oncogenes and tumour suppressors Flashcards by Emily Southall

what are the hallmarks of cancer *

sustaining proliferative signalling

evading growth suppressors

activating invasion adn metastasis

enabling replicative immortality

inducing angiogenesis

resisting cell death

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what are the emerging hallmarks and enabling characteristics of cancer

emerging hallmakrs - deregulating cellular energetics (can depend on anaerobic resp), avoiding immune destruction

enabling characteristics - genome instability and mutation, tumour promoting inflamm (can alter propagation and cancer therapy)

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describe how the cycle fits in with cancer *

cycle checkpoints - growth arrests to ensure genetic fidelity

G1/S checkpoint - check DNA damage and if there is damage arrests the cell cycle and uses different repair genes eg RAD51 like proteins, BRCA1/2 - if cant repair cell goes into apoptosis

G2/M checkpoint - check for damaged DNA and check that all DNA has been adequately duplicated

specific proteins accumulate/are destroyed by the cycle - cyclins, cdks, cdk inhibitors

permanent activation of a cyclin can drive a cell through a checkpoint

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what are proto-onchogenes *

they code of essential proteins involved in maintenace of cell growth, division and differentiation

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how is a proto-oncogene related to an oncogene *

mutation converts a proto-oncogene to an oncogene - whose product no longer responds to control influences

eg upregulation of K-Ras seen in colorectal cancer - provides stimulus for unchecked, uncontrolled support of cancer clone

this can be through a single mutation

oncogenes can be aberrantly expressed, overexpressed or aberrantly active eg MYC RAS ERB SIS

overexpression - HER2 in breast cancer, this is a cell cycle receptor that drives the mutation (look to see how much is present to know if a patient would benefit from herceptin)

overall there is a change in the activation protein menaing that it cant be switched off - perhaps so off signal cant bind, or it doesnt respond to the offsignal

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describe oncogene activation *

normal proto-oncogene - driving, surveillance or stimulation, but controlled

mutation in the coding sequence = change in the binding domain of inhibitory protein so gene cant be switched off anymore eg by affecting phosphorylation sequence aberrently active protein
gene amplification - multiple gene copies all are expressed - overproduction of normal protein - eg HER2 in breast cancer and some gastrooesophageal cancers
chromosomal translocation (chimaeric genes) or insertional mutagenesis (viral infection) - strong enhancer increases normal protein levels to a point you can’t shut off, of genes that are not normally expressed well eg Butkitt’s lymphoma; or get fusion to activelaly transcribed gene overproduces protein or fusion protein in hyperactive

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describe the philidelphia chromosome *

present in some leukaemia

ABL is a strong promotor sequence

Bcr is an anti-apoptosis gene

when have ABL translocated on to bcr = strong anti-apoptosis signal

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describe proteins involved in signal transduction *

tyrosine kinase receptor - ehn activated they send signals through kinases

G-proteins stimulation triggers intracellular kinases

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what are proteins that are involved at different points in signal transduction in cancer *

EGFR mutations in lung cancer, met and neu at TK receptor - neu is acronym for HER1,2,3 receptor complexes

src, ret - pancreatic, breast and prostate cancer

myc, fos, jun at transcription level

G coupled protein receptors - ras, gip1,

ras raf pathway - raf and pim-1

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what is the problem targeting genes higher up in the signal transduction pathway *

things upstream in the system have a lot of effects further down

eg if you try to target EGFR it will have a lot of effects in differnet cancer

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effect of mutation in RAS *

mutant RAS fails to dephosphorylate GTP and so remains active

even when can dephosphorylate doesnt get switched off anyway

mutation present in non-small cell lung cancer and colorectal cancer

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consequence of RAS signalling *

produces all of the things necessary to be alive - for proliferation adn survival

therefore if cell is heavily mutated with cancer - but oncogene is switched on so can still do this pathway - means cancer will be able to survive

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SRC *

function - TK

mechanism in cancer - overexpression because of deletion at the c terminal

it is cytoplasmic

associated cancers - breast, colon, lung and haematological

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MYC *

mechanism in cancer - translocation

it is nuclear

imvolved in Burkitt’s lymphoma

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JUN *

overexpressed because of deletion

cytoplasmic

bladder cancer

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Ha-RAS *

G protein

point mutation

cytoplasmic

bladder cancer

Ki-RAS *

G protein

point mutation

cytoplasmic

colon/lung

what is the significance of mutations *

different in different cancers

ie drugs that work in RAS mutation for colorectal cancer dont work for lung cancer with same mutation and vice versa - therefore more is important than just the driving mutation

describe tumour suppressor genes *

typically proteins whose function is to regulate cellular proliferation and maintain cell integrity

eg RB (checkpoint at G1/S to make sure DNA repair has been done)

each cell has 2 copies of a tumour suppressor gene

mutation of deletion of 1 is USUALLY insufficinet to promote cancer

mutation/loss of both copies means loss of control

however, need to be aware of haploinsufficiency - some genes/circumstances mean 1 mutation is enough to cause cancer phenotype

describe knudson’s 2 hit hypothesis *

hereditory cancer - some people have 1 inherited mutation of tumpur suppressor genes - then when acquire one = cancer phenotype

