The Genetics of Cancer Flashcards
what causes DNA damage which leads to cancer developing
- Inherited this effect germ cells
- Acquired or sporadic somatic cell
- External factors – life style
- External factors – exposure
- Infections (Virus and bacteria)
- Parasites
- Immunosuppression
Name some examples of inherited cancers
- BRACA1/2 – breast and ovarian cancer
- DNA repair genes –xeroderma pigmentosum (XP)
- RB1 – retinoblastoma
- ATM – ataxia telangiectasia mutated-breast cancer
- APC - (adenomatous polyposis coli) – colorectal cancer
- P53- brain tumours, sarcomas
Name some examples of acquired or sporadic cancers
- Ras
- P53
- ATM- ataxia telangiectasia mutated, lymphoma and leukaemia
- Epigenetics
name some examples of external factors (lifestyle choices)that can cause cancers
- Smoking-tobacco (polycyclic aromatic hydrocarbons) - lung cancer
- Alcohol- oral and liver cancer
- Diet
- Exercise
what 3 factors cause up to 20% of all cancers
alcohol
diet
exercise
name some examples of external factors (exposure) that can cause cancer
- Solar radiation (UV – XP, melanoma, basal cell carcinoma and squamous carcinoma
- Ionising radiation- radon gas
- X-rays (e.g. chest = few days of background radiation < 1 in 1 000 000 chance)
- Industrial - asbestos – lung cancer and mesothelioma
- Pharmacological – chemotherapeutic agents
name some examples of infections that can cause cancer
- HPV Cervical cancer
- EBV Burkitt’s lymphoma
- Hep B hepatocellular carcinoma
- H.pylori gastric adenocarcinoma
- HTLV 1 leukaemia/lymphoma
- Schistosomiasis squamous cell/transitional cell bladder cancer
How can immunosuppression cause cancer
- Increased cancers in AIDS and transplant recipients
what are the two things that mutations can be
quantitative
qualitative
What is a quantitative mutation
- this is a change in the amount of products that is produced
what is a qualitative mutation
– altering the gene product to make it constitutively active
what are the 3 mechanisms of gene alterations that activate oncogenes
- point mutations
- chromosomal rearrangements
- gene amplification
how do point mutations cause cancer
– single base changes in DNA for example Ras oncogenes
how do chromosomal rearrangements cause cancer
– translocation
The translocated activated the oncogene by using regulatory elements from a highly transcribed gene to drive the expression of the oncogene for example BCL-2
what is an example of gene amplification causing cancer
HER2
describe how the point mutation in H-ras causes oncogenes to become activated
- Single nucleotide exchange GGC to GTC in bladder cancers
- Results in a glycine changing to a valine
what cancers are examples of point mutations in ras genes causing cancer
pancreas - 90% of tumours thyroid - 60% of tumours colorectal - 25% of tumours bladder - 10% of tumours
what is an example of chromosomal translation causing cancer
Burkitt lymphoma
describe how the chromosomal translation causes burkitt lymphoma
- C-MYC (transcription factor) translocation places the gene under the control of a highly active transcriptional regulatory from an Ig gene (immunoglobulin gene)
- Most common – 75%, t(8:14) (q24;q32)
- Fastest growing tumour
- The disease characteristically involves the jaw or other facial bone, distal ileum, cecum, ovaries, kidney or breast
what cancers are caused by the up regulation of BCL2
- Leukaemia’s – for example nearly all patients with acute lymphocytic leukaemia
- Non hodgkin lymphoma e.g. in follicular lymphoma an estimated 90% of patients have a t(14;18) chromosomal translation
- Solid tumours – e.g. in small cell lung cancer, high bcl-2 expression in greater than 90% of patients reported
what can gene amplification cause
- over expression of porto-oncogenes
- this leads to over expression of oncogenes which leads to tumorigensis
what is an example of gene amplification causing cancer
- HER2 – HER2 positive breast cancer
- EGFR – EGFR positive small cell lung cancer
what is the type of genetic mutation that is found in tumour suppressor genes
Loss of function mutations inactive tumour suppressor genes
- Often point mutations small deletions or truncating mutations
- Sometimes somatic recombination during which the normal gene copy is replaced with a mutant copy
describe the TP53 mutation (tumour suppressor gene)
- TP53 mutations reported in almost every type of cancer at rates varying between 10% (e.g., in hematopoietic malignancies) and close to 100% (e.g. in high-grade serous carcinoma of the ovary).
