Tumor suppressor genes — MCQs

10 questions

A researcher is investigating compounds that modulate the cell cycle as possible chemotherapeutic agents against peripheral T-cell lymphoma. The researcher discovers a group of natural compounds with inhibitory activity against histone deacetylases, a class of enzymes that remove acetyl groups from the lysine residues of histones. A histone deacetylase inhibitor most likely causes which of the following?

Researchers are investigating oncogenes, specifically the KRAS gene that is associated with colon, lung, and pancreatic cancer. They have established that the gain-of-function mutation in this gene increases the chance of cancer development. They are also working to advance the research further to study tumor suppressor genes. Which of the genes below is considered a tumor suppressor gene?

A 58-year-old male undergoes a surveillance colonoscopy in which a 2 cm adenoma is identified and removed. Had this adenoma not been excised, the patient would have been at risk of progression to carcinoma. Which of the following is the final mutational step in the progression from adenoma to carcinoma?

A 28-year-old patient presents to a medical office for a consultation regarding a mole on her nose that is increasing in size. She also complains of frequent headaches, which she associates with stress on the job. She works as a civil engineer and spends much of her time outside. Her past medical history is positive for bronchial asthma; nevertheless, her vitals are stable. The mole is 8 mm in diameter, has irregular borders, and is brown in color. A biopsy is performed and sent for genetic analysis. A mutation is found. A mutation in which gene is characteristic of this patient’s main diagnosis?

A 38-year-old man presents to his primary care practitioner for 2 months of rectal bleeding. He also reports occasional diarrhea and abdominal pain. His family history is relevant for his father and uncle, who died from complications of colorectal cancer. Colonoscopy shows more than 10 colorectal adenomas. Which of the following genes is most likely affected in this patient?

A 5-year-old girl is brought to the physician by her mother because of a 1-month history of a painful ulcer on her face. She has developed painful sunburns in the past with minimal UV exposure. Examination of the skin shows a 2-cm ulcerated nodule on the left cheek. There are scaly, hyperpigmented papules and plaques over the skin of the entire body. Ophthalmologic examination shows decreased visual acuity, clouded corneas, and limbal injection. Examination of a biopsy specimen from the facial lesion shows poorly-differentiated squamous cell carcinoma. Impairment of which of the following proteins is the most likely cause of this patient's condition?

A 62-year-old man seeks evaluation at a local walk-in clinic for mid-low back pain of several weeks. He has tried different rehabilitation therapies and medications with no improvement. He was prescribed some pain medications and sent home last week, but the patient presents today with difficulty walking and worsening of his back pain. He was referred to the ER, where he was examined and found to have hypoesthesia from T12 to S4–S5, significant muscle weakness in both lower limbs, and reduced knee and ankle deep tendon reflexes. A hypotonic anal sphincter with conserved deep anal pressure was demonstrated on digital rectal examination, as well as a multinodular, asymmetric prostate. Imaging studies showed multiple sclerotic bone lesions along the spine. Subsequently, a prostate core biopsy was obtained which confirmed the diagnosis of prostate cancer. Which of the following characteristics would you expect in the specimen?

A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

A 6-year-old girl is brought to the physician for pain and increasing swelling over her scalp for 1 month. She has not had any trauma to the area. There is no family or personal history of serious illness. Vital signs are within normal limits. Examination shows a 3-cm solitary, tender mass over the right parietal bone. X-ray of the skull shows a solitary osteolytic lesion. Laboratory studies show: Hemoglobin 10.9 g/dL Leukocyte count 7300/mm3 Serum Na+ 136 mEq/L K+ 3.7 mEq/L Cl- 103 mEq/L Ca2+ 9.1 mg/dL Glucose 71 mg/dL Which of the following is the most likely diagnosis?

