cancer

oncogenes

EGFR, PI3K, HER2

tumour suppressor genes

p53, PTEN, Rb

smoking?

• contains bulky adducts (polycyclic aromatic hydrocarbons)

  • increasses mutation in p53 tumour suppressor gene

colon cancer

mutation in APC tumour suppressor gene → DNA hypomethylation → increased expression of K-ras oncogene → adenoma

if p53 and 18q tumour suppressor genes are also shot → carcinoma

familial adenomatous polyposis is also due to APC

gastric cancer

mutation in CHD1 gene which codes for E-cadherin

process of neoplastic transformation

normal → mutated oncogene → mutated TMS → immortalisation → genetic instability (increased mutation diversity) → evades apoptosis -> evades IMS → cancer

what causes death in cancer

1. paraneoplastic syndrome

2. pressure of tumour on other organs

3. breaching of infection barriers

4. infiltration into vital organs

clonal haematopoiesis of indeterminate potential

mutation of haematopoietic stem cells causing clonal expansion of a single clone of blood cells

• doesn’t cause blood abnormalities

• increases risk of CVD and other blood cancers as it increases pro-inflammatory IM cells release of inflammatory cytokines → macrophage foam cells

most commonly caused by JAK2V617F mutations which also causes increased NETosis

T cell leukaemia and lymphoma

caused by mutation in proto-oncogene TLC1A

• impaired production of normal haematopoietic stem cells → clonal expansion of immature haematopoietic stem cells

acute pro-myelocytic leukaemia

chromosome 15 and 17 translocation fusion protein

1. stem cells are arrested in the pro-myelocytic stage (precursor of white blood cells)

2. cells are large and contain loads of coagulation granules

3. causes pancytopenia and abnormal clotting

myeloma

cancer affecting a single type of plasma cell causing expansion and accumulation

1. cells produce large amounts of paraprotein

2. begins as monoclonal gammopathy of undetermined significance → progresses to smouldering myeloma (60% or more clonal plasma cells)

lymphomas

1. hodgkin lymphoma contain reed sternberg cells

2. non-hodgkin’s lymphoma: doesnt contain reed sternberg cells

chronic myeloid leukaemia

caused by philadelphia chromosome

1. translocation between chromosome 9 and 22 → BRC:ABL fusion gene

2. activates tyrosine kinase to drive proliferation

causes:

• increased mature WBC

• progresses to blast phase mimicking acute myeloid or acute lymphoblastic leukaemia

macrophages

in cancer:

1. cells express CD47 → binds to SIRP alpha on macrophages → prevents phagocytosis

dendritic cells

cDC1 → able to present exogenous antigens on MHC1 → activates CD8 t cell via cross presentation

1. controlled by WDFY4 gene

cDC2 can only present exogenous antigens on MHCII → activates CD4 T cells

T cells

CD8 → kills using perforin and granzymes

CD4 → helps activity of other IM cells

1. TH1 → macrophage and B cell activation

2. TH2 → reacts to helminth and parasitic infections

3. TH17 → responds to commensal bacteria

4. TFh → germinal center B cell affinity maturation

5. Treg → express IL-2 receptors taking up IL-2 causing T cells to undergo anergy

T cell activation

requires 3 signals otherwise results in anergy

1. MHC binds to TCR and corresponding CD4 or 8

2. CD80/86 on APC binds to CD28 on T cells

3. release of inflammatory cytokines

T cell checkpoints

1. CTLA-4 is stored in vesicles that fuse with membrane

2. has higher affinity for CD80/86 than CD28 → displaces it causing inactivation

PDL1 and 2 binding to PD1 on T cells

1. inhibits the release of granzymes

Tregs contain high amounts of IL2R acting as a sink for IL2

immune mediation of cancer

1. elimination phase: IMS destroys tumour but it is incomplete

2. equilibrium phase: tumour resists IMS attack

3. escape phase: tumour evades IMS and proliferates unchecked

angiogenic switch

stimulators: VEGF-A, PDGF, FGF

inhibitors: angiostatin, endostatin, thrombospondin

how does hypoxia cause angiogenesis

1. allows hypoxia inducible factor 1 alpha to escape degradation and dimerise with HIF1-B

2. acts on hypoxia response elements to increase angiogenesis

bladder cancer

H-Ras oncogene mutation

N-myc gene amplification → oncogene

mechanisms of TSG loss

1. mitotic recombination → when sister chromatids are seperated 2 copies of mutated TSG can be placed in 1 cell

2. gene conversion → DNA polymerase jumps from 1 template strand to another → “other” strand has mutated TSG → loss of functional gene

3. chromosomal non-disjunction → 1 daughter cell retains both copies of mutated TSG, the extra functional chromosome can be shed

what is the name of metabolic change in cancer

warburg effect

1. cell undergo glycolysis instead of oxidative phosphorylation in the mitochondria → build up of lactic acid in the cytplasm

retinoblastoma

Hereditary retinoblastoma →mutation is found in all cells → resection is not curative

non-hereditary retinoblastoma → mutation is only in the eye → resection is currative

1. Rb gene is a check point protein between G1 → S, prevents excessive cell proliferation

2. p53 checkpoint protein between G1 → S, activates DNA repair mechanisms