Describe the p53 mutation (tumour suppressor gene)
- in human tumours is often found to undergo missense mutations via point mutations in which a single nucleotide is substituted by another,
- result in loss of p53 ability to bind DNA in a sequence specific manner
- Loss of suppression function
what is the example of a genetic mutation found in DNA repair genes
ATM
describe the genetic mutation in the ATM DNA repair gene
- Ataxia telangeictasia mutated
- Normally repairs double stranded DNA breaks
- Mutations result in non function truncated protein and ability to repair breaks leading to more mutations
- Mutated in mantel cell lymphoma and in inherited diseases
What are the examples of cancers that are caused by ATM DNA repair gene mutation
- Cerebellar cells are particularly affected – ataxia telangiectasia (A-T syndrome) also increases cancer susceptibility, most likely due to impaired DNA damage repair and genomic instability.
- ATM is one of the most commonly aberrant genes in sporadic cancers (e.g. haematological*) and also found in inherited disease.
What causes testicular cancer
Mutations in KITLG, SPRY4 increase risk of testicular cancer
- Two most common mutations are KIT/KRAS
- Promotes growth of cells through Ras-MAP kinase pathway
what are the pre existing drivers of DNA damage
These are inherited causes of DNA damage
• Breast and ovarian cancer: BREAST CANCER 1/2: BRCA1/2
• Xeroderma pigmentosum: failure to respond adequately UV light, which causes pyrimidine dimers to form in DNA. Nucleotide excision repair is singular pathway for removing these.
• Retinoblastoma; pRB
• Colorectal cancer: APC
• Brain tumours, sarcomas: P53
What are the susceptibility gene
- Small portion of cancers are inherited and are at a higher risk to developing specific cancers
- Proportion of individuals carrying a pathogenic variant who will manifest the disease is referred to as penetrance
What are the classes of genes involved in several classes of gene that may be involved
- tumour suppressor genes
- oncogenes
- DNA repair
- cell cycle control,
- stimulating the angiogenic pathway
what germ line mutation in tumour suppressor genes can develop what cancer
- germ line mutation APC that is autosomal dominant
- Early teenagers – premalignant bowl polyps
- Penetrance almost complete by age of 40 colorectal carcinoma 100%
- 20-30 years earlier than non-inherited colorectal cancer
what germ line mutation in DNA repair genes can develop what type of cancer
BRAC1 and BRAC 2
- Germ line mutation
- Autosomal dominant
- BRAC1 – 65% breast cancer, 39% ovarian cancer
- BRAC1 – 45% Breast cancer, 11% Ovarian cancer
- By 70 years
what are the normal genes that stop DNA methylation from happening
Normal cells H3K4me3
what does H3K4me3 do
stops DNA methylation from happening
what are the genes that cause methylation in the cell promoter region
H3K9me3
what does H3K9me3 do
causes methylation to happen
What is hypermethylation
– transcriptional repression, loss of tumour suppressor gene expression
- at the CpG island stops the transcription of the gene, if this is the tumour suppressor gene then cannot carry out repair or go into apoptosis
what is hypomethylation
– mitotic recombination and genomic instability
- repeated sequences in 3 prime untranslated regions, this causes mitotic recombination and genomic instability
what kind of cancers does an increase in DNA methylation cause
- TSG promoter in cervix and breast increased expression with increasing cancer risk
- DNMT3B associated with colorectal cancer cells
what do the CpG islands do
CpG islands in 5 prime end upstream of the gene, they are not methylated this means that the gene can be transcribed
describe the different types of expression in DNMT3B
- DNMT3B little expression, low amount of brown staining, cytoplasmic in cells underlying the stroma
- Well differentiated adenocarcinoma – DNMT3B expressed more strongly in nuclei of the carcinoma cells
- Poorly differentiated aggressive colon carcinoma – DNMT3B – intense expression on nuclei all of carcinoma cells
What cancer does DNMT3B cause
Colon carcinoma
what type of cancer does the TSG promoter cause
- cervix
- breast
what is the expression and methylation status in the TSG promoter
Low grade squamous intraepithelial lesion of cervix - Promoter methylation is not at surface Normal breast tissue - No promoter methylation High grade lesion of cervix - Promoter methylation in all cells Normal breast tissue - Lobules so uniform promoter methylation, suggests in these normal lobules have undergone initiating steps in cancer progression
what are the two types of mutagenic damage
- endogenous
- exogenous
what is endogenous mutagenic damage
these are indirect acting carcinogens that require metabolic activation
what are examples of endogenous mutagenic activity
polycyclic aromatic hydrocarbons and alcohol
what is exogenic mutagenic damage
direct acting carcinogens
