Causes of cancer

Question 1

Autosomal dominant cancer predisposition syndromes

Answer 1

HNPCC (Hereditary-nonpolyposis colorectal cancer) mutation in DNA mismatch repair. 90% penetrance
HBOC BRCA1/2 mutation. 85% penetrance
Li Fraumeni syndrome (LFS) mutation in TP53 gene. 100% penetrance

Question 2

Autosomal recessive cancer predisposition syndromes

Answer 2

Ataxia telangiectasia biallelic mutations in ATM (involved in DSBR). 90% penetrance
Bloom's syndrome biallelic mutations in BLM gene (HR DNA helicase). 100% penetrance
Xeroderma pigmentosum (XP) biallelic mutations in XPA-G or XP-V (NER repair enzymes). 100% penetrance

Question 3

Non-melanoma skin cancers

Answer 3

Basal cell carcinoma and squamous cell carcinoma
Rarely life threatening
Rarely metastasise (skin poorly vascularised)
More common than melanoma

Question 4

Melanoma

Answer 4

Cancer within melanocytes

Less common type of skin cancer but often fatal

Question 5

UV radiation and skin cancer

Answer 5

UV produces pyrimidine dimers (bonds between adjacent pyrimidines)
C to T mutations if not repaired before replication
UVB directly absorbed by bases

Question 6

FAMMM

Answer 6

Familial atypical multiple mole melanoma syndrome
Up to 90% penetrance
2% of melanoma cases
Inherited missense or nonsense mutations in CDKN2A or CDK4 (very rare)

Question 7

CDK2NA

Answer 7

Encodes two proteins through alternative splicing
Exon 1alpha spliced with exon 2 and 3 gives p16
Exon 2beta with exon 2 gives p14 (ARF)

Question 8

p16

Answer 8

Inhibits cyclin D-CDK4/6 (checkpoint arrest)

Melanoma mutations may inactivate p16 or mutate p16 binding site in CDK4 (activation)

Question 9

p14

Answer 9

ARF stabilises p53 (sequesters Mdm2)

If p14 is mutated then p53 is not activated

Question 10

MC1R

Answer 10

Melanocortin-receptor 1
Encodes G protein coupled receptor expressed in melanocytes
Controls pigmentation pathways (skin colour determination)

Question 11

DNA damage from UV light

Answer 11

ATR stabilises and activates p53. Hyperactive p53 drives apoptosis (skin burning)

Question 12

Low levels of UV exposure

Answer 12

POMC expressed. Elevated levels of melanocyte stimulating hormone (MC1R ligand)
MITF pathway activation. Melanin pigment exported as melanosomes from melanocyte to keratinocyte and forms supranuclear cap above nucleus

Question 13

Melanin formation

Answer 13

Tyrosine converted to dopaquinone by tyrosinase
Dopaquinone spontaneously converts to Dopachrome
Dopachrome processed by TYRP1 (black melanin) or DCT (brown melanin)
Dopaquinone may react with cysteine glutathione to give phaeomelanin (less effective)

Question 14

MC1R polymorphisms

Answer 14

5 SNPs associated with red hair hair (RHC variants)

RHC variants are hypomorphic variants of MC1R. Decreased signalling, decreased eumelanin and increased DNA damage

Question 15

OCA2

Answer 15

Low penetrance melanoma susceptibility gene
Encodes melanosomal transmembrane protein that modifies eye colour and pigmentation
Variant allele significantly increases chance of melanoma