BG7

Question 1

Cancer adaptations

Answer 1

1. self-sufficiency of growth mechanism: most cells grow when stimulated by growth signals.
   - HRAS mutations allow indep. growth.
2. antigrowth signals; some mutations prevent antigrowth working
   - Rb mutations
3. PCD; cancers evade by produce IGF survival factors
4. hayflick limit; remove by switching on telomerase
5. angiogenic factors VEGF inducer: tumours get larger requrie bloood vessels
6. metastasis: late stage cancer invade surrounding tissues
   - E- cadherins mutations

Question 2

NS in cancer

Answer 2

mutation arises increases proliferation - advantage

mutation arises allowing to break free of environment and spread = selected for

Question 3

cancer phylogenies

Answer 3

can reconstruct e.g. breast cancer cell phylogeny shows all cancer cells are descended from a CA and belong to sub-clones with particular genotypes.

Question 4

ancestral to metazoa?

Answer 4

appear in mollusca, arthopoda, vertebrata etc

Question 5

failure of host adaptation to novel envrionment

Answer 5

1. carcinogenes UV toxins etc
   - growth mechanisms of animals not adapted to them
2. aging: no selection to maintain soma.
   - cancer is special case of aging

Question 6

james graham

Answer 6

aruged cancer was result of new cellular conditions arising in evolution and failure of adaptation
analogy: change product in factory = product decline, takes a while to fix the kinks
argued snail shells werent anti-predation but anti-cancer

• armand revived the theory

Question 7

examples backing JG hypothesis

Answer 7

would expect more cancer in organisms with more rapid morphology changes

1. large dogs = more likely to get sarcomas, likelyhood increases up to 40kg then plateus. = anti cancer mech yet to evolve?
2. ovarian cancer in hens selected to produce more eggs
   - hair follicle ovarian cancer - failure of anti-cancer mech to catch up in short length of time`

Question 8

rapid evo in nature?

Answer 8

pediactic cancers are rare
increased risk of osteosarcoma in children tall for their age, occurs at puberty. suggests analagous to dogs. due to pubertal growth spurt
osteosarcoma due to rapid evo of growth rate, anti cancers havent had time to catch up and suppress extra proliferation

Question 9

growth rate in humans compared

Answer 9

macaques dont have pubertal growth spert

paleontologists suggest homo eretus didnt have a grow spurt

Question 10

cancers found mostly in adults

Answer 10

= colon, lung, prostate, endothelial

- almost non existant in children

Question 11

cancers common in children

Answer 11

`1. nervous system tumours - in brain, which has gone fast evo, 3x bigger than apes
2. childhood leukaemia: immune systems have been undergoing continued rapid evo in response to pathogens

Question 12

arguument for prevelance of childhood cancers

Answer 12

child cancers arent the consequence of exposure or old age, but result of evo changes in morphology as tissue hasnt evolved anti-cancer devices yet
e.g. gut tissue proliferates as much in children as adults but dont see gut or skin cancer in children, sorted out kinks as older in evo time?

Question 13

animal diversity in body size

Answer 13

differ enormously
mammals = 0.02kg dog =20kg
human = 75kg whale = 150,000 kg
cell size is similar so cell no. must be greater. 
6/7 magnitudes between mouse and whale

Question 14

neoplasia and body size

Answer 14

if risk of neoplasia is constant would expect bigger animals to have more cancers than smaller
all whales should get cancer.

Question 15

Peto’s paradox

Answer 15

risk of cancer seems constant despite body size changes
wild mice = 46% death by cancer
dogs = 46% death by cancer (US)
humans = 22% death by cancer

Question 16

nunny theory of cancer resistance

Answer 16

M = expected no. of mutations as function of cell no (c).
M = 4(c-1)u
M = 4cu-4u (4neU)

• if cell no. or somatic mutation rate increases, expect no. of mutations to increase

Question 17

proportion of indviduals lacking a mutation

Answer 17

P = e^(-4u(c-1))

P decreases with no. of cells.