Q10

A 69-year-old man comes to the physician because of a 1-week history of blood in the urine and fatigue. He also has had a 5.0-kg (11-lb) weight loss during the past month. Physical examination shows pallor and cachexia. A nontender right flank mass is palpated. A CT scan of the chest, abdomen, and pelvis shows a 5-cm right upper pole renal mass and several pulmonary lesions. A biopsy specimen of an affected area of the lung is obtained. A photomicrograph of the biopsy specimen is shown. Molecular evaluation of the specimen is most likely to show which of the following genetic changes?

Tumor suppressor genes US Medical PG Practice Questions and MCQs

Question 1: A researcher is investigating compounds that modulate the cell cycle as possible chemotherapeutic agents against peripheral T-cell lymphoma. The researcher discovers a group of natural compounds with inhibitory activity against histone deacetylases, a class of enzymes that remove acetyl groups from the lysine residues of histones. A histone deacetylase inhibitor most likely causes which of the following?

A. Prevention of DNA strand reannealing
B. Increased heterochromatin formation
C. Suppression of gene transcription
D. Relaxation of DNA coiling (Correct Answer)
E. Tighter coiling of DNA

Explanation: ***Relaxation of DNA coiling*** - Histone deacetylase (HDAC) inhibitors block the removal of **acetyl groups** from **histones**, leading to increased histone acetylation. - Increased acetylation **reduces the positive charge** of histones, loosening their grip on the negatively charged DNA and causing **relaxation of DNA coiling**. *Prevention of DNA strand reannealing* - This process is primarily influenced by factors affecting **hydrogen bonding** between DNA strands, such as **temperature** or **DNA denaturing agents**, not directly by histone acetylation. - DNA reannealing is the reformation of a **double helix** from single strands, a different mechanism than chromatin structure. *Increased heterochromatin formation* - **Heterochromatin** is characterized by **tightly coiled DNA** and is associated with **deacetylated histones** and gene silencing. - Increased acetylation, as caused by HDAC inhibitors, would lead to less heterochromatin and more **euchromatin**. *Suppression of gene transcription* - **Relaxation of DNA coiling** makes the DNA more accessible to transcription factors and RNA polymerase, thereby generally **promoting gene transcription**, not suppressing it. - **HDAC inhibitors** primarily promote gene expression by increasing the accessibility of DNA to the transcriptional machinery. *Tighter coiling of DNA* - **Deacetylation of histones** leads to stronger interaction between histones and DNA, resulting in **tighter coiling** and chromatin condensation. - HDAC inhibitors, by preventing deacetylation, promote the opposite effect: **DNA uncoiling** and relaxation.

Question 2: Researchers are investigating oncogenes, specifically the KRAS gene that is associated with colon, lung, and pancreatic cancer. They have established that the gain-of-function mutation in this gene increases the chance of cancer development. They are also working to advance the research further to study tumor suppressor genes. Which of the genes below is considered a tumor suppressor gene?

A. Her2/neu
B. BRAF
C. BCL-2
D. JAK2
E. Rb (Correct Answer)

Explanation: ***Rb*** - The **retinoblastoma (Rb)** gene is a classic example of a **tumor suppressor gene**. Its protein product, Rb, plays a critical role in regulating the **cell cycle** by preventing uncontrolled cell division. - When **Rb is mutated or inactivated**, cells can divide without proper checks, leading to tumor formation, particularly in cases like retinoblastoma. *Her2/neu* - **Her2/neu** (also known as ERBB2) is an **oncogene** that encodes a receptor tyrosine kinase involved in cell growth and differentiation. - Its overexpression or amplification is associated with certain cancers, notably **breast cancer**, but it is not a tumor suppressor. *BRAF* - **BRAF** is an **oncogene** that codes for a serine/threonine kinase involved in the RAS/MAPK signaling pathway, which regulates cell growth. - **Gain-of-function mutations** in BRAF are frequently found in melanoma, thyroid cancer, and colorectal cancer, promoting uncontrolled cell proliferation. *BCL-2* - **BCL-2** is an **anti-apoptotic gene**, meaning it prevents programmed cell death. While its overexpression can contribute to cancer by allowing abnormal cells to survive, it is not classified as a tumor suppressor gene. - Instead, BCL-2 is considered an **oncogene** because mutations or overexpression promote cell survival and inhibit apoptosis. *JAK2* - **JAK2** (Janus Kinase 2) is a **proto-oncogene** encoding a tyrosine kinase involved in cytokine receptor signaling, which regulates hematopoiesis. - **Gain-of-function mutations**, such as JAK2 V617F, are frequently found in **myeloproliferative neoplasms** (e.g., polycythemia vera, essential thrombocythemia, myelofibrosis), leading to uncontrolled blood cell production.