sporadic cancer - need need mutations in 2 copies of same gene

therefore sporadic are rarer than corresponding hereditory

be aware haploisufficiency - some cancers only need 1 hit

describe features of inherited cancer suseptibility *

FH of related cancers

unusually early age of onset

bilateral tumours in paired organs

synchonous or successive tumours

tumours in different organ systems in the same individual - worry about a p53 mutation

mutation inherited through the germline eg BRCA mutation - to be screened have to have strong FH, or triple -ve breast cancer

multiple primaries of the same tumour

describe retinoblastoma *

one of the 1st conditions where we realised inherited predisposition

it is malignant cancer of developing retianl cells

sporadic disease usually occurs in 1 eye, hereditory can by unilateral/bilateral

due to mutation of RB1 tumour suppressor gene on chromosome 13q14

RB1 encodes a nuclear protein that is involved in regulation of the cell cycle - involved in cdk 4 and 6 - move cell from G1 to S phase

what are the functional classes of tumour suppressor genes *

regulate cell prolif

maitain cellular integrity

regulate cell growth

regulate the cell cycle

nuclear TF

DNA repair proteins

cell adhesion molecules

cell death regulatiors - regulate apoptosis

(they all suppress the neoplastic phenotype)

p53 *

tumour suppressor gene

cell cycle regulator

nuclear

associated with many cancers eg colon, breast, bladder lung - because it is ubiquitous means it is difficult to target

BRCA1 \*

tumour suppressor gene cell cycle regulator by atm, atr or RAD3 like protein - involved in single strand break repair - if you outcompete single strand break repair, BRCA1 can push DNA down double strand repair pathway by non-homologous end joining or homologous recombination repair nuclear breast ovarian prostate

PTEN \*

tumour suppressor gene involved in cowden syndrome tyrosine and lipid phosphtase cytoplasmic prostate and glioblastoma

APC \*

tumour suppressor gene function - cell signalling cytoplasmic colon cancer

p16^{-INK4A *}

tumour suppressor gene cell cycle regulator nuclear for colon and other cancers new drugs developed for ER positive, HER2 -ve, metastatic breast cancer - called cdk4/6 inhibitors eg abemocyclib - have possibility to work in p16 pts so given in trials to small cell ling cancer, colon cancer, mesothelioma

MLH1 \*

tumour suppressor gene mismatch repair genes nuclar colon gastric

what does it mean that tumour suppressor genes are embryonically lethal \*

if the mutations occured in embryo - the child wouldnt be born

describe the roles of p53 \*

it is a tumour suppressor gene things taht activate p53 - oxidative stress, NO, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction. oncogene activation, dna replication stress, double strand break, telomere erosion p53 is involved in regulation of p53 target genes and protein-protein interactions p53 target genes cause metabolic homeostsis, antioxident defence, dna repair, growth arrest, senescence, apoptosis - as go from mild and physiological stress to severe stress p53 partners with MDM2 (mitotic regulator) - regulates itself eg when high oxidative stress - p53 will upregulate itself

describe p53 in cancer \*

need to know if it is a driver or passenger mutation - as it is involved in a lot of systems can ofter be passenger mutation - therefore targetting it would not cure the cancer targetting p53 is impossible - we cnat effect all the differnet pathways and also effect healthy tissues if you have p53 mutation - poor prognosis - early and multimalignancies and get less common cancers eg sarcoma although it is a tumour suppressor gene - mutants of p53 act in a dominant manner - so mutation of a single copy is sufficient to get dysregulation of activity

describe cancer from APC mutation \*

APC is a tumour suppressor gene - is a driver in familial adenomatous polyposis coli (colorectal cancer) due to a deletion in chromosome 5q21 resulting in loss of APC gene apc gene is involved in cell adhesion in stroma of anchoring and not anchoring, and MAPK signalling suffers get multiple benign adenomatous polyps in the colon there is 90% risk of developing colorectal carcinoma

mechanism of APC \*

participates in the WNT signalling pathway it is a negative regulator of B-catenin B-catenin has a role in division and adhesion therefore APC prevents uncontrolled cell division mutation of APC is frequent in colon cancer - allows dysregulation of cell division and cell architecture and anchoring role

summarise the route to cancer \*

when have mutation in proto-oncogene - create environment for cancer, but the tumour suppressor gene buts a break on this when have mutation in tumour suppressor but proto-onco is fine - not a cancer prone environment but removed the breaks if have oncogene and mutation of tumour suppressor - leads to cell growth and proliferation = cancer

describe the development of colorectal cancer \*

have normal epi mutation in APC (tumour suppressor) = hyperproliferation of epithelium = proliferation is faster so have more risk of a point mutation K-Ras (oncogene) mutation and DNA hypomethylation leads to adenoma p53 mutation is a passenger mutation but causes carcinoma carcinoma can metastasis the path goes from hyperplasia to metaplasia to dysplasia to carcinogenesis

summarise oncogenes \*

gene active in tumour specific translocations/point mutations mutations rarely hereditory dominant at cell level broad tissue specificity found in leukaemia and lymphoma

summarise tumour suppressor genes \*

gene inactive in tumour deletions or mutations mutations can be inherited recessive at cell level considerable tumpur specificity solid tumours

describe COSMIC

catalogue of somatic mutations in cancer give location and therefore meaning of a mutation - allow us to determine whether a tumour will respond to treatment this is important for precision medicine