Question 18

P = e^(-4u(c-1))

Answer 18

animal few cells proportion that lack mutation (p) = 1

animal 1 mill cells p = 0 (everyone has a mutation)

Question 19

selection differential and cancer

Answer 19

if animal has cancer causing muttion which is lethal can estimate selection differential acting against cancer causing mutations
S = 1-P, S = 1-e ^-4u(c-1) 
c = 1000 (c. elegans)
u = 10^5 (know from data)
selection differential = 0.04

Question 20

what is required for selection to be effective

Answer 20

S > 1/N
S = 0.04
N = 100
1./ 100 = 0.01
even in small population size of 100 cells there will be selection for cancer resistance
** no. of TS genes increase in evo as animals increase in body size = constant rate of cancer

Question 21

Tumour suppressor genes

Answer 21

defined as genes in which mutants causing lack of function cause cancer
homo/hetero = responsible for most ases of inherited cancer

Question 22

inherited cancer example TS

Answer 22

1. mouse gets mutation and loses one copy TS in germline = gametes defective breeding produce hetero
   mouse protected by single copy, another somatic mutation = gets no protein = neoplastic

Question 23

commonly mutation TS leading to cancer

Answer 23

NFI - neurofibromatosis
BRCA1 - breast cancer
Rb - retinoblastoma eye
P53 - many cancer

Question 24

solution to peters paradox

Answer 24

evolution of TS
- to get cancer need multiple losses of TS genes
- some cancers caused by mutations in single gene Rb, but others requrie sereis of mutations in multiple genes. - e.g. colon cancer
colon cancer need to have many mutations in many genes - suggest big animal have evolved more TS genes

Question 25

tumour resistance due to TS

Answer 25

multiplicative - probability of getting new mutation in any one copy of TS = P probablility og getting two mutations [ p^2 more TS = more resitance

Question 26

TS and body size

Answer 26

gaining one extra TS protects for a considerably larger body size until size increases again and need more.

Question 27

cancer evolution and suppression fish

Answer 27

mexican fish X. maculatus: platy = has spots for camoflage against cichlid predator X. helleri = sword tail - can hybridise to produce fertile F1 and F2

Question 28

X. maculatus and X hellari cross phenotypes

Answer 28

F1 = intermediate F2 = diversity of phenotypes - some no spots, some some, some huge ones that develop cancer ** spots caused by melanocytes which have tendancy to cause tumours

Question 29

X. maculatus and X. hellari cross genotypes causing cancer

Answer 29

interaction between two loci cause cancer Tu-m = causes spots, cancer in hellari Tu h = doesnt priduce spots or cancer Diff -m = suppreses spots and cancer Diff h = doesnt suppress cancer or spot === epistatic interaction, so F2 with tum and diffh get cancer = dissociated alleless

Question 30

selection in x. maculatus

Answer 30

if hellari genotypes are ancestral then maculatus has been under selection for cancer suppression due to spots. dynamic begins leading to larger spots, greater suppression

Question 31

homology of tu and diff

Answer 31

``` tu = homologous to EGF-1 = mammalian oncogene diff = homologous to CD2 = mamamlaian TS ```

Question 32

why do large long lived animals not have a n increase risk of cancer relative to small?

Answer 32

cancer resistance mechs 1. reduced rate of somatic mutation 2. increased no. of selective barriers to mutations = TS 3. reduced selective advantage of mutation

Question 33

do large animals have relatively reduced rate of somatic mutation

Answer 33

``` humans = 5x10^11 bp/division mice = 1.8x10-10 humans = slower mutation rate. ```

Question 34

what could mutation rate be related to

Answer 34

basal metabolic rate - if mutations are caused by free radicals which are product of metabolism, a higher metabolic rate would produce more mutations. although large animals have lower metabolic rate relative to body size BMR increases with body size across species linear

Question 35

reduced rate of oncogenic mutation

Answer 35

selection works on reducing oncogene mutation specifically? e.g. via oncogene deletion. - little evidence, if oncogene missing could be sequence error, plus they are important ** teleomerase activity decrease relative to body size, humans little activity = tightly controlled potenitally to reduce risk of upreg that causes cancer

Question 36

increasing no of TS

Answer 36

in mice extra copies of p53 = tumour free for longer than WT, increased longevity probs a cost to this

Question 37

deep evo of TS

Answer 37

phylogeny of TS - no. of tumour suppressors spikes around origin o metazoa dont seem to increase in more elaborate body plans most TS seem to be ancient

Question 38

elephant TS

Answer 38

``` 19 copies of p53 hyrax = only 1 evidence that elephant cells undergo PCD more readily than humans perhaps due to DNA damage, more copies of p53 high expression in cells harder to make elephant cells neoplastic - requires more p53 KOs ```

Question 39

naked mole rat

Answer 39

eusocial, burrowing, live for up to 35 years cancers never seen

Question 40

naked mole rat and cancer

Answer 40

skin fibroblast produced hyluronan - composed of repeated disacchariddes of glucoronic acid and acetyl glucosamines - - molecule also confers cancer resistance by altering contanct inhibition of cells. if take cells and inhibit p53 and rb dont become neoplastic Ko hyluronan by overepxression of breakdown enzyme they do.