lecture 36 Flashcards
what is leukocoria
white reflex in pupil
sign something is blocking blood vessel in eye = like retinoblastoma
what is retinoblastoma
rare childhood cancer of eye
affects 1/15000
describe pedigree analysis of retinoblastoma
shows that 40% of cases involved an inherited - familial - mutation - predisposes them
describe type of retinoblastoma
may be unilateral = affects one eye
or bilateral = affects both eyes
what is two hit hypothesis
1971
alfred knudson
observed difference in kinetics of retinoblastoma development between uni and bilateral cases
describe 2 hit hypothesis
bilateral = 1st order kinetic = most are familial
unilateral = slower, most are sporadic, 2nd order kinetics = depends on independent events
describe knudsons hypothesis - what he propose
Proposed that retinoblastoma results from 2 separate genetic defects - mutations = 2 hit s
describe sporadic cases of retinoblastoma
sporadic
1/10^6 x 1/10^6 = probability of 2 events
rare that 2 somatic mutations in single cell
2 hits must happen to single cell = event is rare and takes longer to develop
2nd order kinetics
describe inherited cases of retinoblastoma
bilateral
born with first hit - in multiple cells= have more than one tumour cancers
cells must undergo single somatic mutation
single mutation can produce cancer
rate of one hit happening - higher chance and it could happen to more than one cell
consistent with idea of having recessive mutations in both alleles of single gene
describe conformation of 2 hit hypothesis
chromosomal abnormality frequently found in retinoblastoma
= ban missing on chrom 13, usually deleted
1986 = the rb1 gene clone and discovery of first tsg, 4.7kb segment deleted in rb
are mutant alleles recessive
yes
both alleles must be mutated
since haplosufficient
or mutation in one and deletion in other
how are tsgs inherited - pedigree of familial adenomatous polyposis (apc)
often as dominant trait
even tho recessive
1/2 progeny affected
bc chance of getting 2 hits quite high
chance of getting 2nd mutation in somatic cell is high = in theory, single cell getting 2nd mutation = enough to cause cancer
not all carriers will develop cancer * penetrance
describe cell cycle checkpoint
rb
important fot g1/2 checkpoint
prevents entering s phase if not ready
describe rb and cell cycle
rb protein binds e2f and keeps it inactive = prevents transcription
increasing concentrations of cyclin d-cdk and e-cdk = phosphorylate rb and inactives it
so then e2f now can bind to dna and stimulate transcription
what are oncogenes - for rb
cyclin d-cdk
cyclin e-cdk
if hyperactive = inactivates rb = BAAAADDD
describe p53
guardian of genome
kinases activate p53 if cell damage
p53 = tf
helps promote transient cell cycle arrest, senescence and apoptosis = instead of becoming cancer
describe p53 mutation
inherited in li fraumeni syndrome
inherited in more than 50% of all human tumours
p53 protein = transcription activation domain, dna binding domain, oligomerization domain
many mutations in dna binding domain = unable to bind dna but still can form tetramer
how do many p53 mutant alleles in cancer function
dominant negative
p53 = tf that binds dna as homotetramer
if one mutation = still oligomerizes but inactivates wild type so one mutated allele enough to affect other
describe hpv
associated with cervical cancer
95% of cervical cancer patients are infected with hpv
dna tumour virus
descrive viral oncoproteins from dna tumour virus
viral oncoproteins from dna tumour virus bind and inactivate p53 and rb— virus genome composed of dna so wants no rb so can replicate so e2f activate and makes genes needed for dna synthesis and cell cycle increases
caused by dna = infects cells and inactivates tsgs - sv40, adenovirus, hpv
describe clonal evolution of cancer cells
get multiple mutations
single cell acquiring mutation that provides proliferative advantage gives rise to clones of mutated cells
single cell from clones may acquire secondary mutation = provides additional proliferative advantage
Eventually = cycle of acquiring mutations and clonal expression gives rise to fully transformed cancer cells
single cells –> clones –> these acquire mutations
malignant cell = will have all mutations developed
describe colon cancer development
defined genetic changes
apc gene = familial adenomatous polyposis
loss of normal apc (first hit = born with) =
1- polyp forms on colon wall
2- benign precancerous tumour grows
activation of oncogene ras
3- adenoma (benign tumour) grows
loss of tsg p53
4 - carcinoma (malignant tumour) develops
other changes - loss of antimetastasis gene
5 - cancer metastasizes = spreads to other tissues through blood stream
what is cancer
multi step process
involves many genetic alterations
not always in same order
describe pd1 activation by tumour cells
tumour leads to increased expression for ligand pore = inhibit cells cytotoxic activity so wont kill
solution = produce antibody for pd1 = now tumour wont bind
