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Oncology- Oncogenes and Tumor Suppressor Genes
I. Oncogenes
A. Definition: Genes whose normal function promotes cell proliferation and inhibits apoptosis (programmed cell death). When mutated or overexpressed, they contribute to uncontrolled cell growth, a hallmark of cancer.
B. Key Examples & Mechanisms of Activation:
A. Definition: Genes that normally restrain cell proliferation, promote apoptosis, or repair DNA damage. Loss of function contributes to cancer development.
B. Two Main Classes:
I. Oncogenes
A. Definition: Genes whose normal function promotes cell proliferation and inhibits apoptosis (programmed cell death). When mutated or overexpressed, they contribute to uncontrolled cell growth, a hallmark of cancer.
B. Key Examples & Mechanisms of Activation:
- RAS family (HRAS, KRAS, NRAS): Normally activated by growth factor signaling (e.g., EGFR) through GTP binding. Mutations (codons 12, 13, 61) lock RAS in the active GTP-bound state, leading to constitutive signaling, independent of growth factors.
- Other Oncogenes: BRAF, RET, SRC, ERBB2/3, MYC.
- Mechanisms of Overexpression (beyond mutation):
- Gene amplification: Increased gene copy number leads to higher protein levels (e.g., ERBB2 in breast cancer, SRC in colon cancer).
- Chromosomal fusions: Oncogene fused to a highly active promoter, resulting in overexpression in specific tissues.
- Deregulation of signaling pathways: Oncogene expression triggered by activation of pathways like RAS and Wnt (e.g., MYC).
A. Definition: Genes that normally restrain cell proliferation, promote apoptosis, or repair DNA damage. Loss of function contributes to cancer development.
B. Two Main Classes:
- Regulators of Cell Growth and Apoptosis: These genes directly inhibit cell proliferation or promote apoptosis. Examples include TP53, APC, and PTEN. Loss of function leads to uncontrolled growth, similar to oncogene activation. Note that APC's role is particularly significant in intestinal homeostasis.
- DNA Repair Genes: Genes involved in repairing DNA damage. Loss of function leads to a "mutator phenotype" – increased genomic instability and accumulation of mutations, increasing the likelihood of cancer development. Examples include BRCA1/2 (involved in non-homologous end joining) and mismatch repair genes (e.g., MLH1, MSH2).
- Two-hit hypothesis (previously dominant view): Both copies of a tumor suppressor gene need to be mutated for a significant effect. This often occurs through somatic mutations in one allele, and inheriting a mutated copy (germline mutation) in the other.
- Germline mutations: Inherited mutations increase cancer risk; individuals with one mutated copy are predisposed to developing cancer in specific tissues upon loss of the second allele (e.g., Li-Fraumeni syndrome (TP53), FAP (APC), Cowden disease (PTEN)). The specific tissue affected often reflects the gene's role in that tissue.
- Epigenetic inactivation: Mechanisms like methylation can silence tumor suppressor gene expression without altering the DNA sequence itself (e.g., MLH1 in colorectal cancer).
- Mutant p53: In addition to loss of p53 function, mutations can create a non-functional but stable protein that exhibits oncogenic activity, interacting with other p53 family members (p63, p73) to disrupt their function and promote metastasis.
- TP53: The most frequently mutated tumor suppressor gene. Its role in apoptosis, growth arrest, DNA repair, and genomic stability is vital. Loss of p53 function contributes to multiple aspects of tumor progression.
- APC: Negative regulator of the Wnt signaling pathway, crucial for intestinal homeostasis. Loss of APC contributes to colorectal cancer.
- PTEN: Involved in cell growth regulation; loss contributes to several cancers.
- BRCA1/2: Key roles in DNA repair; mutations increase risk of breast, ovarian, and pancreatic cancers.
- Mismatch repair genes (MSH2, MLH1): Involved in DNA mismatch repair; mutations predominantly increase colorectal cancer risk. MLH1 inactivation via methylation is common in microsatellite instability (MSI) cancers.
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