ON2 Cancer pathogenesis

Oncogenesis is the mechanism by which a tumor arises, involving DNA ❌. If the DNA is not repaired, the cell will
continue to ❌ and 'fix' the mutation in place. Successive mutations can build up until the cell division is no longer regulated.

Oncogenesis:
• 1 mutation is not enough, need ❌ mutations
• Number of mutations varies – impacts on ❌
• These should generally be picked up at the ❌ points, and the DNA repaired, unless the checkpoint itself is mutated (‘❌’ mutation)…

DNA replication
• normal DNA replication introduces 1 mutation /10^7 nucleotides
• most mutations still ❌ cause cancer, however there are some ❌ gene families in which a mutation can lead to oncogenesis:
- tumor suppressor genes(❌ in cancer): ❌ factors & growth regulators, repair & ❌ genes, contact inhibition genes
- activator genes (oncogenes & proto-oncogenes, ❌ in cancer): angiogenic genes – eg ❌ growth factor (VEGF), genes which allow metastasis and escape from ❌ surveillance

Inherited mutations
• some forms of cancer have a higher occurrence in some families
• they have inherited either:
- defective ❌ genes
- activated ❌

BRCA is a tumor ❌ gene involved in repairing DNA ❌. BRCA1/2 mutation results is a 56–84% lifetime risk of developing ❌ cancer and an 36–63% risk for ❌ cancer.

Environmental Insult:
• Chemical = carcinogens. Either ❌ damage DNA or their ❌ damage DNA. Types of damage are strand ❌, gene ❌, nucleotide deletions & substitutions. Most common chemically induced cancer - lung cancer (❌% of all cancer deaths).
• Physical = radiation – variable toxicity.
Non-ionizing:
• UV, microwaves.
• UV causes ❌
Ionizing:
• X-rays, g-rays, atomic bombs, nuclear reactors
• ❌ tumor development (thyroid, breast, bone marrow)

Human Papillomavirus Viruses (HPV) is an infectious agent that can cause cancer. HPV is isolated from > 90% of ❌ tumors. HPV also causes ❌ carcinoma. High risk’ cancer-causing types:
- HPV-❌ (55% of tumors)
- HPV-18 (15%)
- HPV-45 (10%)

CD8 T cells must be activated by a professional ❌ (APC) to kill cancerous cells. The problem is we need to get activation of the APC, but there is no infection. Hopefully there is enough ❌ and/or cell ❌ to activate the APC.
The ❌ immune response should kill tumours but tumors are ❌ tissues. CD8 T cells are not allowed to destroy cells expressing self ❌. The solution is an immune response directed against: ❌ antigens (new proteins in genetically unstable cells), viral proteins, or ❌ antigens.

Tumor is immunosuppressive.
• Tumour expresses ❌ molecules eg Fas L
• Tumour secretes anti-inflammatory or suppressive molecules eg TGFb, ❌