Name sume examples of exogenous mutagenic damage
oxygen species,
chemical mutagens,
x rays,
UV radiation
where do spontaneous mutations occur in DNA
- S, G1 and G2 – Eukaryotes = Rate 10-4 -10-6 per gene per generation
– Natural error rate for DNA polymerase
– Many are fixed
what is spontaneous DNA damage caused by
- Errors in proofreading
- Deamination of bases – taking of the NH2 group of cytosine to convert it to uracil, changes the codon
- Depurination – spontaneous cleavage of the bond linking purine (A or G) to the deoxyribose which removes the base, this is caused by OH- and H+, 1017 chemically altered nucleotides day, most common mutation, changes in the codon
- Depyrimidination – acts as a lower rate removes T and C pyrimidine bases
- Oxidation – most common on guanine
how many carcinogens are in cigarette smoke
more than 70 carcinogens
what does smoking cause
- Responsible for double strand breaks
- DNA is damaged by polycyclic aromatic hydrocarbons
- Forms DNA adducts when the carcinogen combines with a base
What is the example of smoking causing damage
- E.g. BP (found in tobacco smoke) – multiple benzene rings fused together, metabolic activation,
- cytochrome P450 enzymes make compounds more soluble for excretion but this produces chemical species (ultimate carcinogen) that is highly reactive DNA therefore highly mutagenic
- BP procarcinogen – has to be metabolised to get to the ultimate carcinogen
what does the ultimate carcinogen form when it interacts with DNA
- DNA adducts
describe the formation of DNA adducts in lung cancer
- Ultimate carcinogen highly reactive species that interact with DNA to form DNA adducts
- The genetic lesions often occur in the cells where the initial metabolic activation occurs
- BPDE – forms adduct with guanosine residues in lung epithelial cancer
how do DNA adducts form in oral and oesophageal cancers
- Acetaldehyde interacts with deoxguanosine forming a weak mutagen (DNA adduct- most abundant) which forms a stronger mutagen (DNA adduct)
What are the two types of radiation
direct and indirect
what happens in indirect radiation
creation of free radicals where the presence of unpaired electrons damage bases or breaks DNA backbone
what happens in direct radiation
comes from alpha particles, beta particles or x rays/ these create ions that break the sugar phosphate backbone and causes damage between the base pairs or chemically alter bases
what does UV damage do to the DNA
- Formation of pyrimidine dimers – covalent bonds between 2 adjacent pyrimidines on the same strand
what are examples of cancers forming due to pyrimidine dimers
- Melanosomes – protect keratinocytes from UVB by acting as sunshade in melanocytes
- E.g. Basal cell carcinomas many mutation p53 alleles have dipyrimidine substitution
- Cylcobutane prumidine dimers – very stable
what is the cause of xeroderma pigmentosum
- Defect in human nucleotide repair – XPA gene
- Nucleotide excisions repair is the only pathway to remove pyrimidine dimers in humans
what are the symptoms of xeroderma pigmentosum
- Very light sensitivity
- High risk of sunlight induced skin cancer
- Neurological abnormalities (high rate of oxidative metabolism in neurones)
what cancers are caused by xeroderma pigmentosum
Non-melanoma (basal cell and squamous cell) skin cancer at UV exposed site
- 10,000x increased risk
- Median age onset 9 years (60 years earlier than general population)
Cutaneous melanoma
- 2000x increased risk
- Median age 22 years (30 years earlier than general population)
how many cancers are caused by infectious agents
- 15% cancers worldwide thought linked directly or indirectly to infectious agents predominately in developing world
how can some viruses cause cancer
- Some viruses can cause cancer by integrating genes (often oncogenes or TSG inhibitors) into the chromosomal DNA of infected cell
what cancer type does HPV causes and how is it transmitted
- cervical cancer
- sexual contact
what cancer does EBV cause and how is it transmitted
- Burkitts lymphoma, Hodkins lymphoma
- Saliva
Blood/transplants
what cancer does leukaemia virus type 1 cause and how is it transmitted
Adult T-cell leukaemia/lymphoma (ATLL)
- mother to child
- sexual contact
- blood transfusion
what cancer does hepatitis B and C cause and how is it transmitted
hepatocellular carcinoma
- blood transfusion
- organ transplant
- contaminated needles
what are examples of viruses causing cancer
HPV
EBV
leukaemia virus type 1
hepatitis B and C
what can helicobacteri pylori cause
- Helicobacter pylori infection predispose individuals towards gastric adenocarcinoma later in life
how does helicobacter pylori transmit its disease
• indirect inflammatory effects of Helicobacter pylori on the gastric mucosa
• direct epigenetic effects of Helicobacter pylori on individual cells.
Schistosomiasia (parasitic worms - blood flukes) and squamous cell and transitional cell bladder cancer. Formation of N-nitroso compounds
