A scientist is researching the long term effects of the hepatitis viruses on hepatic tissue. She finds that certain strains are oncogenic and increase the risk of hepatocellular carcinoma. However, they appear to do so via different mechanisms. Which of the following answer choices correctly pairs the hepatitis virus with the correct oncogenic process?

Hepatitis B virus - integration of viral DNA into host hepatocyte genome

Hepatitis A virus - chronic inflammation

Hepatitis C virus - chronic inflammation

Hepatitis E virus - integration of viral DNA into host hepatocyte genome

Hepatitis A virus - integration of viral DNA into host hepatocyte genome

A 2-year-old boy from a rural community is brought to the pediatrician after his parents noticed a white reflection in both of his eyes in recent pictures. Physical examination reveals bilateral leukocoria, nystagmus, and inflammation. When asked about family history of malignancy, the father of the child reports losing a brother to an eye tumor when they were children. With this in mind, which of the following processes are affected in this patient?

Regulation of the G1-S transition

A 16-year-old boy is brought to the physician because of a lesion that has been growing on his jaw over the past several months. He recently immigrated to the USA from Kenya with his family. Physical examination shows a 3-cm solid mass located above the left mandible. There is cervical lymphadenopathy. Biopsy of the mass shows sheets of lymphocytes and interspersed reactive histiocytes with abundant, clear cytoplasm and phagocytosed debris. Which of the following mechanisms is most likely directly responsible for the malignant transformation of this patient's cells?

Impairment of receptor function

Inhibition of cell cycle arrest

A 62-year-old man comes to the physician because of easy bruising and recurrent nosebleeds over the past 4 months. During the same time period, the patient has felt weak and has had a 10-kg (22-lb) weight loss. Physical examination shows mucosal pallor and bruising on the upper and lower extremities in various stages of healing. The spleen is palpated 4 cm below the left costal margin. Laboratory studies show anemia and thrombocytopenia. A photomicrograph of a peripheral blood smear is shown. Histologic examination of a bone marrow biopsy in this patient is most likely to show which of the following findings?

Neoplastic lymphocytes that stain positive for tartrate-resistant acid phosphatase

Neoplastic granulocytes with low leukocyte alkaline phosphatase score

Neoplastic myeloid cells that stain positive for myeloperoxidase

Neoplastic lymphoid cells that stain positive for terminal deoxynucleotidyl transferase activity

Dysplastic erythroid cells that stain positive for iron

Oncogenes and proto-oncogenes for USMLE Step 2 CK: High-Yield Pathology Lessons

Proto-oncogenes - Good Guys Gone Bad

Proto-oncogenes: Normal genes that regulate cell growth, division, and differentiation.
Oncogenes: Mutated proto-oncogenes that exhibit a gain-of-function, leading to uncontrolled cell proliferation.
Activation Mechanism: Requires a mutation in only one allele (dominant effect), the "one-hit" hypothesis.

⭐ Oncogene activation is like having a car's accelerator pedal stuck down, leading to constant, unchecked cellular proliferation.

Oncogene activation mechanisms and protein products

Activation Mechanisms - Flipping the Evil Switch

Point Mutation (e.g., RAS)
- Single nucleotide change → constitutively active protein.
- Classic example: KRAS mutation locks it in a GTP-bound, active state, driving constant cell proliferation.
Gene Amplification (e.g., MYC, HER2)
- Increased number of gene copies → protein overexpression.
- Examples: N-MYC (neuroblastoma), HER2/NEU (breast cancer).
Chromosomal Translocation (e.g., ABL)
- Gene moved to a new locus → overexpression or novel fusion protein.
- Example: BCR-ABL fusion in CML via t(9;22), the Philadelphia chromosome.

Oncogene Activation Mechanisms

⭐ In Burkitt Lymphoma, a t(8;14) translocation places the c-MYC oncogene under the control of the highly active immunoglobulin heavy-chain promoter.

Key Oncogenes - The Usual Suspects

Oncogene	Function/Pathway	Associated Neoplasms
RAS	GTP-binding protein (signal transduction)	Pancreatic, colon, lung, melanoma
MYC	Transcription factor	Burkitt lymphoma (c-myc), Neuroblastoma (N-myc)
HER2/neu (ERBB2)	Receptor tyrosine kinase	Breast, ovarian, gastric cancers
ABL	Non-receptor tyrosine kinase	Chronic Myeloid Leukemia (CML), ALL (t(9;22))
BRAF	Serine/threonine kinase (MAPK pathway)	Melanoma, hairy cell leukemia, colon cancer
RET	Receptor tyrosine kinase	Papillary thyroid ca, MEN 2A & 2B (📌 REarranged during Transfection)
KIT	Cytokine receptor (stem cell factor)	Gastrointestinal Stromal Tumor (GIST), seminoma

Signaling Pathways - Cellular Chain of Command

Proto-oncogenes encode proteins that regulate cell growth. Activating mutations can lead to constitutive signaling, driving cancer. Two major pathways are crucial:

RAS-MAPK Pathway: The primary cascade for stimulating cell proliferation.

PI3K/AKT/mTOR Pathway: A key parallel pathway that promotes cell growth and survival.

⭐ The RAS gene family (KRAS, HRAS, NRAS) represents the most frequently mutated proto-oncogenes in human cancers.

High‑Yield Points - ⚡ Biggest Takeaways

Proto-oncogenes become oncogenes via gain-of-function mutations, requiring only one mutated allele.

Activation occurs via point mutation (RAS), gene amplification (HER2, N-MYC), or translocation (c-MYC, ABL).

RAS mutations create a constitutively active GTP-bound protein, constantly signaling for growth.

c-MYC translocation t(8;14) is seen in Burkitt lymphoma; N-MYC amplification in neuroblastoma.

HER2/neu (ERBB2) amplification in breast cancer is a key therapeutic target.

The BCR-ABL fusion t(9;22) is a constitutively active tyrosine kinase driving CML.

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