Lecture 16 - Cancer Genetics Flashcards
Most common cancer causing death in men and women?
Lungs
Why have male death rates due to stomach cancer been dropping?
Increasing and proper use of refrigeration and less fermented foods in diet
How many oncogenes in human genome?
Over 100 known ones
Definition of oncogene?
Overexpressed or mutation activated proliferation gene causing cancer
What is a gain of function mutation?
Single mutation event converting proto-oncogenes into oncogenes
What is a loss of function mutation?
2 consecutive inactivating mutation events suppress/eliminate a tumor suppressor gene
What are 2 classifications of mutations that cause cancer? 2 names for each
Is each dominant or recessive?
- Gain of function = overactivity mutation: dominant
2. Loss of function = underactivity mutation: recessive
What would be an example of a a gain of function mutation on Growth factor receptor?
Constitutive activation (always active regardless of whether the receptor is bound)
What would be an example of a a gain of function mutation on Growth factor receptor?
Constitutive activation (always active regardless of whether the receptor is bound)
What is the second mutation event a lot of the time in a loss of function mutation?
Loss of the second chromosome
What are the 4 types of accidents that can make a proto-oncogene overactive and convert it to an oncogene? What does each lead to?
- Deletion or point mutation in coding sequence => hyperactive protein made in normal amounts
- Regulatory mutation => normal protein overproduced
- Gene amplification => normal protein overproduced
- Chromosome rearrangement => nearby regulatory DNA sequence causes normal protein to be overproduced OR fusion of 2 genes to overproduce hyperactive protein
What kinds of proteins do most oncogenes code for? Provide 5 types and examples for each.
Proteins within growth and cell cycle pathways:
- Growth factors: PDGF, EGF
- Growth factor receptors
- Intracellular signal transducers: GTP-binding proteins like Ras, RTKs
- Cytoplasmic proteins: protein kinases, hormone receptors
- Nuclear transcription factors
Can mutations enzymes in the glycolytic pathway lead to gain of function?
NOPE
What is a very common player in cancer?
v-ras = Harvey murine sarcoma virus (20% of cancers)
What is an experimental method to identify a human oncogene?
- Extract human DNA from a cancerous cell
- Insert the DNA in mouse cells and growth them
- Extract one of the cell that transforms and clone it separately
- Extract the DNA from these cells
- Create a phage library with the DNA and probe it with the human DNA you had used to screen it
What cascade contains many proto-oncogenes? How does it work
MAPK cascase
Mutations at all levels can cause cancer AND ERK-mediated transcription can result in the upregulation of EGFR ligands (epidermal growtg factor receptor), such as TGF (transforming GF), thus creating an autocrine positive feedback loop that is critical for Ras-mediated cancers
What cancers are heritable?
Cancers caused by germline mutations
What cancers are nonheritable?
Cancers caused by somatic mutations
What are driver mutations?
Cancer mutations that are causally implicated in oncogenesis by conferring a growth advantage to the cancer cell
What are passenger mutations?
Cancer mutations that have NOT conferred clonal growth advantage to the cell and have NOT contributed to cancer development but are within cancer genomes as inert somatic mutations and are present in the final cancer
Describe the timing of somatic mutations acquired by a cancer cell and the processes that contribute to them.
- Fertilized egg to adulthood: intrinsic mutation processes and environmental/lifestyle exposures lead to many passenger mutations
- Early clonal expansion and benign tumor due to intrinsic mutation processes and environmental/lifestyle exposures causing driver mutations
- Early-late invasive cancer due to mutator phenotype
- Chemotherapy resistant recurrence due to chemotherapy
What is the Warburg effect?
Loss of p53 in cancer cells leads to them preferring to undergo anaerobic glucose metabolism by converting pyruvate to lactate even in the presence of oxygen => growth advantage because they have 3 C products available to build many other macromolecules compared to CO2 which they cannot use
Describe the 3 characteristics of autosomal dominant inheritance.
- Each child has a 50% chance of inheriting the gene
- No skipped generations
- Equally transmitted by men and women
Describe the 3 characteristics of autosomal recessive inheritance.
- Need 2 germline mutations (one from each parent) to develop the disease
- Equally transmitted by men and women
- NEVER 3 consecutive generations affected
What does gene penetrance mean? How is it expressed?
Fraction of those with the gene that express the trait by showing signs or symptoms of disease = ALL OR NOTHING
Expressed as a frequency at different ages
What does incomplete penetrance mean?
It means that the frequency of expression of the phenotype for those who have the gene is less than 100%
What 2 factors affect simple Mandelian inheritance patterns?
- Penetrance
2. Expressivity
What are 2 examples of 2 oncogenes with incomplete penetrance?
BRCA1 and 2
What kind of penetrance do autosomal dominant diseases exhibit?
Reduced penetrance
What kind of penetrance do autosomal recessive diseases exhibit?
Complete penetrance
What 4 factors affect penetrance? What does this mean?
- Modifier genes
- Carcinogens
- Response to DNA damage
- Hormonal/reproductive factors
Means that not everyone with an altered gene will develop cancer and that older people are more at risk because the penetrance increases with age
What does gene expressivity mean?
Severity of expression of the phenotype among individuals with the same disease causing genotype
When can we say a disease has variable expressivity?
When the severity of a disorder differs in people with the same genotype
What is an example of a disease with variable expressivity?
Neurofibromatosis Type 1
Describe the inheritance, penetrance, and expressivity of most cancer susceptibility genes.
- Autosomal dominant
2. Incomplete penetrance
Do people inherit cancer?
NOPE, they inherit cancer susceptibility genes
What is the Two-Hit hypothesis? What does it explain?
Cancer is the result of accumulated mutations to a cell’s DNA and the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells is much greater than the chances for a noncarrier to get two somatic hits in the same cell.
It explains the early onset of an inherited form of cancer called hereditary retinoblastoma
How are tumor suppressor genes inherited?
Recessively at the phenotypic level (both alleles must be mutated/lost for cancer to develop)
How many mutations do most adult epithelial cancers require?
5-7
What % of protein coding genes in humans show recurrent somatic mutations in cancer leading to cancer development? What % of these are dominant?
1.6%
90% of them are dominant
Other than genetic gene inactivation, what else can cause a loss of function mutation?
Epigenetic gene inactivation using heterochromatin or DNA methylation
