Genetics of Oncogenes (LEC)

What is a protooncogene?

Protooncogenes are normal genes that encode proteins promoting cell growth and division.

What is an oncogene?

Oncogenes are mutated versions of protooncogenes that have undergone mutations leading to cancerous behavior.

How can mutations activate protooncogenes?

Mutations can lead to either an excessive increase in normal functions or a completely new function in the affected gene product, known as gain of function mutations.

What is the impact of a single copy mutation in oncogenes?

A mutation in a single copy of a protooncogene can lead to cancer, as oncogenes are dominant over normal alleles.

How do oncogenes transform cells?

Oncogenes can transform cells through several mechanisms, including: 1) Overproduction of growth factors; 2) Increased receptor sensitivity; 3) Mutation of intracellular signaling pathways; 4) Uncontrolled cell division.

What are tumor suppressor genes?

Tumor suppressor genes usually produce proteins that inhibit the cell cycle and prevent proliferation. Mutations in these genes result in a loss of function, and both alleles must be affected before malignant transformation can occur, as tumor suppressor genes behave in a recessive manner.

What are DNA repair genes?

DNA repair genes are responsible for recognizing and repairing nonlethal genetic damage. Mutations in these genes impair the cell's ability to maintain genomic stability.

What are oncogenes?

Oncogenes are mutated forms of protooncogenes that undergo gain of function mutations, leading to excessive cell growth and replication, which can contribute to cancer development.

How do tumor suppressor genes and oncogenes differ in their function?

Tumor suppressor genes inhibit cell growth and prevent proliferation, whereas oncogenes promote excessive cell growth and replication.

How do the effects of mutations differ between tumor suppressor genes and oncogenes?

Mutations in tumor suppressor genes result in a loss of function, requiring both alleles to be mutated for cancer development. In contrast, changes in oncogenes result in gain of function, where a mutation in just one copy can lead to cancer.

What are point mutations in protooncogenes?

Point mutations are changes in a single nucleotide that can lead to the activation of a protooncogene to an oncogene. An example is the ERBB1 gene, which encodes the epidermal growth factor receptor (EGFR). Point mutations in ERBB1 can result in the constitutive activation of the EGFR tyrosine kinase, seen in some lung adenocarcinomas.

What are nonsense mutations in protooncogenes?

Nonsense mutations introduce a premature stop codon that can inactivate a receptor tyrosine kinase, leading to the production of a truncated protein. For example, a nonsense mutation in growth factor receptors can result in the ErbB oncoprotein, creating a constitutively active protein tyrosine kinase that functions even in the absence of signaling.

What are chromosomal translocations?

Chromosomal translocations involve the rearrangement of DNA segments, which can lead to the activation of oncogenes. An example is chronic myelogenous leukemia (CML), where the ABL gene on chromosome 9 is translocated to chromosome 22, next to the BCR gene, resulting in the BCR-ABL fusion gene that encodes a constitutively active nonreceptor tyrosine kinase.

What is gene amplification in protooncogenes?

Gene amplification can occur in two ways to activate oncogenes: 1) double minutes, which are extrachromosomal fragments of DNA containing amplified oncogenes, leading to hundreds of copies; 2) homogeneously staining regions (HSRs), which are amplified oncogenes attached to chromosomes. Both methods result in excessive and unregulated production of the oncoprotein, perpetuating cell division.

What is the chromosomal translocation involved in chronic myeloid leukemia (CML)?

In chronic myeloid leukemia (CML), the chromosomal translocation involves the ABL gene on chromosome 9 being translocated to chromosome 22, next to the BCR gene, resulting in the BCR-ABL fusion gene.

What is the molecular basis of tumorigenesis in CML?

The BCR-ABL fusion gene encodes a constitutively active nonreceptor tyrosine kinase, which activates signaling pathways that promote excessive proliferation and survival of myeloid cells, leading to cancer development.

What is the chromosomal translocation involved in Burkitt lymphoma?

In Burkitt lymphoma, the chromosomal translocation typically involves the MYC gene on chromosome 8 being translocated to chromosome 14, juxtaposing it with the immunoglobulin gene locus.

What is the molecular basis of tumorigenesis in Burkitt lymphoma?

The translocation results in the overexpression of the MYC oncogene, which drives uncontrolled cell proliferation by regulating genes involved in cell growth and division.

What is interpreted from a cytogenetic test that detects translocations in CML and Burkitt lymphoma?

A cytogenetic test for CML may reveal the Philadelphia chromosome, indicating the presence of the BCR-ABL fusion gene, while a test for Burkitt lymphoma would show the translocation of the MYC gene, confirming the diagnosis and aiding in treatment decisions.

What is Herceptin (Trastuzumab)?

Herceptin is a monoclonal antibody against the HER2 receptor that blocks its activity. It is used in the treatment of breast cancer patients who have ERBB2 amplification and HER2 overexpression.

How does Herceptin work in treating HER2+ breast cancer?

Herceptin causes tumor size regression, stops tumor growth, and induces apoptosis of the tumor cells by inhibiting the activity of the HER2 receptor.

What is Imatinib mesylate (Gleevec)?

Imatinib mesylate is a BCR-ABL tyrosine kinase inhibitor that is used as a treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Why is Imatinib mesylate effective for CML?

Most CML tumor cells require the BCR-ABL signaling pathway to survive and proliferate. Inhibiting its activity with Imatinib mesylate effectively suppresses tumor proliferation.

What is the function of Receptor Tyrosine Kinases (RTKs)?

Receptor Tyrosine Kinases (RTKs) are proteins that, when mutated, can become constitutively active, meaning they are active even in the absence of a signal. This leads to uncontrolled cell proliferation and growth.

What is the role of Ras in oncogenesis?

Ras is a crucial protein in oncogenesis, where its hyperactivity promotes tumor growth. The active form, Ras-GTP, activates growth pathways, whereas the inactive form, Ras-GDP, does not. Mutations that inhibit GTPase activity can lead to constitutive activation of Ras, with specific point mutations at Gly12 or Gln61 often isolated in tumor cells.

What are transcription factors and their role in cancer?

Transcription factors are DNA-binding proteins that play a key role in regulating gene expression. They activate genes that drive DNA replication and cell division, and alterations in their function can contribute to oncogenesis by promoting uncontrolled cell growth.

How do RTKs, Ras, and transcription factors compare in their role in oncogenesis?

RTKs become constitutively active due to mutations that allow cell proliferation without signals; Ras functions through its GTP/GDP cycle, where hyperactivity leads to active growth signals; transcription factors drive gene expression that leads to DNA replication and cell division. All three can contribute to oncogenesis, but they operate through different mechanisms: RTKs and Ras through signaling pathways, and transcription factors through gene regulation.