Genetic Mechanisms in Cancer Flashcards
What tissues are ectoderm?
Skin, nervous tissue
What tissues are mesoderm?
Muscles, bone, urogenital, blood
What tissues are endoderm?
Digestive, respiratory
80-90% of cancers are from ecto/endoderm. What are they called and where are they?
Carcinomas. Arise from epithelial cells in skin, lung, breast, pancreas
1% of cancers are sarcomas. What tissues are these from?
Mesodermal tissues - mesenchymal, connective tissue, bone, muscle, fat
Haem cancers are 10% of cancers. Name some types and what tissue germ layer is this from?
Lymphoma, leukaemia, myeloma - mesoderm.
What’s the most common of all cancers? It’s a type of carcinoma. And what percentage?
Skin cancer, 30% of all cancers
What’s the breakup of skin cancers:
75% -
20% -
1% -
The breakup of skin cancers:
75% - basal cell
20% - squamous cell
1% - melanoma
What are some of the most common carcinomas?
Skin, lung, breast, colorectal, prostate
How many subtypes of carcinoma are there?
200
Radiation like UV typically causes skin cancer through what mechanism?
UV induces covalent bonds between adjacent pyramidines, these are misrepaired causing C>T transitions
Smoking causes lung cancer through what mechanism?
Polycyclic aromatic hydrocarbons causing C>A Transitions
Viruses cause 15-20% of cancers, name 3 viruses that do this
EBV, HPV, Herpes
What percentage of cancers are from inherited predisposition?
5-10%
What other things can cause cancer?
Lifestyle, hormones, chronic inflammation, chemical carcinogens etc. age
What is a mutation signature?
The combination of mutations that are common for a given mutagen
Cancers tend to have more mutations if what?
They are later onset, just due to age and the accumulation of mutations
It’s harder to identify the driver mutations in what cancers?
The older onset ones due to the accumulation of mutations, whereas child onset ones like rhabdoid tumours have fewer.
Name an oncogene in each category:
Positive growth regulator -
Signal Transduction -
Transcription Factors -
Cell Cycle Regulators -
Name an oncogene in each category:
Positive growth regulator - PDGF-R
Signal Transduction - Ras
Transcription Factors - MYC
Cell Cycle Regulators - Cyclins/CDK
Name a Tumour Suppressor in each category:
Transcription factors -
Negative Growth Regulators -
DNA Repair Genes -
Name a Tumour Suppressor in each category:
Transcription factors - TP53
Negative Growth Regulators - PTEN (30-50% of cancers)
DNA Repair Genes - BRCA1, BRCA2, MSH1
Which chromatin remodelling complex is important in several cancers? What percentage of cancers?
SWI/SNF. 20%
What genes does SWI/SNF regulate expression for?
It regulates the expression of many genes for neural differentiation, embryonic stem cell differentiation, hepatic liquid metabolism, glucose metabolism.
What are first and second hits normally?
First hit might be the loss of genetic material like a deletion. Then there’s a second hit be a loss through mitotic recombination so you lose your heterozygosity, or some inactivating SNV or deletion
What is microsatellite instability?
When MMR is deficient, tandem repeats of 1-6bp expand or contract from faulty DNA repair.
What epigenetics can cause cancer?
Hypermethylation of a tumour suppressor or hypomethylation of a proto-oncogene
How can you detect loss of heterozygosity/mitotic recombination in tumours?
Use a matched blood and tumour sample. Then use high density SNP arrays, Array CGH, or low pass WGS. Copy number will stay the same but BAF will be 0.
What happens after a first and second hit?
An accumulation of additional somatic mutations.
Meningiomas are 1/3 of brain tumours with how many histological subtypes?
15
In a Meningioma case the three tumour all had monosomy 22 which contains what?
NF2, which is commonly disrupted in meningiomas
In the Meningioma case what was seen between her grade I, II and III tumours?
A progressive LOH of various regions as the grade increased. And an acquisition of mutations in the TERT promoter and ARID1A.
What percentage of CRC has MSI?
15%
What does MSI suggest in a tumour?
MMR not working
A sporadic cause of MSI in CRC is what hypermethylation?
The promoter of MLH1
CRC tumours with MSI have better prognosis than those without, true or false?
True
20% of the time MSI CRC is caused by what?
Lynch syndrome (or HNPCC), the other 80% is sporadic
Mutations in Lynch syndrome are generally in which genes?
MLH1, MSH2, MSH6 and PMS2
Sometimes there are heritable epimutations, explain
A haplotype that is resistant to reprogramming, or inheriting a variant that causes methylation to be re-established in development.
BRCA1 promoter methylation is in X% of sporadic breast cancer, as well as inherited BRCA1 variants
10% of sporadic breast cancer
Hypermethylation of the BRCA1 promoter when present can be seen in every germ layer, true or false?
True
Heritable epimutations are a rare mechanism but are found in multiple ________
Heritable epimutations are a rare mechanism but are found in multiple cancer syndromes
What is Kataegis in some cancers?
The regional clustering of substitution variants. 6 or more with an average inter-mutation distance of <1kb.
Where do Kataegis mutations cluster?
Open chromatin, transcription start sites
What is likely to cause Kataegis?
Aberrant expression of APOBEC
Kataegis is in what percentage of breast cancers?
55%
Breast cancers with Kataegis are more likely to have what?
TP53 variants. Be estrogen negative, progresterone negative, HER2 positive. So less likely to have hormone therapy.
Breast cancers with Kataegis are more likely to be…
Higher grade, and thus poorer survival. Generally older presentation though.
