erythropoietin is low. The patient is informed about a new treatment with ruxolitinib for the main cause of his symptoms. Which of the conditions below can develop due to the same mutation that is causing this patient's symptoms?
A. Acute monocytic leukemia
B. Essential thrombocythemia (Correct Answer)
C. Mantle cell lymphoma
D. Chronic myelogenous leukemia
E. Burkitt's lymphoma
Explanation: ***Essential thrombocythemia***
- The patient's symptoms (headaches, abdominal pain, splenomegaly, hepatomegaly, plethora, gastric ulcers, hypercellular bone marrow with fibrosis, low erythropoietin) are classic for **Polycythemia Vera (PV)**, which is almost always caused by a **JAK2 V617F mutation**.
- **Essential thrombocythemia (ET)** is another **BCR-ABL1 negative myeloproliferative neoplasm** that shares the same **JAK2 V617F mutation** in about 50-60% of cases, making it a condition that can arise from the same genetic abnormality.
*Acute monocytic leukemia*
- This is a type of **acute myeloid leukemia**, characterized by a proliferation of **monoblasts** and **monocytes**.
- It is not typically caused by the **JAK2 V617F mutation**; rather, it often involves mutations in genes like *NPM1*, *FLT3*, or *RUNX1*.
*Mantle cell lymphoma*
- This is a **B-cell non-Hodgkin lymphoma** characterized by the **t(11;14)(q13;q32) translocation**, leading to overexpression of **cyclin D1**.
- It is completely unrelated to the **JAK2 V617F mutation** and does not present with features of a myeloproliferative neoplasm.
*Chronic myelogenous leukemia*
- This is a **myeloproliferative neoplasm** characterized by the **BCR-ABL1 fusion gene** (Philadelphia chromosome **t(9;22)**).
- While it is a myeloproliferative neoplasm, it is distinct from Polycythemia Vera and is not caused by the JAK2 V617F mutation.
*Burkitt's lymphoma*
- This is an aggressive **B-cell non-Hodgkin lymphoma** strongly associated with translocations of the **MYC gene**, most commonly **t(8;14)**.
- It has no connection to the **JAK2 V617F mutation** or myeloproliferative disorders.
Question 2: An investigator is studying the function of the endoplasmic reticulum in genetically modified lymphocytes. A gene is removed that facilitates the binding of ribosomes to the endoplasmic reticulum. Which of the following processes is most likely to be impaired as a result of this genetic modification?
A. Production of secretory proteins (Correct Answer)
B. Neutralization of toxins
C. Ubiquitination of proteins
D. α-Oxidation of fatty acids
E. Synthesis of ketone bodies
Explanation: ***Production of secretory proteins***
- Ribosomes bound to the **rough endoplasmic reticulum (RER)** are responsible for synthesizing proteins destined for secretion, insertion into membranes, or delivery to organelles like lysosomes.
- If ribosomes cannot bind to the ER, these proteins will be synthesized in the **cytosol** and lack the proper signals and processing for their intended destination and function.
*Neutralization of toxins*
- The **smooth endoplasmic reticulum (SER)**, not the RER, is primarily involved in **detoxification** processes, particularly drug metabolism and neutralization of toxins.
- This function relies on enzymes embedded within the SER membrane and is largely independent of ribosome binding.
*Ubiquitination of proteins*
- **Ubiquitination** is a post-translational modification that tags proteins for degradation by the **proteasome** or for trafficking to specific cellular compartments.
- This process occurs primarily in the **cytosol** and does not directly rely on ribosome binding to the ER for protein synthesis.
*α-Oxidation of fatty acids*
- **α-oxidation of fatty acids** is a metabolic pathway that occurs primarily in the **peroxisomes**.
- It is distinct from protein synthesis on the ER and would not be directly impacted by the inability of ribosomes to bind to the ER.
*Synthesis of ketone bodies*
- The **synthesis of ketone bodies** (ketogenesis) primarily occurs in the **mitochondria** of liver cells.
