lecture 36

Question 1

what is leukocoria

Answer 1

white reflex in pupil
sign something is blocking blood vessel in eye = like retinoblastoma

Question 2

what is retinoblastoma

Answer 2

rare childhood cancer of eye
affects 1/15000

Question 3

describe pedigree analysis of retinoblastoma

Answer 3

shows that 40% of cases involved an inherited - familial - mutation - predisposes them

Question 4

describe type of retinoblastoma

Answer 4

may be unilateral = affects one eye
or bilateral = affects both eyes

Question 5

what is two hit hypothesis

Answer 5

1971
alfred knudson
observed difference in kinetics of retinoblastoma development between uni and bilateral cases

Question 6

describe 2 hit hypothesis

Answer 6

bilateral = 1st order kinetic = most are familial
unilateral = slower, most are sporadic, 2nd order kinetics = depends on independent events

Question 7

describe knudsons hypothesis - what he propose

Answer 7

Proposed that retinoblastoma results from 2 separate genetic defects - mutations = 2 hit s

Question 8

describe sporadic cases of retinoblastoma

Answer 8

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

Question 9

describe inherited cases of retinoblastoma

Answer 9

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

Question 10

describe conformation of 2 hit hypothesis

Answer 10

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

Question 11

are mutant alleles recessive

Answer 11

yes
both alleles must be mutated
since haplosufficient
or mutation in one and deletion in other

Question 12

how are tsgs inherited - pedigree of familial adenomatous polyposis (apc)

Answer 12

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

Question 13

describe cell cycle checkpoint

Answer 13

rb
important fot g1/2 checkpoint
prevents entering s phase if not ready

Question 14

describe rb and cell cycle

Answer 14

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

Question 15

what are oncogenes - for rb

Answer 15

cyclin d-cdk
cyclin e-cdk
if hyperactive = inactivates rb = BAAAADDD

Question 16

describe p53

Answer 16

guardian of genome
kinases activate p53 if cell damage
p53 = tf
helps promote transient cell cycle arrest, senescence and apoptosis = instead of becoming cancer

Question 17

describe p53 mutation

Answer 17

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

Question 18

how do many p53 mutant alleles in cancer function

Answer 18

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

Question 19

describe hpv

Answer 19

associated with cervical cancer
95% of cervical cancer patients are infected with hpv
dna tumour virus

Question 20

descrive viral oncoproteins from dna tumour virus

Answer 20

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

Question 21

describe clonal evolution of cancer cells

Answer 21

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

Question 22

describe colon cancer development

Answer 22

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

Question 23

what is cancer

Answer 23

multi step process
involves many genetic alterations
not always in same order

Question 24

describe pd1 activation by tumour cells

Answer 24

tumour leads to increased expression for ligand pore = inhibit cells cytotoxic activity so wont kill
solution = produce antibody for pd1 = now tumour wont bind

Question 25

describe patient treated with ctla-4 and pd-1 antibodies

Answer 25

before = tumours
then 4 weeks after treatment = tumours gone down in size
prevents cancer from tricking immune system = so immune system can just kill cancer cells itself

Question 26

describe role of environmental factors in cancer

Answer 26

increases chances of getting cancer
like tabacco

Question 27

describe role of environmental factors in cancer- specific ex

Answer 27

expected deaths from lung cancer = decreased - not as high as expected = bc this is when ppl realized smoking is bad and
also US band on in flight smoking began with domestic flights of 2 or less hours in april 1988
all planes became smoke free by end of the 1990s