Question 3: A 58-year-old male undergoes a surveillance colonoscopy in which a 2 cm adenoma is identified and removed. Had this adenoma not been excised, the patient would have been at risk of progression to carcinoma. Which of the following is the final mutational step in the progression from adenoma to carcinoma?

A. p53 inactivation (Correct Answer)
B. APC mutation
C. COX-2 overexpression
D. SMAD 2/4 loss
E. K-ras mutation

Explanation: ***p53 inactivation*** - **p53 loss of function** is typically the final genetic event in the **adenoma-to-carcinoma sequence**, facilitating unrestricted cell growth and preventing apoptosis in dysplastic cells. - The **p53 tumor suppressor gene** normally checkpoints cell division and induces programmed cell death, making its inactivation critical for malignant transformation. *APC mutation* - **APC (adenomatous polyposis coli) mutation** is often the **initiating event** in colorectal adenoma formation, leading to aberrant crypt foci and polyp formation. - While critical for early tumor genesis, it does not represent the final step in progression to invasive carcinoma. *COX-2 overexpression* - **Cyclooxygenase-2 (COX-2) overexpression** leads to increased prostaglandin production, which can promote cell proliferation, angiogenesis, and inhibit apoptosis. - It is an important factor in tumor growth and progression but occurs earlier in the sequence and is not the terminal mutational step for carcinoma. *SMAD 2/4 loss* - **SMAD 2/4 loss of function** disrupts the **TGF-β signaling pathway**, which normally inhibits cell growth and promotes differentiation. - This event typically occurs in the late adenoma stage, contributing to dysplasia, but **p53 inactivation** is considered the final critical step for full malignant transformation. *K-ras mutation* - **K-ras mutation** is a well-known event in the **adenoma-to-carcinoma sequence**, occurring earlier than p53 inactivation, usually in intermediate-sized adenomas. - It leads to constitutive activation of the RAS/MAPK pathway, promoting cell growth and survival, but generally before full malignant transformation.

Question 4: A 28-year-old patient presents to a medical office for a consultation regarding a mole on her nose that is increasing in size. She also complains of frequent headaches, which she associates with stress on the job. She works as a civil engineer and spends much of her time outside. Her past medical history is positive for bronchial asthma; nevertheless, her vitals are stable. The mole is 8 mm in diameter, has irregular borders, and is brown in color. A biopsy is performed and sent for genetic analysis. A mutation is found. A mutation in which gene is characteristic of this patient’s main diagnosis?

A. DCC
B. APC
C. BRAF (Correct Answer)
D. c-MYC
E. BCL-2

Explanation: ***BRAF*** - The patient's presentation with an **enlarging mole** on the nose with **irregular borders** and significant sun exposure strongly suggests **melanoma**. - **BRAF mutations** are found in approximately 50% of melanomas and are a key target for therapy. *DCC* - The DCC (Deleted in Colorectal Carcinoma) gene is primarily associated with **colorectal cancer**. - While it plays a role in apoptosis and cellular differentiation, it is not a characteristic mutation for melanoma. *APC* - The APC (Adenomatous Polyposis Coli) gene is a **tumor suppressor gene** most famously linked to **familial adenomatous polyposis** and **colorectal cancer**. - Mutations in APC are not characteristic of melanoma. *c-MYC* - The c-MYC gene is an **oncogene** involved in cell growth, proliferation, and apoptosis, commonly amplified or mutated in various cancers like lymphomas and some solid tumors. - While important in cancer biology, c-MYC mutations are not a primary driver or characteristic mutation for melanoma. *BCL-2* - BCL-2 is an **anti-apoptotic gene** known for its role in preventing programmed cell death, and its overexpression is common in lymphomas (especially follicular lymphoma). - It is not a characteristic mutation associated with melanoma development or progression.

