Genetics vs Environment Flashcards
Where do mutations arise from?
SOMATIC
= occur during lifetime’s lifetime
= result from damage to DNA through exogenous (e.g. carcinogens) and endogenous (spontaneous) (e.g. from normal biological processes - oxidative phosphorylation) sources
= if not repaired = cancer
GERMLINE
= inherited from parental sperm / egg (e.g. faulty tumour suppressor gene inherited)
= all cell will contain the mutation
= basis for cancer predisposition syndromes (e.g. retinoblastoma, FAP)
What are some risk factors for cancer?
= Age (more cell divisions, more unrepaired DNA damage, high mutational load in body)
= Tobacco use
= Diet
= Obesity
= Infectious agents
= Reproductive / hormonal effects
= Radiation
= Other environmental / occupational exposure (e.g. asbestos = mesothelioma)
= Genetic factors
(impact of each can vary on the type of cancer)
(higher income countries usually more environmental - exception is cervical cancer)
What are the genetics of cancer?
SPORADIC
= 75-80% of cancers
= caused by random mutation
(can be influenced by environment, lifestyle, medical factors)
= generally more common with increasing age
INHERITED / HEREDITARY
= 5-10% of cancers
= caused by inheritance of a mutated gene (Mendelian inheritance pattern)
= tend to be younger onset than sporadic forms
FAMILIAL
= cancers that cluster in families
= BUT NOT due to inheritance of a single gene
= multifactorial: combination of several genes, lifestyle factors
What are cancer predisposition syndromes?
Highly penetrant
= some up to 100%
= likely to present at young age
Genes usually identified by linkage analysis and positional cloning
Typically autosomal dominance inheritance
= usually involve mutation of a tumour suppressor
What are some examples of autosomal dominant syndromes?
FAP - Familial Adenomatous Polyposis
= mutation in the APC TSG
= penetrance near 100%]
= incidence 1:8300
HBOC - Hereditary Breast Ovarian Cancer
= mutation in BRCA1/BRCA2 (repair of DNA DSBs)
= penetrance up to 85% (BRCA1 has higher penetrance)
= incidence 1:500 - 1:1000 = increased in some sub populations (e.g. Ashkenazi Jews)
Cowden syndrome
= mutation in PTEN - lipid phosphatase (AKT pathway)
= penetrance 90-95%
= incidence 1:200,000
LFS - Li Fraumeni Syndrome
= mutation in the TP53 gene
= penetrance 100%
= incidence very rare
EXTRA READING
MEN1 - Multiple endocrine neoplasia type 1
= caused by mutation in MEN1 gene
= increases risk of many cancers including pancreatic and pituitary tumours
VHL - Von Hippel-Lindau
= mutations in VHL gene
= increases risk of tumours : kidney, adrenal gland and blood vessels
Gorlin syndrome
= also called nevoid basal cell carcinoma syndrome
= mutations in PTCH1 gene
= increases risk of basal cell carcinoma
What are some examples of Autosomal recessive syndromes?
= less common
AT - Ataxia telangiectasia
= biallelic mutations in ATM (kinase involved in DSBR)
= penetrance 90%
= incidence 1:40,000 - 1:100,000
= shrinkage of cerebellum (end up in wheelchair by age 20)
Bloom’s syndrome
= biallelic mutations in the BLM gene (HR DNA helicase)
= pentrance 100%
= incidence 1:48,000 in Ashkenazi Jews
XP - Xeroderma pigmentosum
= biallelic mutations in XPA-G or XP-V (NER repair enzymes)
= penetrance 100%
= incidence 1:40,000 - 1:1,000,000
EXTRA READING
FA - Fanconi anemia
= mutation in DNA repair genes
= increases risk of leukaemia, solid tumours in liver, head and neck
NBS - Nijmegan breakage syndrome
= mutations in NBN gene
= increased risk of lymphoma, brain tumours, osteosarcomas
What is an example of genes and environment in a cancer?
Malignant Melanoma
= skin cancer
XP patients
= vastly increased risk of developing skin cancer
(other populations can also have increased risk - melanoma predisposition syndrome)
HOWEVER
= epidemiology shown that main cause of skin cancer is exposure to solar UV (environmental)
2 types of skin cancer:
Non- melanoma skin cancers
= rarely life-threatening (poor blood supply, don’t spread a lot)
= e.g. Basal cell carcinoma, Squamous cell carcinoma
= 1.2 M cases/year worldwide
Melanoma
= less common, often fatal (due to metastasis)
= 325,000 cases/year worldwide
How does UV radiation cause mutations?
UV (ultra-violet)
= UVC - screened out by O2 (most harmful)
= UVB - screened out by O3
= UVA - not screened (least harmful)
UV produced pyrimidine dimers
= cause C to T mutations
(worldwide rate highest in Australia - also most melanoma cases)
What is FAMMM?
= Familial atypical multiple mole melanoma syndrome
= 7-15% of MM cases occur in patients with a family history of the disease
= highly penetrant (up to 90%)
= inherited missense / nonsense mutations in CDKN2A or CDK4 genes
CDK2NA
= frameshift mutations
= alternative splicing = gives 2 different genes = p16 / p14
= accounts for up to 2% of melanoma cases
= cutaneous melanoma
= dysplastic nevi (moles)
= pancreatic cancer
= neural system tumours
What do p16 / p14 do?
p16 = inhibits Cyclin D-CDK4/6
Melanoma associated mutations:
= inactivation of p16
OR
= activation of CDK4 (mutation in codon 24 blocks p16 binding site)
p14 = stabilises p53
= stops accumulation of p53
What is the 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
What is the molecular pathway of tanning?
- UV enters cell and damages DNA
- Cytokines and growth factors released
= trigger immune response + inflammation - Inflammation activated melanocytes = begin to produce melanin
- Melanin synthesised in melanosomes
= contain enzyme tyrosinase
= catalysis conversion of tyrosine to melanin
(tyrosine to dopoquinone to dopachrome)
(then if TYRP1 = black melanin)
(if DCT = brown melanin)
(addition of cyteine glutathione = phaeomelanin) - Melanin transported from melanocytes to skin cells
= accumulates forming protective shoeld against further UV damage
What are the risks associated with MC1R polymorphisms?
5 SNPs associated with red hair, fair skin, freckling
= D84E, R142H, R151C, R160W, D294H
RHC variants
= very hypomorphic:
↓ signalling, ↓eumalanin, ↑ DNA damage
= 2.2-3.9 fold risk of melanoma for a single allele
(effects are additive , therefore 2 alleles = >4-fold increase)
How do co-interactions modify risk?
Gene-environment interaction
= penetrance of CDK2NA varies according to geographic location
= e.g. Australia (91%) and Europe (53%)
Gene-gene interaction
= MC1R RHC alleles also increase the penetrance of CDKN2A mutations (50% to 84%)
= and decrease age on onset by 20 years
What is GWAS used for?
= genome wide association studies
Genetic epidemiology
= use SNP arrays to analyse populations (cases and controls)
= can identify low penetrance SNPs
(small effects)
Future
= may be able to identify further SNPs / combinations that modify cancer risk
= could have a personalised medicine application