- This metabolic pathway is not directly dependent on ribosome binding to the endoplasmic reticulum for its function.
Question 3: A 59-year-old man is brought to the physician by his wife for a psychiatric evaluation. Over the past 12 months, his behavior has become increasingly disruptive. His wife no longer brings him along shopping because he has attempted to grope a female cashier on 2 occasions. He has begun to address the mail carrier using a racial epithet. Three years later, the patient dies. Light microscopy of sections of the frontal and temporal lobes shows intracellular inclusions of transactive response DNA binding protein (TDP-43). These proteins are bound to a regulatory molecule that usually marks them for degradation. The regulatory molecule in question is most likely which of the following?
A. Kinesin
B. Chaperone
C. Cyclin
D. Ubiquitin (Correct Answer)
E. Clathrin
Explanation: ***Ubiquitin***
- **Ubiquitin** is a small regulatory protein that marks other proteins for degradation, typically by the **proteasome**. In neurodegenerative diseases like **frontotemporal dementia (FTD)**, aggregates of misfolded proteins, such as **TDP-43**, can accumulate when the ubiquitin-proteasome system is overwhelmed or dysfunctional.
- The patient's clinical presentation of **behavioral changes** (disruptive, inappropriate, racial epithets) and the pathological finding of **TDP-43 inclusions** in the frontal and temporal lobes are highly characteristic of **FTD**. The accumulation of TDP-43, despite being marked for degradation, points to a failure of the normal ubiquitin-mediated protein disposal pathway.
*Kinesin*
- **Kinesin** is a motor protein that facilitates **anterograde axonal transport**, moving cargo away from the cell body along microtubules.
- While important for neuronal function, kinesin is not directly involved in marking proteins for degradation.
*Chaperone*
- **Chaperones** are proteins that assist in the proper **folding of other proteins** and can help refold misfolded proteins, preventing aggregation.
- While chaperones play a role in protein quality control, they do not directly mark proteins for degradation in the same way as ubiquitin.
*Cyclin*
- **Cyclins** are a family of proteins that regulate the progression of cells through the **cell cycle** by activating cyclin-dependent kinases (CDKs).
- They are primarily involved in cell division and growth, not protein degradation pathways.
*Clathrin*
- **Clathrin** is a protein that plays a key role in the formation of **coated vesicles** involved in endocytosis and intracellular trafficking.
- It is crucial for forming vesicles that transport cargo, but it is not directly involved in marking proteins for degradation.
Question 4: A group of scientists is studying the mechanism of action of various pancreatic hormones in rats. The scientists studied hormone A, which is secreted by the β-cells of the pancreas, and found that hormone A binds to a complex dimeric receptor on the cell membrane and exerts its effects via phosphorylation and subsequent downstream signaling that includes dephosphorylation of different intracellular proteins. Now they are studying hormone B, which is secreted by the α-cells and antagonizes the actions of hormone A. Which 2nd messenger system would hormone B utilize to exert its cellular effects?
A. Direct cytoplasmic receptor binding
B. Phospholipase C
C. Tyrosine kinase
D. Direct nuclear receptor binding
E. Adenylyl cyclase-cyclic AMP (Correct Answer)
Explanation: ***Adenylyl cyclase-cyclic AMP***
- Hormone B is **glucagon**, secreted by pancreatic α-cells, which antagonizes the effects of insulin (hormone A). Glucagon primarily acts through a **G protein-coupled receptor** that activates **adenylyl cyclase**, leading to an increase in intracellular **cyclic AMP (cAMP)**.
- Increased cAMP then activates **protein kinase A (PKA)**, which phosphorylates various intracellular proteins to promote **glycogenolysis** and **gluconeogenesis**, thereby raising blood glucose levels.
*Direct cytoplasmic receptor binding*
- This mechanism is characteristic of **steroid hormones**, which are lipid-soluble and can diffuse across the cell membrane to bind to receptors in the cytoplasm.
- Pancreatic hormones like glucagon are **peptide hormones**, which are water-soluble and typically bind to cell surface receptors.