Question 5: A 38-year-old man presents to his primary care practitioner for 2 months of rectal bleeding. He also reports occasional diarrhea and abdominal pain. His family history is relevant for his father and uncle, who died from complications of colorectal cancer. Colonoscopy shows more than 10 colorectal adenomas. Which of the following genes is most likely affected in this patient?

A. RAS
B. TP53
C. hMLH1
D. PPAR
E. APC (Correct Answer)

Explanation: ***APC*** - This patient's presentation with **numerous colorectal adenomas** (over 10), early-onset symptoms (38 years old), and a strong **family history of colorectal cancer** (father and uncle) is highly characteristic of **Familial Adenomatous Polyposis (FAP)**. - FAP is an **autosomal dominant** condition caused by a germline mutation in the **APC tumor suppressor gene**, leading to the development of hundreds to thousands of adenomatous polyps in the colon, which inevitably progress to colorectal cancer if untreated. *RAS* - **RAS mutations** are commonly found in sporadic colorectal cancers and play a role in tumor growth and progression, but they are not typically associated with the **hereditary syndrome of multiple adenomas** seen in this patient. - RAS activation leads to an increase in **cell proliferation** and can contribute to the development of many cancers, but not as the primary genetic defect in a polyposis syndrome. *TP53* - **TP53** is a well-known tumor suppressor gene, and mutations are involved in various cancers, including colorectal cancer (often in its later stages). However, germline mutations in TP53 are associated with **Li-Fraumeni syndrome**, which involves a broad spectrum of early-onset cancers and is not primarily characterized by numerous colonic adenomas. - TP53 mutations are generally hallmarks of **genomic instability** and are more often seen in the progression of sporadic cancers rather than initiating a polyposis syndrome. *hMLH1* - **hMLH1** is a gene involved in **DNA mismatch repair**. Germline mutations in this gene, along with other mismatch repair genes (e.g., MSH2, MSH6, PMS2), are responsible for **Lynch syndrome (hereditary non-polyposis colorectal cancer - HNPCC)**. - While Lynch syndrome is an important cause of hereditary colorectal cancer, it is characterized by fewer polyps (typically <10) that progress rapidly to cancer, and an increased risk of other cancers (e.g., endometrial), which differs from the presentation of **hundreds of adenomas** seen in FAP. *PPAR* - **PPARs (Peroxisome Proliferator-Activated Receptors)** are a group of nuclear receptor proteins that play roles in metabolism, cell differentiation, and inflammation. - While PPAR pathways have been investigated for their potential role in cancer development and as therapeutic targets, **mutations in PPAR genes are not directly linked** to a common hereditary colorectal cancer syndrome characterized by numerous adenomas like FAP.

Question 6: A 5-year-old girl is brought to the physician by her mother because of a 1-month history of a painful ulcer on her face. She has developed painful sunburns in the past with minimal UV exposure. Examination of the skin shows a 2-cm ulcerated nodule on the left cheek. There are scaly, hyperpigmented papules and plaques over the skin of the entire body. Ophthalmologic examination shows decreased visual acuity, clouded corneas, and limbal injection. Examination of a biopsy specimen from the facial lesion shows poorly-differentiated squamous cell carcinoma. Impairment of which of the following proteins is the most likely cause of this patient's condition?

