ON2 Cancer pathogenesis

Oncogenesis is the mechanism by which a tumor arises, involving DNA [blank_start]mutation[blank_end]. If the DNA is not repaired, the cell will continue to [blank_start]divide[blank_end] 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 [blank_start]multiple[blank_end] mutations • Number of mutations varies – impacts on [blank_start]immunogenicity & prognosis[blank_end] • These should generally be picked up at the [blank_start]check[blank_end] points, and the DNA repaired, unless the checkpoint itself is mutated (‘[blank_start]driver[blank_end]’ mutation)…

Which of these is not an origin of mutations?

DNA replication • normal DNA replication introduces 1 mutation /10^7 nucleotides • most mutations still [blank_start]won’t[blank_end] cause cancer, however there are some [blank_start]key[blank_end] gene families in which a mutation can lead to oncogenesis: - tumor suppressor genes([blank_start]inactive[blank_end] in cancer): [blank_start]growth[blank_end] factors & growth regulators, repair & [blank_start]apoptosis[blank_end] genes, contact inhibition genes - activator genes (oncogenes & proto-oncogenes, [blank_start]active[blank_end] in cancer): angiogenic genes – eg [blank_start]vascular endothelial[blank_end] growth factor (VEGF), genes which allow metastasis and escape from [blank_start]immune[blank_end] surveillance

Inherited mutations • some forms of cancer have a higher occurrence in some families • they have inherited either: - defective [blank_start]tumor suppressor[blank_end] genes - activated [blank_start]oncogenes[blank_end] BRCA is a tumor [blank_start]suppressor[blank_end] gene involved in repairing DNA [blank_start]damage[blank_end]. BRCA1/2 mutation results is a 56–84% lifetime risk of developing [blank_start]breast[blank_end] cancer and an 36–63% risk for [blank_start]ovarian[blank_end] cancer.

Environmental Insult: • Chemical = carcinogens. Either [blank_start]directly[blank_end] damage DNA or their [blank_start]metabolites[blank_end] damage DNA. Types of damage are strand [blank_start]breakage[blank_end], gene [blank_start]truncation[blank_end], nucleotide deletions & substitutions. Most common chemically induced cancer - lung cancer ([blank_start]30[blank_end]% of all cancer deaths). • Physical = radiation – variable toxicity. Non-ionizing: • UV, microwaves. • UV causes [blank_start]melanoma[blank_end] Ionizing: • X-rays, g-rays, atomic bombs, nuclear reactors • [blank_start]Spontaneous[blank_end] tumor development (thyroid, breast, bone marrow)

Human Papillomavirus Viruses (HPV) is an infectious agent that can cause cancer. HPV is isolated from > 90% of [blank_start]cervical[blank_end] tumors. HPV also causes [blank_start]anogenital and oropharnygeal[blank_end] carcinoma. High risk’ cancer-causing types: - HPV-[blank_start]16[blank_end] (55% of tumors) - HPV-18 (15%) - HPV-45 (10%)

The immune system has pro-tumor effects - chronic inflammation has been associated with oncogenesis, and anti-tumor effects - immune system can kill cancer cells.

CD8 T cells must be activated by a professional [blank_start]antigen presenting cell[blank_end] (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 [blank_start]necrosis[blank_end] and/or cell [blank_start]stress[blank_end] to activate the APC. The [blank_start]cytotoxic[blank_end] immune response should kill tumours but tumors are [blank_start]self[blank_end] tissues. CD8 T cells are not allowed to destroy cells expressing self [blank_start]antigens[blank_end]. The solution is an immune response directed against: [blank_start]mutated[blank_end] antigens (new proteins in genetically unstable cells), viral proteins, or [blank_start]inappropriately expressed[blank_end] antigens.

Which of these is NOT an immune evasion strategy used by tumours?

Tumor is immunosuppressive. • Tumour expresses [blank_start]T cell apoptosis[blank_end] molecules eg Fas L • Tumour secretes anti-inflammatory or suppressive molecules eg TGFb, [blank_start]IL-10, PGE-2[blank_end]