In-depth Notes on Tumour Suppressor Genes and Cancer

Tumour Suppressor Genes (TSGs)

  • TSGs protect against cancer development by inhibiting cell proliferation, repairing DNA, and inducing apoptosis.
  • Mutations in TSGs are usually recessive, requiring both alleles to be mutated for cancer to develop.

Characteristics of TSGs

  • Encode proteins inhibiting cell growth and survival.
  • Inactivated by loss of function (LOF) mutations that abolish protein activity.
  • Associated with cancer predisposition syndromes, e.g., familial retinoblastoma.
  • Often inhibit pathways activated by oncogenes.

TSG Examples

  • Retinoblastoma (RB): Prototype TSG controlling the G1-S checkpoint in the cell cycle.
  • TP53 (p53): Known as the "guardian of the genome", it plays a key role in maintaining genome integrity.

Mechanisms of TSG Inactivation

  • TSGs may be inactivated through various mutations:
    • Nonsense mutations (creating stop codons)
    • Frameshift mutations
    • Splice site mutations
    • Large deletions
  • Both alleles must be inactivated for cancer to be initiated.

The RB1 Gene and Retinoblastoma

  • Biallelic inactivation of the RB1 gene results in retinoblastoma, a type of childhood cancer.
  • Accounts for about 2% of childhood cancers; >90% are curable if detected early.
  • Loss of RB leads to uncontrolled cell proliferation and inappropriate entry into the S phase of the cell cycle.

Knudson’s 2-Hit Hypothesis

  • Proposes that retinoblastoma is caused by two mutations (hits) affecting both alleles of the RB1 gene.
    • First hit: inheritance or spontaneous mutation affecting one allele.
    • Second hit: inactivation of the second allele, potentially through loss of heterozygosity (LOH).

Frequency of RB1 Mutations and LOH

  • Loss of both RB1 alleles often through:
    • Point mutations
    • Gene silencing (e.g., promoter methylation)
    • Other mechanisms like chromosomal loss, non-disjunction, or mitotic recombination.

Role of p53 in Tumour Suppression

  • p53 regulates the cell cycle, mediating cell cycle arrest and apoptosis in response to DNA damage.
  • Mutations in p53 are common in various cancers, notably leading to a gain of function where p53 may acquire new roles unrelated to its original function.
  • p53 mutations often exhibit atypical patterns compared to other TSGs, predominantly being missense mutations.

TSGs Involved in Genome Integrity

  • Examples of TSGs that maintain genomic integrity:
    • TP53: Central to cell cycle control; linked with Li-Fraumeni syndrome.
    • BRCA1/BRCA2: Involved in DNA double-strand break repair; mutations predispose to breast and ovarian cancer.
  • Tumour suppressor mutations can induce genomic instability, leading to further mutations in oncogenes and other TSGs, accelerating cancer progression.

Summary of Cancer-Associated TSG Mutations

  • TSG mutations usually result in complete or partial protein loss, primarily through nonsense, frameshift, and splice site alterations.
  • Germline mutations can indicate predisposition to specific cancer syndromes and tendencies toward higher incidences of certain cancers.

Oncogenes vs. TSGs

  • Tumour development requires both oncogene activation and TSG inactivation, illustrating the interplay between oncogenes and TSGs in cancer progression.

Conclusion

  • Understanding TSG functions and their associated pathways is crucial for cancer research and therapy development. TSGs are pivotal in maintaining genomic stability and regulating cell proliferation.