A. Rb nuclear protein
B. Base-specific glycosylase
C. Excision endonuclease (Correct Answer)
D. ATM serine/threonine kinase
E. DNA helicase

Explanation: ***Excision endonuclease*** - This patient's presentation with **painful sunburns**, **early-onset squamous cell carcinoma** on the face, and **ocular abnormalities (clouded corneas, decreased visual acuity)** is highly suggestive of **xeroderma pigmentosum (XP)**. - XP is an autosomal recessive disorder caused by a defect in **nucleotide excision repair (NER)**, which is responsible for removing DNA damage primarily induced by **UV radiation**. **Excision endonucleases** are key enzymes in the initiation phase of NER, recognizing and excising the damaged DNA segment. *Rb nuclear protein* - The **Rb nuclear protein** is a tumor suppressor involved in cell cycle regulation (G1/S checkpoint). - Impairment of Rb is associated with **retinoblastoma** and several other cancers, but not typically with this specific constellation of light sensitivity, skin cancer, and ocular damage seen in XP. *Base-specific glycosylase* - **Base-specific glycosylases** are involved in **base excision repair (BER)**, which primarily corrects small, non-helix-distorting base lesions (e.g., deaminated or alkylated bases). - While important for DNA repair, defects in BER would not explain the extreme UV sensitivity and subsequent skin cancers characteristic of xeroderma pigmentosum, as these are primarily linked to UV-induced pyrimidine dimers. *ATM serine/threonine kinase* - **ATM (ataxia-telangiectasia mutated) kinase** is a critical protein involved in initiating the cellular response to **DNA double-strand breaks**. - Defects in ATM cause **ataxia-telangiectasia**, characterized by cerebellar ataxia, immunodeficiency, and a predisposition to lymphoid malignancies, but not the specific skin and eye findings of XP. *DNA helicase* - **DNA helicases** are enzymes that unwind DNA and are involved in various DNA processes, including replication, recombination, and repair. - While critical for many functions, a general defect in **DNA helicase** would lead to a broader range of severe developmental and cellular defects, and is not specifically linked to the clinical phenotype of xeroderma pigmentosum which results from specific NER pathway defects.

Question 7: A 62-year-old man seeks evaluation at a local walk-in clinic for mid-low back pain of several weeks. He has tried different rehabilitation therapies and medications with no improvement. He was prescribed some pain medications and sent home last week, but the patient presents today with difficulty walking and worsening of his back pain. He was referred to the ER, where he was examined and found to have hypoesthesia from T12 to S4–S5, significant muscle weakness in both lower limbs, and reduced knee and ankle deep tendon reflexes. A hypotonic anal sphincter with conserved deep anal pressure was demonstrated on digital rectal examination, as well as a multinodular, asymmetric prostate. Imaging studies showed multiple sclerotic bone lesions along the spine. Subsequently, a prostate core biopsy was obtained which confirmed the diagnosis of prostate cancer. Which of the following characteristics would you expect in the specimen?

A. Well-formed glands with an increase in interglandular stroma
B. Fat invasion
C. Prostatic intraepithelial neoplasia
D. Small, closely-packed, well-formed glands
E. Perineural invasion (Correct Answer)

Explanation: ***Perineural invasion*** - **Perineural invasion** is a common finding in prostate adenocarcinoma, indicating that cancer cells have invaded the nerves surrounding the prostatic glands. This feature is often associated with a higher Gleason score and increased likelihood of extraprostatic extension and metastasis. - While not visible on gross examination, its presence on biopsy can influence staging and treatment decisions for prostate cancer, particularly regarding the risk of recurrence and spread to other tissues. *Well-formed glands with an increase in interglandular stroma* - This description is more indicative of **benign prostatic hyperplasia (BPH)**, a non-cancerous enlargement of the prostate, characterized by an increase in both glandular and stromal components. - In BPH, the glands typically remain well-formed, and the stroma often proliferates, but these features do not represent malignancy. *Fat invasion* - **Fat invasion** is not a typical characteristic of prostate cancer within the prostate gland itself, as the prostate is not primarily composed of fat. - While prostate cancer can invade periprostatic fatty tissue if it extends beyond the prostatic capsule, fat invasion within the biopsy specimen from the prostate proper is not a diagnostic feature of adenocarcinoma. *Prostatic intraepithelial neoplasia* - **Prostatic intraepithelial neoplasia (PIN)** is a pre-malignant lesion where the prostatic ductal and acinar cells show cytologic atypia but remain confined within the basement membrane. - While PIN (especially high-grade PIN) can be associated with prostate cancer and may precede its development, it is not cancer itself and is not the definitive diagnosis in this case where prostate cancer has been confirmed. *Small, closely-packed, well-formed glands* - This description could represent a **low-grade prostate adenocarcinoma** (Gleason pattern 3), where the glands are still relatively well-formed but are more numerous and crowded than in benign tissue. - However, compared to perineural invasion, which is a more definitive sign of aggressive behavior and advanced disease in a patient presenting with metastatic features (sclerotic bone lesions, neurologic symptoms), this histological finding alone is less specific for the advanced cancer described.

