Lecture 5 Flashcards
How do mutations arise?
Either somatic or germline
Majority are somatic:
- Occur during individual’s lifetime
- Result from damage to DNA through exogenous and endogenous sources
Germline:
- Inherited from parental sperm or egg
- All cells contain mutation
- Basis for cancer predisposition syndromes e.g. retinoblastoma, FAP
Major risk factors for cancer
Age
Tobacco use
Diet
Obesity
Infectious agents
Reproductive/hormones
Radiation
Genetics
Environmental factors
The proportion of cancers
- 75-80% sporadic which are caused by a random mutation and are generally more common with increasing age
- 5-10% caused by inheritance of a mutated gene and tend to be younger onset than sporadic forms
- Familial - Cancers that cluster in families but not due to single gene inheritance, and often multifactorial
Cancer predisposition syndromes
- Highly penetrant - up to 100%
- Genes usually identified by linkage analysis and positional cloning
- Often autosomal dominant and involve tumour suppressor mutation
Autosomal dominant syndromes
- Familial adenomatous polyposis - mutation in APC TSG, penetrance near 100%; incidence is 1 in 8300
- Hereditary breast ovarian cancer (HBOC) - mutation in BRCA1/BRCA2 (repair of DNA DSBs), penetrance 85%; incidence 1 in 500-1000
- Cowden syndrome (PTEN mutation) - lipid phosphatase (AKT pathway), penetrance 90-95%; incidence is 1 in 200,000
- Li Fraumeni syndrome (LFS) - Mutation in TP53; penetrance is 100%; incidence very rare
Autosomal recessive
Ataxia telangiectasia (A-T) - Biallelic muation in ATM - penetrance is 90%; incidence is 1 in 40,000-100,000
Bloom syndrome - Biallelic mutations in BLM gene (HR DNA helicase); penetrance 100%; incidence is 1 in 48,000 in Ashkenazi jews
Xeroderma pigmentosum
Biallelic mutations in XPA-G or XP-V gene
Penetrance is 100%; incidence is 1 in 40,000-1,000,000
XP and skin cancers
XP patients in particular have a greater risk of developing cancer (over 1000 fold), particularly skin cancers
Two mains types of skin cancer:
Non-melanoma skin cancer (rarely life threatening):
Basal cell carcinoma and squamous cell carcinomas; 1.2M cases a year
Melanoma (less common, often fatal):
332,000 cases/year worldwide
UV radiation in cancers
Sun produces UV (short wavelength, higher energy)
On Earth, people are exposed to UVA and UVB (90% of UVB and 100% UVC screened out by ozone layer)
UV absorbance produces helix distorting pyrimidine dimers (CPDs, 6, 4 photoproducts).
Replication of these dimers produces C->T mutations - DNA backbone distorted and blocks replication.
Exome sequencing of UV signature mutations in sun-exposed sites
Most mutations in sun-exposed, metastatic, age >65.
Dipyramidine and nonpyramidine- C->T most common
More common in USA, Australia and Europe
Normal skin pathway
- Damage recognition by XPC and XPE
- Unwinding by XPA, XPG, and XPB
- Incision by ERCC1 on XPF and XPG
- Excision by XPG
- Gap filling with DNA pol and PCNA
- Ligation by ligase I
Familial atypical multiple mole melanoma syndrome (FAMMM)
- 7-15% of MM cases occur in patients with a family history of the disease.
- FAMMM is the most penetrant (up to 90%)
- Caused by inherited missense or nonsense mutation in CDKN2A or rarely CDK4 genes.
- Accounts for 2% of melanomas
p16 inhibits cyclin D-CDK4/6
Melanoma associated mutations:
- Inactivation of p16 in FAMMM caused by CDKN2A mutation
- Activation of CDK4 (mutation in codon 24 blocks p16 binding site) - associated with susceptibility to CMM3 (cutaneous malignant melanoma 3 - 6 families identified)
Melanocortin-receptor 1 (MC1R)
Single exon, highly polymorphic gene (>100 variants)
Encodes G-protein coupled receptor
Expressed in melanocytes
Determinant of skin colour
Pathway for Melanocortin-receptor 1
ligand binds serpentine receptor protein, allowing for inactive G protein to bind to activate
GDP -> GTP
Activated a subunit and activated By subunit activate various effectors
Molecular pathway of pigment production
- UV exposure
- DNA damage where TP53 transcription factors forms aMSH in keratinocyte
- aMSH in keratinocyte -> MC1R to allow for MC1R pathway
- cAMP and CREB signalling pathway in melanocytes form PKA and activate MITF transcription factor to form pigment genes
- Melanosome formation where pigment genes activate TYRP1/TYR/DCT/PMEL complex to form melanin
- UV protection by melanin in keratinocyte
Focused view on different types of melanin formation
Tyrosine -> Dopaquinone by tyrosinase
Dopaquinase -> Dopachrome
Dopachrome -> black melanin by tryosine related protein 1 (TYRP1)
Dopachrome -> brown melanin by dopachrome tautomerase (DCT)
Dopaquinone -> phaeo-melanin by cysteine glutathione
Explain Risk-associated MC1R polymorphisms
5 SNPs associated with red hair, fair skin, and freckling (RHC variants): D84E, R142H, R151C, R160W, and D294H.
Hypomorphic variants: less signalling, less eumelanin and more DNA damage
2.2-3.9 fold increase of melanoma for single allele
Effects are additive (two alleles, >4-fold)
Do genetic and environmental co-interactions modify risk?
Yes
Overall risk is combination of genes and environment
Penetrance of CDKN2A varies according to geographic location: Australia (91%) > UK (53%) - Gene-environment interactions
MC1R RHC alleles increase penetrance of CDKN2A mutations (e.g. 50%->84%) and decrease age inset by 20 years - Gene-gene interactions
Genome wide association studies (GWAS)
Genetic epidemiology - use SNP arrays to analyse populations (cases and control)
Identify low penetrance SNPs - small effects (1.2-1.4 fold increase)
Examples of low penetrance genes for skin cancer
Pigmentation genes
DNA repair/damage response genes
Immune genes
Biotransformation genes
Vitamin D receptor polymorphisms
