Lecture 5 - Causes of cancer: genes vs environment Flashcards
Somatic mutations
- Occurs during individual’s lifetime
- result from damage to DNA through exogenous and endogenous (spontaneous) sources
Germline mutations
- Inherited from paternal sperm/egg
- All cells will contain the mutation
- The basis for cancer predisposition syndromes e.g. retinoblastoma, FAP
Risk factors for cancer
Age
Tobacco use
Diet
Obesity
Infectious agents
Reproductive/hormonal effects
Radiation (ionizing and non-ionizing)
Other environmental/occupational exposure
Genetic factors
Cancer genetics
75-80% of cancers - Sporadic
- Caused by random mutation (influenced by medical factors, lifestyle, environment etc)
- More common with increasing age
5-10% of cancers - Inherited
- Caused by inheritance of a mutated gene (mendelian inheritance pattern)
- Tend to be younger onset than sporadic forms (two-hit hypothesis)
Familial
- Cancers that cluster in families but not due to inheritance of a single gene
- Multifactorial: Combination of several genes, lifestyle factors etc
Cancer predisposition syndromes
Highly penetrant (some up to 100%)
Genes usually identified by linkage analysis and positional cloning
Typically autosomal dominant inheritance and involve mutation of tumour suppressor
Examples of autosomal dominant dyndromes
Familial adenomatous polyposis (FAP_
- Mutation in APC TSG
- Penetrance near 100%; incidence 1 in 8300
Hereditary breast ovarian cancer (HBOC)
- Mutation in BRCA1/BRCA2 (repair of DNA DSBs)
- Penetrance up to 85%; incidence is 1 in 1000-1500
Cowden syndrome
Mutation in PTEN – lipid phosphatase (AKT pathway)
Penetrance 90-95%; Incidence 1:200,000
Li Fraumeni Syndrome (LFS)
Mutation in the TP53 gene (See L3)
Penetrance 100%; Incidence very rare
Ataxia telangiectasia (A-T)
Biallelic mutations in ATM (kinase involved in DSBR)
Penetrance 90%; Incidence 1:40000 to 1:100000
Bloom’s syndrome
Biallelic mutations in the BLM gene (HR DNA helicase)
Penetrance 100%; Incidence 1:48 000 (in Ashkenazi Jews), undetermined in general population
Xeroderma pigmentosum (XP)
Biallelic mutations in XPA-G or XP-V (NER repair enzymes)
Penetrance 100%; Incidence 1:40 000 to 1:1 000 000
Genes and environment in malignant melanoma
- XP patients have increased risk of cancer development, especially skin
- Two main types of skin cancer:
Non-malignant skin cancers (rarely life threatening): Basal cell carcinoma and squamous cell carcinoma - 1.2M cases/year worldwide
Melanoma (less common, often fatal) - 332,000 cases/year worldwide
Epidemiology has shown exposure to solar UV is the main cause of skin cancers
UV radiation causes mutations
Sun produces UV radiation
On Earth’s surface, we’re exposed to UVA and UVB (ca. 90% of UVB is screened out by the ozone layer)
Absorbance of UV by DNA produces pyrimidine dimers
Pyrimidine dimers are helix-distorting
Replication produces C->T mutations
Cyclobutane and 6,4 photoproduct pyrimidines
UV signature mutations seen in melanoma in sun-exposed sites
Many more malignant mutations in people exposed to sun and who are aged over 65
Where is the highest rate of cancer?
Australia
Xeroderma Pigmentosum
Can’t recognise damage in skin
DNA unwinding failure
Leads to incision failure by ERCC1, which then leads to excision failure
Unrepaired DNA damage, leading to malignant tumour formation
Familial atypical multiple mole melanoma syndrome (FAMMM)
7-15% of malignant melanoma cases occur in patient with family history of disease
FAMMM is most highly penetrant (up to 90%)
Genetic basis: missense or nonsense mutations in CDKN2A or CDK4 (rarely) genes
Accounts for 2% of melanoma cases
p16 inhibits Cyclin-D-CDK4/6
Melanoma associated mutations:
- Inactivation of p16 in FAMMM (associated with CDKN2A mutation)
- Activation of CDK4 (mutation in codon 24 blocks p16 binding site) - associated with susceptibility to Cutaneous Malignant melanoma 3 (CMM3 - just 6 families identified)
Melanocortin-receptor 1 (MC1R)
Single exon, highly-polymorphic gene (>100 variants)
Encodes a G-protein coupled receptor
Expressed in melanocytes
Major determinant of human skin colour
Molecular pathway of pigment production
- UV exposure (UVA + UVB)
- DNA damage
Tyrosine -> Dopaquinone by Tyrosinase (TYR)
Dopaquinone -> Dopachrome
Dopachrome -> Black melanin by Tyrosinase related protein 1 (TYRP1)
Dopachrome -> Brown melanin by dopachrome tautomerase (DCT)
Dopaquinone -> phaeo-melanin by cysteine glutathrione
Risk-associated MC1R polymorphisms
- 5 SNPs associated wtih red hair, fair skin and freckling (RHC variants): D84E, R142H, R151C, R160W, and D294H
- RHC variants are hypomorphic: Decreased signalling and Eumelanin, increased DNA damage
- 2.2-3.9 fold risk of melanoma for a single allele
- Effects are additive (two alleles, > 4-fold)