Question 8: A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

A. Activating mutation of the Ras protooncogene
B. Inactivating mutation of the p53 tumor suppressor gene (Correct Answer)
C. RET/PTC rearrangement
D. BRAF mutation
E. RET gene mutation

Explanation: ***Inactivating mutation of the p53 tumor suppressor gene*** - The patient's presentation with a **rapidly enlarging, fixed, non-tender thyroid mass**, *hoarseness*, *dysphagia*, *weight loss*, and *palpable cervical lymph nodes* is highly suggestive of **anaplastic thyroid carcinoma (ATC)**, an aggressive malignancy. - Inactivating mutations of the **p53 tumor suppressor gene** are frequently associated with the development and progression of ATC, contributing to its uncontrolled growth and poor prognosis. *Activating mutation of the Ras protooncogene* - **Ras mutations** are more commonly found in *follicular thyroid carcinoma* and *follicular variants of papillary thyroid carcinoma*. - While they can indicate malignancy, they are not typically the primary genetic driver for the highly aggressive features seen in anaplastic carcinoma. *RET/PTC rearrangement* - **RET/PTC rearrangements** are characteristic genetic alterations found in **papillary thyroid carcinoma (PTC)**. - PTC typically presents with a *slower growth rate* and *less aggressive features* compared to the rapid progression described in the patient. *BRAF mutation* - The **BRAF V600E mutation** is the most common genetic alteration in **papillary thyroid carcinoma (PTC)**, especially the conventional and tall-cell variants. - While it indicates a more aggressive subset of PTC, it is generally not the primary mutation associated with the extremely aggressive and rapidly progressing features of anaplastic thyroid carcinoma. *RET gene mutation* - **Germline RET mutations** are primarily associated with **medullary thyroid carcinoma (MTC)**, often occurring as part of Multiple Endocrine Neoplasia type 2 (MEN2). - The clinical presentation with a *rapidly growing, fixed mass* and *compressive symptoms* is less typical for MTC, which can also be aggressive but usually presents differently.

Question 9: A 6-year-old girl is brought to the physician for pain and increasing swelling over her scalp for 1 month. She has not had any trauma to the area. There is no family or personal history of serious illness. Vital signs are within normal limits. Examination shows a 3-cm solitary, tender mass over the right parietal bone. X-ray of the skull shows a solitary osteolytic lesion. Laboratory studies show: Hemoglobin 10.9 g/dL Leukocyte count 7300/mm3 Serum Na+ 136 mEq/L K+ 3.7 mEq/L Cl- 103 mEq/L Ca2+ 9.1 mg/dL Glucose 71 mg/dL Which of the following is the most likely diagnosis?

