Cancer Genetics Summary

Tumor Suppressor Genes

• Act recessively; both alleles must be inactivated for loss of function.

• Crucial for controlling cell growth, division, and DNA repair, especially at cell cycle checkpoints (G1/S, G2/M).

• Examples:

  • APC: Regulates Wnt signaling, linked to colorectal cancer.

  • BRCA1/BRCA2: Involved in DNA repair; mutations increase breast/ovarian cancer risk.

  • p53: "Guardian of the genome," induces cell cycle arrest or apoptosis.

  • RB: Key G1/S cell cycle checkpoint regulator.

Key Concepts

• Loss of Heterozygosity (LOH): Inactivation of the remaining functional allele of a tumor suppressor gene in an individual who inherited one mutated allele (e.g., $(RB1<em>{\text{WT}}/mut) \to (RB1</em>{\text{mut}}/mut)$).

• Haploinsufficiency: One functional allele is insufficient to maintain normal function, increasing cancer susceptibility (e.g., $(RB1_{\text{WT}}/mut)$).

p53 - The Guardian of the Genome

• A transcription factor (encoded by $TP53$) vital for genomic integrity.

• Activated by stress (DNA damage, oncogene activation, hypoxia).

• Mechanisms of action:

  • Cell-cycle arrest: Induces $p21$, inhibiting CDKs for DNA repair.

  • Apoptosis: Triggers programmed cell death via pro-apoptotic genes like $BAX$ if damage is irreparable.

  • DNA repair: Regulates DNA repair pathways.

• Mutated in >50% of human cancers, leading to loss of protective functions.

Oncogenes

• Mutated or overexpressed proto-oncogenes that drive cell proliferation.

• Act dominantly; one mutated allele is sufficient for function.

• Mechanisms of activation:

  • Point mutations: Hyperactive protein (e.g., $RAS$).

  • Gene amplification: Excessive protein (e.g., $HER2$).

  • Chromosomal translocations: Novel fusion proteins or altered regulation (e.g., $BCR-ABL$ in CML, $c-myc$ in Burkitt's lymphoma).

  • Viral insertion: Overexpression.

Chromosomal Aberrations

• Common in cancer cells, contributing to genome instability and tumorigenesis.

• Types include:

  • Aneuploidy: Abnormal chromosome number.

  • Translocations: Chromosome segment rearrangements, forming fusion genes.

  • Deletions: Loss of chromosome segments, potentially removing tumor suppressor genes.

  • Amplifications: Repeated copies of chromosomal segments, overexpressing oncogenes.

Testing for Oncogenic Potential

• Experimental approaches to determine if a gene can transform normal cells.

• Involves expressing the suspected gene in normal cells (e.g., fibroblasts) and observing for oncogenic changes:

  • Loss of contact inhibition.

  • Anchorage independence.

  • Tumor formation in immunocompromised animals.