L9 oncogenes and tumour suppressor genes Flashcards
normal cells
socially responsible for the survival of the whole organism
divide, move, differentiate and die when appropriate
cancer cells
selfish
accumulate mutations, divide uncontrollably and move throughout the body at the expense of neighbouring cells and the whole organism
cancer is caused by genetic (or epigenetic changes)
caused by genetic changes that affect gene expression/function
genetic changes caused by:
- mutations
- chromosomal abnormalities
- introduction of genes by viruses
Categories of cancer
see onenote
- carcinoma
- sarcoma
- melanoma
- leukemia
- lymphoma
- retinoblastoma, glioblastoma, medulloblastoma, neuroblastoma
cancer
disease featuring abnormal and improperly controlled cell division resulting in invasive growths, tumours that may spread throughout the body
strongly related to age
long exposure to mutagens increases incidence
benign vs malignant tumours
benign
- non cancerous
- generally stop growing, do not spread to other parts of the body and do not create new tumours
malignant
- cancerous
- can invade healthy tissues, interfere with body functions, can draw in blood vessels to get nutrients and oxygen for more growth
- can spread to other parts of the body and create new tumours
Hallmarks of cancer
- sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative immortality
- inducing angiogensis
- resisting cell death
Tumorigenesis
- resisting cell death
- sustaining proliferative signalling
- evading growth suppressors
Metastasis
the spread of cancer cells from one site in the body to another site
Tubes throughout your body, if tumour can get into transport system, can get throughout your body
- inducing angiogenesis
- activating invasion and metastasis
Tumour development
see onenote diagram
cancer occurs by cells acquiring multiple mutations over a long period of time that gradually transform them into cancer cells
Tumorigenesis is a balance between proliferation and cell death
increase proliferation/decrease apoptosis => tumour
apoptosis: programmed cell death
cell proliferation: increase in cell number by division
senescence: cell which is still alive but not actively dividing, in a state of arrest which is normally irreversible
Oncogene
see onenote
a gene that, when mutated/expressed at high levels helps turn a normal cell into a cancer cell (transformation)
normal form - proto-oncogene, involves in cel proliferation, growth, invasiveness e.g. Ras, PI3K, twist
Tumour suppressor gene
see onenote
a gene that acts to prevent a normal cell from turning into a cancer cell
- limit cell proliferation, promoting cell death, preventing metastasis
- knudson two hit theory
- anti-oncogenes
- p53, pten, Rb
Normal cellular roles of proto-oncogenes and tumour suppressor genes
see onenote
oncogenes vs tumour suppressor genes
see onenote
Possible ways by which proto-oncogenes can be activated
see onenote
Knudson “two hit” model for the inactivation of tumour suppressor genes
see onenote slides
Knudson “two-hit” model
- One copy knocked down, wait for the other copy to be knocked out => loss of function
- Loss of first copy could be random or inherited
Loss of second copy - loss of heterozygosity
Inactivation of tumour suppressor genes can involve both genetic/epigenetic changes
see onenote
sequencing of many cancers reveal different pattern of mutations in oncogenes vs TSGs
see onenote
Can tell if its oncogene or tumour suppressor from looking at amount and spread of mutations
TSGs most mutations are truncating
oncogenes mutations found repeatedly at key aa positions, truncating mutations are rare
Burkitt’s lymphoma
see onenote slides
aggressive cancer of the lymphatic system involving over proliferation of B lymphocytes
protooncogenic translocation to a region of high transcriptional activity
- reciprocal translocation between chromosome 8 and 14
- Myc protooncogene gets put next to powerful enhancer => expressed at high level, drive cell growth and proliferation pathway at high levels
Increased myc expression causes cell proliferation
see onenote
Myc is a TF, promotes cell growth and proliferation by controlling expression of target genes in response to many signalling pathways
excessive myc => hyper-proliferation of lymphocytes
Chronic myeloid leukaemia (CML)
cancer in which the bone produces too many granulocytes (a type of white blood cell)
- reduced number of healthy white blood cells, RBC and platelets
- leads to increased infection, anaemia and easy bleeding
Possible ways proto-oncogene can be activated - gene fusion event creating an altered function protein
see onenote
CML caused by reciprocal chromosomal translocation
see onenote
reciprocal translation between chromosomes 9 and 22
- results in philadelphia chromosome and a fusion between c-abl gene which encodes kinase and Bcr genes => increases kinase activity
Bcr-Abl oncogene is constitutively active
see onenote
constitutively active kinase => misregulation of cellular signalling pathway that it mediates
Retinoblastoma (Rb)
regulates the cell cycle
rare childhood tumour which develops from neural progenitor cells in the immature retina
Rb protein inhibits the cell cycle
see onenote slides
Without Rb, E2F is costanlty turned on
p53
see onenote
tumour suppressor, “guardian of the genome”
homozygous loss of p53 found in many carcinomas
Almost every cancer has lost p53 function
P53 turns on most anti-cancer mechanisms
Li-Fraumeni syndrome (LFS)
cancer predisposition syndrome where the molecular basis is a loss of function germline mutation in the p53 gene
inheriting 1 faulty copy of p53 increases risk of cancer and lowers median age at diagnosis