*Phospholipase C*
- Activation of **phospholipase C (PLC)** leads to the production of **inositol triphosphate (IP3)** and **diacylglycerol (DAG)**, which mobilize intracellular calcium and activate protein kinase C, respectively.
- While some G protein-coupled receptors activate PLC, **glucagon's primary signaling pathway** involves adenylyl cyclase.
*Tyrosine kinase*
- **Tyrosine kinase receptors** are often associated with growth factors and insulin (hormone A) signaling, leading to phosphorylation of tyrosine residues on target proteins.
- Glucagon's receptor is a **G protein-coupled receptor**, not a receptor tyrosine kinase, and its actions are mediated through serine/threonine phosphorylation via PKA.
*Direct nuclear receptor binding*
- This mechanism is typical for **steroid hormones** and **thyroid hormones**, which are lipid-soluble and bind to receptors in the nucleus to directly influence gene transcription.
- As a peptide hormone, glucagon binds to cell surface receptors and does not directly interact with nuclear receptors.
Question 5: 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 6: A newborn is brought to the pediatric clinic by his mother because she has noticed a swelling in the belly while dressing her baby. On physical examination, the newborn is found to have a non-tender upper abdominal mass. The clinician also noticed absent irises and undescended testes in this baby. A magnetic resonance image (MRI) scan of the abdomen shows a mass of intra-renal origin. Which 1 of the following genetic disorders is most probably the cause of this neonate’s symptoms and signs?
A. WT-1 missense mutation
B. Deletion 11-p-13 (Correct Answer)
C. Duplication of 11-p-15
D. Amplification of MYCN (N-myc) proto-oncogene
E. Trisomy 18
Explanation: ***Deletion 11-p-13***
* This describes the genetic abnormality associated with **WAGR syndrome**, which stands for **Wilms tumor**, **Aniridia**, **Genitourinary anomalies** (like undescended testes), and **intellectual disability** (though not explicitly mentioned, it's part of the syndrome).
* The presence of a **nephroblastoma (Wilms tumor)**, **absent irises (aniridia)**, and **undescended testes** in a newborn strongly points to WAGR syndrome, caused by a deletion on chromosome 11 at band p13, affecting the *WT1* gene locus.
*WT-1 missense mutation*
* While *WT1* gene mutations are associated with Wilms tumor, a **missense mutation** specifically in *WT1* is more commonly linked to **Denys-Drash syndrome**, which presents with Wilms tumor, diffuse mesangial sclerosis (nephropathy), and male pseudohermaphroditism, but typically *not aniridia*.
* The constellation of symptoms including aniridia and undescended testes together with a Wilms tumor is more characteristic of a larger deletion encompassing *PAX6* (responsible for aniridia) and *WT1*.
*Duplication of 11-p-15*
* A **duplication of 11p15** is associated with **Beckwith-Wiedemann syndrome**, which includes macrosomia, macroglossia, omphalocele, and an increased risk of Wilms tumor.
* However, Beckwith-Wiedemann syndrome does *not* typically present with aniridia or undescended testes as core features.
*Amplification of MYCN (N-myc) proto-oncogene*
* **MYCN amplification** is a significant genetic alteration found in neuroblastoma, a common extracranial solid tumor of childhood, originating from neural crest cells.
* **Neuroblastoma** is distinct from Wilms tumor (which is intra-renal) and does not typically present with the specific features of aniridia or undescended testes as co-occurring symptoms.
*Trisomy 18*
* **Trisomy 18 (Edwards syndrome)** is characterized by severe developmental delays, distinctive facial features, rocker-bottom feet, and various congenital anomalies affecting multiple organ systems (e.g., heart defects, kidney abnormalities, omphalocele).
* While kidney abnormalities can occur, **aniridia** and **isolated undescended testes combined with a Wilms tumor** are not classic features of Trisomy 18.