A. Giant-cell tumor of bone
B. Langerhans cell histiocytosis (Correct Answer)
C. Ewing sarcoma
D. Multiple myeloma
E. Aneurysmal bone cyst

Explanation: ***Langerhans cell histiocytosis*** - The presentation of a **solitary osteolytic skull lesion** in a child, especially with pain and swelling, is highly suggestive of **Langerhans cell histiocytosis (LCH)**. - LCH can manifest as **eosinophilic granuloma**, which is a localized form primarily affecting bone, often the skull, and commonly presents in children. *Giant-cell tumor of bone* - This tumor typically occurs in **young adults (20s-40s)**, not children, and most commonly affects the **epiphysis of long bones**, such as the distal femur or proximal tibia. - While it can be lytic, its demographic and usual location are inconsistent with this case. *Ewing sarcoma* - Ewing sarcoma also presents in children and young adults with bone pain and swelling, but it often involves the **diaphysis of long bones** or the pelvis. - Radiographically, it is classically described as an **"onion-skin" periosteal reaction** or a permeative lesion, which is not indicated here. *Multiple myeloma* - This is a malignancy of **plasma cells** almost exclusively seen in **older adults**, typically over 60 years of age. - It presents with widespread **punched-out lytic lesions** in the skull, vertebrae, and other bones, along with systemic symptoms like anemia and renal dysfunction. *Aneurysmal bone cyst* - An aneurysmal bone cyst is a benign, expansile, lytic bone lesion that can occur in children and often causes pain and swelling. - However, it typically presents as an **eccentric, expansile lesion** with a thin rim of periosteal new bone formation, and more often affects the metaphysis of long bones or vertebrae, rather than a purely lytic lesion in the parietal bone without trauma.

Question 10: A 69-year-old man comes to the physician because of a 1-week history of blood in the urine and fatigue. He also has had a 5.0-kg (11-lb) weight loss during the past month. Physical examination shows pallor and cachexia. A nontender right flank mass is palpated. A CT scan of the chest, abdomen, and pelvis shows a 5-cm right upper pole renal mass and several pulmonary lesions. A biopsy specimen of an affected area of the lung is obtained. A photomicrograph of the biopsy specimen is shown. Molecular evaluation of the specimen is most likely to show which of the following genetic changes?

A. NF1 gene inactivation
B. TSC1 gene insertion
C. WT1 gene deletion
D. PKD1 gene mutation
E. VHL gene deletion (Correct Answer)

Explanation: ***VHL gene deletion*** - The clinical presentation of a **right flank mass** with **hematuria**, **weight loss**, and **pulmonary lesions** points to **renal cell carcinoma (RCC)**, which is further supported by the photomicrograph showing clear cells. The **VHL gene** is a tumor suppressor gene, and its inactivation (e.g., through deletion) is the most common genetic alteration in **clear cell RCC**. - The image displays classic features of **clear cell RCC**, characterized by cells with **clear cytoplasm** due to abundant lipids and glycogen, arranged in **nests or cords with fine vascular networks**. *NF1 gene inactivation* - **NF1 gene inactivation** is associated with **neurofibromatosis type 1**, a genetic disorder that predisposes individuals to various tumors, including neurofibromas, optic gliomas, and pheochromocytomas, but not typically clear cell RCC. - While patients with neurofibromatosis type 1 can develop kidney tumors, they are usually not clear cell RCC and the absence of other NF1 stigmata makes this less likely. *TSC1 gene insertion* - **TSC1 gene mutations** are linked to **tuberous sclerosis complex**, a genetic disorder characterized by tumor formation in multiple organs, including the brain, skin, heart, and kidneys (e.g., angiomyolipomas). - While kidney tumors can occur, typical clear cell RCC is not the primary renal manifestation, and the image does not suggest angiomyolipoma. *WT1 gene deletion* - **WT1 gene deletion** is primarily associated with **Wilms' tumor (nephroblastoma)**, a childhood kidney cancer. - This patient is 69 years old, making Wilms' tumor highly unlikely. *PKD1 gene mutation* - **PKD1 gene mutations** are responsible for **autosomal dominant polycystic kidney disease (ADPKD)**, a condition causing multiple cysts in the kidneys and other organs. - While ADPKD can lead to kidney failure and may rarely be associated with RCC, the clinical presentation and microscopic image are not characteristic of ADPKD or its associated RCC type, which is often papillary RCC.

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