Cancer Genetics Flashcards
What factors can cause cancer?
Environmental: Chemicals and radiation
Endogenous: Viruses can introduce their genes
Genetics: Alterations in genes, increase susceptibility can be passed on
What differentiates benign and malignant tumors?
Benign cells are well-differentiated lacks ability to invade and metastasise. Malignant are poorly differentiated and capable of metastasis.
What are microscopic characteristics of Cancers? (7)
Large number of dividing cells Large, variably shapes nucleus Large nucleus cytoplasm ratio Variation in size and shape Loss of normal cell features Disorganised arrangement Poorly defined tumor boundary
What is the link in the Gene expression of nuclearporins in advanced prostrate cancer?
APC ( tumor suppressor gene by controlling beta-cotinine levels)
Nuclear pore increase = influx of beta-cotinine
Beta-cotinine is a transcription F which is often mutated in cancer.
What are the differences between Carcinomas and Sarcomas?
Carcinoma : cells covering external/internal body surfaces ( lung, breast, colon - epithelial cancers)
Sarcoma : cells found in supporting tissues ( bone, cartilage, fat, connective tissue, muscle )
Why do children has higher rates of ALL, AML, Germ cell, Brain cancers?
Higher risk of cancer in the tissues undergoing higher rate of proliferation
What are the 6 hallmarks of cancer?
( These override the anti-cancer defence in cells )
- Self sufficiency in growth signals
- Insensitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- Sustained angiogenesis
- Evading apoptosis
What are germ-line mutations?
Mutation in egg or sperm which leads to all cells being affected in offspring.
These are hence heritable
Rare cancers ( 10% )
Why are Somatic mutation cancers ‘genetic’ but ‘non-heritable?
Genetic because they occur through gene events affected by environment etc
Cannot be passed on to offspring
( 90% of cancers )
How are cancer germ-line mutations identified?
Positional cloning linkage studies
gene mapping followed by gene identification.
Once chromosome region identified and sequenced, can compare with normal population
Which Gene is usually mutated in hereditary breast ovarian cancer syndrome
BRCA 1 gene
What types of genetic mutations may occur?
Deletions Duplications Inversions Translocation Single base substitutions Chromosome instability Aneuploidy
Which types of genes are usually mutated?
Provide a example
Oncogenes, Tumour suppressor genes, DNA repair genes
Colon cancer can begin with APC defect (tumor suppressor gene) = cell proliferation
Proliferation = more mutations e.g. repair genes, growth related genes (K-ras)
What are some emerging cancer hallmarks and cancer enabling characteristics?
- Avoiding immune destruction
- Deregulating cellular energetics
- Genome instability mutation
- Tumor promoting inflammation
What is the mutational signature of UV light damage?
C to T transition
Formation of a covalent bond between two adjacent pyridimes ( C and T ) creating a dimer
If these changes happen in certain genes it can cause malignant malenoma
What is the mutational signature of smoking causing lung cancer?
G to T transitions become prevalent
What are passenger mutations?
Mutations that don’t contribute to development of cancer but have occurred during growth of cancer. Driver mutations can come subsequently.
What are driver mutations?
Contribute to cancer development, provide a selective growth advantage so will lead to clonal expansion
What are Oncogenes?
1 mutation at high level can cause cancer
Dominant, gain-of-function mutation by driver mutations
Most acquired not inherited mutations
How can Driver mutations be distinguished from passenger mutations?
By comparing risk of cancer from the normal rate of background mutations from various genes to a sample in which a certain gene is mutating more frequently and is linked to a higher risk of cancer.
Or
Driver mutations tend to have a greater impact on protein function than passenger mutations do.
Example of an acquired oncogene mutation which causes a cancer?
Chromosome rearrangement leading to BCR-ABL gene formation
Leads to CML
How can an mutated Ras protein lead to cancer?
Once switched on the protein causes a signalling pathway switches on other proteins and inevitably genes linked to cell cancer enabling hallmarks.
Example of Multiple endocrine neoplasia type 2 (MEN2) as an inherited mutation of an oncogene?
Mutation in RET gene
People with this syndrome can develop medullary cancer of thyroid
What do the following inherited oncogene mutations cause?
KIT gene
MET gene
CDK4 gene
GISTs
Hereditary papillary renal cancer
Malignant melanoma
Why are most loss-of-function mutations in tumour suppressor genes recessive?
2-Hit hypothesis:
Both alleles that code for a protein must be affected for affect to be manifested
1st event : inherited mutation
2nd event : loss of good copy somatically
Leads to cancer
What does the 2 Hit hypothesis mean in relation to germ-line or somatic cell mutations?
Because in germ-line mutations every cell already has an affected copy. Chances of getting a 2nd somatic mutation is higher. Than a somatic cell getting mutations to both its loss-of-function genes.
What does TP53 gene damage lead to?
Reduces p53 which is a tumour suppressor gene and regulates the cell cycle
In what two ways can the TP53 gene be damaged?
Li-Fraumeni syndrome : inherit one functional copy of TP53 and so will be likely to develop tumours early
By mutagens
What are BRCA1/BRCA2 examples of?
DNA repair genes : code for proteins to repair errors during cell DNA replication before the cell divides.
What can mutations in DNA repair genes lead to? (3)
Cell with DNA damage will either:
- dormancy
- apoptosis
- cell divisions leading to mutation accumulation and cancer
How can viruses affect cell behaviour?
DNA damage by inserting their genomes
Cell regulation disruption ( can increase rate of growth )
Altered versions of genes they may have picked up from previous hosts can be inserted
What are three examples of cancers associated with viruses?
Cervical cancer : Papillomavirus
Liver cancer : hepatitis virus
Burkitt’s Lymphoma : Epstein-Barr virus
Stomach cancer : H Pylori
Ovarian cancer : HPV
How can we identify cancer susceptibility genes in a population?
Genome wide association studies
