Makindo Medical Notes.com

Overview of Tumour Suppressor Genes

Tumour suppressor genes are genes that help regulate cell growth and division, preventing the formation of tumours. When these genes are mutated or inactivated, cells can grow uncontrollably, leading to cancer.

Key Concepts

• Functions of Tumour Suppressor Genes:
  • Regulate cell cycle progression.
  • Repair DNA damage.
  • Induce apoptosis (programmed cell death).
  • Maintain genomic stability.
• Mechanisms of Action:
  • Gatekeepers: Directly regulate cell cycle checkpoints and apoptosis (e.g., p53).
  • Caretakers: Maintain genomic integrity by repairing DNA damage (e.g., BRCA1, BRCA2).

Key Tumour Suppressor Genes

• p53:
  • Known as the "guardian of the genome."
  • Activates DNA repair proteins when DNA has sustained damage.
  • Can initiate apoptosis if the DNA damage is irreparable.
  • Mutations in p53 are found in approximately 50% of all cancers.
• RB (Retinoblastoma Protein):
  • Regulates the cell cycle by controlling the G1/S transition.
  • Prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide.
  • Mutations in RB are associated with retinoblastoma and other cancers.
• BRCA1 and BRCA2:
  • Involved in DNA repair through homologous recombination.
  • Mutations in these genes increase the risk of breast, ovarian, and other cancers.
• PTEN (Phosphatase and Tensin Homolog):
  • Regulates cell growth by inhibiting the PI3K/AKT signaling pathway.
  • Mutations in PTEN are associated with a variety of cancers, including breast, prostate, and endometrial cancers.
• APC (Adenomatous Polyposis Coli):
  • Involved in the Wnt signaling pathway, which controls cell growth and differentiation.
  • Mutations in APC are associated with familial adenomatous polyposis (FAP) and colorectal cancer.

Mechanisms of Inactivation

• Mutations:
  • Point mutations, insertions, deletions that result in loss of function.
• Epigenetic Modifications:
  • DNA methylation and histone modifications that silence gene expression.
• Loss of Heterozygosity (LOH):
  • Loss of the normal, functioning allele in a cell that already has one mutated allele.

Clinical Relevance

• Cancer Diagnosis:
  • Genetic testing for mutations in tumour suppressor genes can help diagnose hereditary cancer syndromes (e.g., BRCA1/2 for breast and ovarian cancer).
• Cancer Prognosis:
  • The status of tumour suppressor genes can influence the prognosis of certain cancers (e.g., p53 mutations often indicate a poor prognosis).
• Targeted Therapy:
  • Understanding the pathways involving tumour suppressor genes can lead to the development of targeted therapies (e.g., PARP inhibitors for BRCA-mutated cancers).

Examples of Cancer Syndromes Involving Tumour Suppressor Genes

• Li-Fraumeni Syndrome:
  • Caused by inherited mutations in the p53 gene.
  • Characterized by a high risk of various cancers, including sarcomas, breast cancer, brain tumours, and adrenocortical carcinoma.
• Retinoblastoma:
  • Caused by mutations in the RB gene.
  • Leads to the development of retinal tumours in children.
• Familial Adenomatous Polyposis (FAP):
  • Caused by mutations in the APC gene.
  • Characterized by the development of numerous polyps in the colon and rectum, with a high risk of progressing to colorectal cancer.
• Cowden Syndrome:
  • Caused by mutations in the PTEN gene.
  • Characterized by multiple noncancerous, tumour-like growths and an increased risk of several types of cancer, including breast, thyroid, and endometrial cancer.

Summary

Tumour suppressor genes play a crucial role in regulating cell growth, maintaining genomic integrity, and preventing cancer. Mutations or inactivation of these genes can lead to uncontrolled cell proliferation and tumour development. Understanding the function and regulation of tumour suppressor genes is essential for diagnosing, prognosticating, and developing targeted therapies for cancer.