molecular biology of skin cancer

Question 1

what are the 3 most common skin cancers

Answer 1

1. BCC;
2. SCC
3. cutanous malignant melanoma

Question 2

what to look for when determining if there is a melanoma

Answer 2

A - asymmetry;
B - boarders;
C - colour (different colours within);
D - diameter;
E - evolving/elevation

Question 3

what causes skin cancers ( and which ones - 7)

Answer 3

1. UV - SCC, BCC, MM;
2. ionising radiation - BCC, SCC;
3. immunosuppresson - SCC, BCC, MM;
4. chronic scarring and ulceration - SCC, BCC;
5. wart virus - SCC;
6. arsenic - BCC;
7. hereditary factors - BCC, MM, SCC

Question 4

how does UV light cause cancer

Answer 4

UVB radiation causes damge to DNA -> mutations + increases skin sensitivity to sun, thus exacerbating the effect

Question 5

3 heriditary factors for skin cancer

Answer 5

1. germline (familial melanoma);
2. acquired mutation (e.g. BRAFv600e);
3. epigenetic (e.g. arsenic toxicity)

Question 6

what protects people from skin cancer (and which types - 5)

Answer 6

1. skin pigmentation - MM, SCC, BCC;
2. immune system - SCC, BCC, MM;
3. DNA repair - MM, SCC, BCC;
4. accurate control of cell division;
5. behaviour (avoiding UV, wearing SPF)

Question 7

what are the gene mutations seen in BCCs (4)

Answer 7

germline - MC1R, PTCH1, PTCH2;
acquired - PTCH1, PTCH2, RASA1

Question 8

what pathway is disrupted in BCCs

Answer 8

hedgehog pathway - PTCH1/2 codes for a receptor in this pathway

Question 9

what is the hedgehog pathway

Answer 9

a pathway involved in cell differentiation and proliferation

smoothened molecule promotes cell division while patched inhibits smoothened singalling -> (sonic) hedgehog molecule binds to patched to that it can’t inhibit smoothened (cell division occurs)

Question 10

what happens if there is a fault in smoothened or patched (hedgehog pathway)

Answer 10

if there is a fault in patched - cant fully control smoothened => proliferation;

if there is a fault in smoothened - can’t be fully controlled by patched => proliferation

Question 11

what drug can block smoothened

Answer 11

Vismodegib

Question 12

what pathway does RASA1

Answer 12

MAP-kinase (RAS molecule)

Question 13

MAP kinase pathway

Answer 13

receptor TKa recieves signal -> RAS (may go via RET first) -> BRAF -> MEK ->ERK –(into cell nucleus)–> activates TFs -> promotes cell differentiation, proliferation and survival

Question 14

what is Gorlin’s syndrome

Answer 14

PCTH1 mutation - multiple BCCs at an early stage

Question 15

what are pre-cancerous conditions (in skin)

Answer 15

conditions that can lead to SCCs - solar keritosis (Actinic keratosis) and Bowen’s disease

Question 16

solar keratosis appearance

Answer 16

appearance varies - A flat or thickened papule/plaque;
White or yellow; scaly, warty, or horny surface;
Skin coloured, red, or pigmented;
Tender or asymptomatic

Question 17

what is another name for bowen’s disease

Answer 17

squaemous cell carcinoma in situ

Question 18

what mutations are associated w SCCs

Answer 18

germline - MC1R; OCA1/2; XP; p53; RASA1 etc.
acquried - p53, RASA1

Question 19

what other condition does OCA1/2 mutation cause

Answer 19

Oculocutaneous albinism - reduction or complete lack of melanin pigment in the skin, hair and eyes -> white hair, pale skin and poor vision (slightly better vision and less pale if OCA2 is the one affected)

Question 20

what does XP (xeroderma pigmentosum) mutation result in and why

Answer 20

increased sun burn, freckles, blistering after going in the sun - due to defect of the enzyme system that repairs DNA after damage from ultraviolet rays

Question 21

what does p53 do

Answer 21

tumour suppressor gene - guardian of the genome; halts the cell cycle to allow for DNA repair and can induce apop in cells if damage is too bad

Question 22

gene mutations associated with malignant melanoma

Answer 22

gerlimine - MC1R; CDNK2A; Rb; BRCA2; XP mutations; p53;
acquired - p53; RASA1; BRAF; cKIT

Question 23

what syndrome is CDKN2A/CDK4 associated with

Answer 23

atypical naevus syndrome - presents with many moles

Question 24

what is BRAF mutation associated with

Answer 24

superficial spreading and nodular melanoma

Question 25

what does cKIT code for and what is a mutation associated with

Answer 25

tyrosine kinase receptors - acral+mucosal melanoma

Question 26

what is vemurafenib

Answer 26

monoclonal antibody that inhibits BRAF production - stops cells proliferating

Question 27

what are the 2 mutations that cause the majority of melanomas

Answer 27

BRAF; BRAFV600E