Cancer bio 11/5: UV and skin cancer II

cause of red hair/fair skin/no tanning phenotype

mutations in MC1R

melanocytes shut down

golden zebrafish gene

SLC24A5

a cause of pale skin in europeans

what does SLC24A5 do

ion transporter in melanosomes

regulates pH

SLC24A5 alleles

Thr-111 → 100% europeans. fair skin, small size/number melanosomes

Ala-111 → 99% africans, ast asians. darker skin, large size/number

ancestral SLC24A5 allele

Ala-111

Thr-111 appeared ~12,000 years ago; end of ice age

skin pigmentation evolution

KIT-L (melanocyte growth factor) variants ~30,000 years ago

ancestral eurasians → lighter skin

EITHER:

• OCA2 (tyrosine transport) variants (His615Arg) → east asians

• SLC24A5 variant, SLC45A2 (OCA4; pH) variants, MC1R variants → northern europeans (~12,000 years ago)

melanoma incidence in US by race

even a little melanin offers protection

SIGNIFICANT decrease for all races besides white people

japan melanoma incidence compared to white americans

5%

MDM2 SNP

typically: negatively regulates p53

SNP309 is in promoter/enhancer sequence; 32% of US population has

WT: T at position 309, typical levels of MDM2, p53

SNP302: G at position 309, highly increased levels of MDM2 → decreased p53

leads to: decreased apoptosis/sunburns

MDM2-SNP309 sex difference

no difference in men, increased incidence of B cell lymphoma with SNP before age 60

MDM2-SNP309 cancer risks for women

soft tissue sarcoma

breast carcinoma

both become less pronounced of a difference at age 60

other cancers with increased risk for carriers of MDM2-SNP309

gastric carcinoma risk

lung cancer

elier colon cancer

other cancers with decreased survival for carreirs of MDM2-SNP309

oral and gastric carcinoma

soft tissue sarcome

renal carcinoma

B cell leukemia

lung cancer

pancreatic cancer

estrogen and SNP309

SNP309 causes higher affinity for Sp1

MDM2 transcription needs both Sp1 and estrogen receptor

young women have higher levels of estrogen

premenopausal women and melanoma

much higher risk, starts around puberty and levels out around age 60

what was the selection pressure for MDM2-SNP309

vitamin D metabolism

farther away from the equator → less access to sun → less UV → more efficient UV absorption process

disease from insufficient vitamin d

rickets

bowed legs

selection pressure for vitamin d

in addition to bowed legs, vit d deficiency caused malformed pelvis bones causing women and the child to die during childbirth → people reproducing are better able to metabolize vit d

prevention of vit d deficiency

cod liver oil

modern day sun, skin color, and vit d deficiency

black skin in northern countries have 10-50 times less vit d production

• ~40% african americans in canada/north US have low vit d

• african and asian immigrants to northern european countries have low vit d

dark skin double sided coin

protects against UV damage but less efficient at absorbing vit d

lifetime risk of skin cancer in australia

50%

socks in tanning bed?

soles are more susceptible to UV damage because there are no/few melanocytes on soles/palms

pomc

pro-opiomelanocortin

precursor of MSH

p53 role in tanning

required for UV to cause POMC → MSH → MC1R → melanin

POMC products

beta endorphin

adrenocorticotrophic hormone (ACTH), melanocyte stimulating hormone (MSH)

beta endorphin

triggers opioid receptors in brain → sun seeking behavior

reason for sun addictions

ACTH

ACTH → adrenal glad steroids → inhibits inflammation

UV addiction experiment

when mice were treated with UV and opioid antagonist, they exhibited withdrawal like symptoms → had an addiction

beta endorphin KO mice

when no beta endorphin, mice treated with opioid antagonist had no withdrawal symptoms → no addiction without beta endorphin

p53 roles in cancer summary

increase MSH → tanning

reward via beta endorphin

promotes vit d synthesis

apoptosis (sunburns)

increased DDB2 for CPD repair and XPC for CPD and 6-4PP repair

why more estrogen in pregnancy

causes low levels of tanning which means more vit d absorption

melanoma increasing or decreasing? surprising? why?

increasing

surprising bc we have sunscreen and spend more time inside

why might melanoma be increasing

sunscreens are claiming to offer protection they aren’t truly offering

no standard in measurement

no UVA coverage means over exposed → maybe UVA does contribute to melanoma

UVA and melanoma

melanin required for melanoma formation by UV-A

sunscreen protection against BRAF melanomas

partial protection, but not that much

circadian oscillation in human epidermal stem cells and cancer

stem cell replication happens more at night so that cells can be in more fragile state without having to worry about UV damage

jet lag messes up circadian rhythm, so cells will divide during the day and are more susceptible to damage