Cancer Genetics - Gene Game Gone Wrong
- Oncogenes: Proto-oncogenes with gain-of-function mutations (e.g., RAS, MYC, EGFR). Drive cell proliferation.
- Tumor Suppressor Genes (TSGs): Loss-of-function mutations (e.g., TP53, RB1, APC). Knudson's two-hit hypothesis.
- DNA Repair Genes: Mutations lead to genomic instability (e.g., BRCA1/2, MSH/MLH in Lynch syndrome).
- Epigenetic Changes: Alter gene expression without DNA sequence change (e.g., methylation, acetylation).
- Hereditary Cancer Syndromes: Often autosomal dominant inheritance (e.g., Li-Fraumeni, Lynch, FAP).
⭐ TP53 (guardian of the genome) is the most frequently mutated gene across all human cancers, involved in >50% of cases.
Hereditary Syndromes - Cancer Families
| Syndrome | Gene(s) | Cancers | Inheritance |
|---|---|---|---|
| Lynch | MSH2, MLH1+ | CRC, Endometrial, Ovarian, Stomach | AD |
| FAP | APC | CRC (100%), Duodenal, Thyroid | AD |
| Li-Fraumeni | TP53 | Sarcoma, Breast, Brain, Leukemia, Adrenal | AD |
| HBOC | BRCA1/2 | Breast, Ovarian, Prostate, Pancreatic | AD |
| VHL | VHL | Hemangioblastoma, RCC (clear), Pheo | AD |
| MEN1 | MEN1 | Parathyroid, Pancreatic NET, Pituitary (3P's) | AD |
| MEN2 | RET | MTC, Pheo; Parathyroid (2A)/Neuromas (2B) | AD |
| Retinoblastoma | RB1 | Retinoblastoma, Osteosarcoma | AD |
⭐ Knudson's "two-hit" hypothesis is key for RB1 (Retinoblastoma) & other tumor suppressor genes.
Oncogenes & TSGs - Accelerators & Brakes
Oncogenes act as "accelerators" for cell growth, requiring one activating mutation. Tumor Suppressor Genes (TSGs) act as "brakes", typically needing two inactivating mutations (hits) to lose function.
| Feature | Oncogenes (OG) | Tumor Suppressor Genes (TSG) |
|---|---|---|
| Analogy | 🚗 Accelerator | 🛑 Brake |
| Function | Promote cell growth/division | Inhibit cell growth/division, repair DNA |
| Mutation | Gain-of-function (GoF) | Loss-of-function (LoF) |
| Alleles | 1 hit (dominant) | 2 hits (recessive, Knudson's) |
| Examples | RAS, MYC, HER2, ABL, BRAF | TP53, RB1, BRCA1/2, APC, PTEN |
⭐ "Guardian of the Genome": TP53 is a critical TSG; its mutation is found in >50% of human cancers.
Simplified p53 Activation & Role (TSG Example):
DNA Repair - Cellular Fix-it Fails
Defective DNA repair leads to genomic instability, a hallmark of cancer. Key pathways:
| Pathway | Key Gene(s) | Associated Disorder(s) |
|---|---|---|
| Mismatch Repair (MMR) | MSH2, MLH1, PMS2 | Lynch Syndrome (HNPCC) |
| Nucleotide Excision Repair (NER) | XPA-XPG | Xeroderma Pigmentosum (XP) |
| Base Excision Repair (BER) | MUTYH | MUTYH-associated polyposis |
| Homologous Recombination (HR) | BRCA1, BRCA2, ATM, PALB2 | Hereditary Breast/Ovarian Cancer, Ataxia-Telangiectasia (AT) |
| Non-Homologous End Joining (NHEJ) | XRCC4, LIG4 | LIG4 syndrome |
⭐ Xeroderma Pigmentosum (XP) results from NER defects, leading to extreme UV sensitivity and skin cancer development at a young age.
Clinical Cancer Genetics - Precision Strikes
- Genetic Testing: Identifies germline (inherited, e.g., BRCA) & somatic (tumor-specific, e.g., EGFR) mutations.
- Precision Oncology: Guides targeted therapies (e.g., imatinib, olaparib) & immunotherapy selection.
- Prognosis & Risk: Assesses tumor behavior, recurrence risk, and hereditary cancer predisposition for family screening.
⭐ Liquid biopsies analyzing circulating tumor DNA (ctDNA) offer minimally invasive tumor genotyping and monitoring of treatment response.
High‑Yield Points - ⚡ Biggest Takeaways
- Knudson's two-hit hypothesis applies to tumor suppressor genes (e.g., RB1, TP53).
- Proto-oncogenes (e.g., RAS, MYC) require one activating mutation.
- Germline TP53 mutations cause Li-Fraumeni syndrome, predisposing to multiple cancers.
- BRCA1/BRCA2 mutations confer high risk for hereditary breast and ovarian cancer.
- Lynch syndrome (HNPCC) involves DNA mismatch repair gene defects (e.g., MSH2, MLH1).
- Philadelphia chromosome t(9;22) (BCR-ABL) is key in CML.
- Loss of heterozygosity (LOH) often inactivates the second allele of tumor suppressor genes.
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