Question 7: An 11-year-old girl presents to her primary care physician because she has been having difficulty hearing her teachers at school. She says that the difficulty hearing started about a year ago, and it has slowly been getting worse. Her past medical history is significant for multiple fractures in both her upper and lower extremities. She also recently had a growth spurt and says that her friends say she is tall and lanky. A mutation in which of the following genes is most likely associated with this patient's condition?
A. Type 4 collagen
B. Type 3 collagen
C. Fibrillin
D. Type 1 collagen (Correct Answer)
E. Fibroblast growth factor receptor
Explanation: ***Type 1 collagen***
- This patient's symptoms—hearing difficulty, multiple fractures, and tall/lanky stature—are classic signs of **osteogenesis imperfecta (OI)**, a genetic disorder caused by mutations in genes encoding **Type I collagen**.
- **Type I collagen** is a major component of bone, so defects lead to fragile bones and susceptibility to fractures, and it also plays a role in the structure of the ear, affecting hearing.
*Type 4 collagen*
- Mutations in **Type 4 collagen** are primarily associated with **Alport syndrome**, which classically presents with **hematuria**, progressive renal failure, and hearing loss.
- While hearing loss is present, the patient's other key symptoms of **multiple fractures** and **tall, lanky stature** are not characteristic of Alport syndrome.
*Type 3 collagen*
- Defects in **Type 3 collagen** are linked to **Ehlers-Danlos syndrome, vascular type**, which is characterized by fragile blood vessels, organs, and skin, leading to easy bruising, arterial rupture, and bowel perforation.
- While Type 3 collagen is found in connective tissues, its primary clinical manifestations do not align with the patient's presentation of recurrent fractures and hearing loss.
*Fibrillin*
- Mutations in **fibrillin-1** are responsible for **Marfan syndrome**, which presents with tall stature, long limbs (**arachnodactyly**), and cardiovascular issues like aortic dilation.
- While tall stature is observed, the patient's primary complaints of **recurrent fractures** and hearing loss are not typical features of Marfan syndrome.
*Fibroblast growth factor receptor*
- Mutations in **fibroblast growth factor receptor 3 (FGFR3)** are most commonly associated with **achondroplasia**, a form of dwarfism characterized by short stature, short limbs, and a large head.
- This is inconsistent with the patient's **tall and lanky stature** and does not account for the recurrent fractures or hearing difficulties.
Question 8: A 78-year-old man receives chemotherapy for advanced hepatocellular carcinoma. Despite appropriate therapy, he dies 4 months later. Histopathological examination of the cancer cells shows the presence of a transmembrane efflux pump protein that is known to cause decreased intracellular concentrations of chemotherapeutic drugs. Which of the following best describes this membrane protein?
A. G protein
B. Cadherin
C. P-glycoprotein (Correct Answer)
D. Tyrosine receptor
E. Channel protein
Explanation: **P-glycoprotein**
- **P-glycoprotein** (also known as **MDR1**) is a well-known **efflux pump** that actively transports many chemotherapy drugs out of cancer cells, leading to **multidrug resistance**.
- Its presence explains the **decreased intracellular concentrations** of chemotherapy drugs and the poor response to treatment in this patient.
*G protein*
- **G proteins** are intracellular signaling molecules that mediate responses to various extracellular stimuli, not primarily involved in drug efflux.
- They are typically associated with **G protein-coupled receptors** and downstream signaling pathways, not direct drug transport.
*Cadherin*
- **Cadherins** are cell adhesion molecules that play a crucial role in cell-cell binding and maintaining tissue structure.
- They are not involved in the active transport of drugs across the cell membrane.
*Tyrosine receptor*
- **Tyrosine kinase receptors** are transmembrane proteins that bind to growth factors and initiate intracellular signaling cascades, promoting cell growth and differentiation.
- They are involved in signaling, not in the active transport of chemotherapy drugs out of the cell.
*Channel protein*
- **Channel proteins** facilitate the passive diffusion of ions or small molecules across the cell membrane, typically down their electrochemical gradient.
- While they are transmembrane proteins, they do not actively pump drugs out against a concentration gradient, which is characteristic of multidrug resistance.
Question 9: 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.
Question 10: 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.
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