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13 Cards in this Set
- Front
- Back
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Identify the genetic component in the initiation and progression of cancer |
All cancer has a genetic component, but most are NOT heritable - only 5-10% have a direct hereditary link
Cancer mutations are typically somatic in origin and therefore cannot be transmitted to the next generation
A cell must accumulate multiple mutations (typically after exposure to an environmental mutagen) in order to become cancerous |
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Identify the various mechanisms of gene disruption that can lead to cancer |
UV exposure - dimers
Viruses - insert viral genome into human genome - sometimes they have oncogenes that can be directly incorporated into our genomes
Carcinogens
DNA mutations
- Frame Shifts - Breaks - Translocations Epigenetic problems (this is an important one and doesn’t involve changing the sequence of our DNA) - methylation - regulation - acetylation
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Define the concept of loss of heterozygosity |
Occurs in tumor suppressor genes
Normally you have two working alleles producing the gene product
If you lose one of those alleles (i.e. to a mutation) then you have lost heterozygosity for that gene
The patient may or may not show symptoms as the single allele may allow them to be haplosuffcient
If the second allele is lost (to another mutation or via some other mechanism) then the patient will be at an increased risk for cancer |
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Recognize how mutations in oncogenes, tumor suppressor, and DNA repair genes can contribute to cancer |
Think of oncogenesis like a car race:
- Mutations in proto-oncogenes that cause them to become oncogenes accelerate the car (allow for more unrestricted proliferation)
- Mutations in tumor suppressor genes disable the brakes (prevent the cell from inhibiting proliferation)
- Mutations in the DNA repair genes disable the gear shift (prevent the cell from regulating cell cycle progression) |
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Identify the inheritance pattern of familial cancer syndromes |
Most cancer susceptibility genes are inherited in an autosomal dominant fashion and exhibit reduced penetrance
Remember that an individual inherits a SUSCEPTIBILITY to cancer, not cancer in and of itself
Tumors present in both areas of bi-lateral tissues is often indicative of familial cancers - think breast cancer |
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Define the Knudson Two-Hit Hypothesis (Multi-Hit Hypothesis) using examples |
Knudson Two-Hit Hypothesis:
Cancer is caused by accumulated mutations to a cell's DNA
First hit could involve loss of a tumor suppressor gene (p53) that prevents the cell from recognizing that it is senescent
Second hit could be mutation in a protooncogene (Ras) that leads to unregulated cell proliferation
Additional hits could involve loss of DNA repair enzyme activity (BRCA1) that prevents the cell from repairing mutations that arise as it continues to proliferate such as activation of telomerase which would only serve to make th cell "immortal"
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Define the role of epigenetics in cancer |
DNA mutations are often linked with cancer initiation, but not progression
Initial DNA mutations can lead to epigenetic changes that facilitate cancer progression
Epigenetic factors can also lead to cancer initiation as well
Epigenetic changes can also "prime" cells to promote transformation after a DNA mutagenic event |
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Define the role of DNA methylation in cancer |
Hypermethylation of CpG islands can prevent transcription of tumor suppressor genes
Global hypermethylation can lead to genomic instability and inappropriate activation of oncogenes
DNA-methyltransferases maintain genomic methylation levels - over expression of these proteins is very common in cancer - loss of imprinting for a gene can lead to this over expression
Aging, diet, and environment all affect DNA methylation levels - ingested folate and methoinine provide the necessary methyl groups - cadmium induces global HYPOmethylation by inactivating DNA-methyltransferases
These are theoretically reversible
Similar issues can arise with DNA acetylation |
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Outline the guidelines for cancer predisposition screening |
Always remind patients that testing will only determine whether or not they are at an increased risk for developing cancer
CANNOT determine if they will or will not develop it in the end
Higher incidences of cancer, observation of related cancers in family member, and diagnosis of cancer in a 1st degree family member all put a patient at in increased risk for cancer - diagnosis in direct 1st degree relative = 2x increase in risk of developing cancer
Always screen an affected first degree (ideal) relative for mutation, then test consultand |
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Explain genetic testing and counseling strategies in cancer |
Late stage (metastatic) cancers often have extremely aberrant karyotypes (multiploidy and marker chromosomes)
CGH allows us to visualize gene expression in cancer cells that can help explain varying phenotypes in patients with very similar karyotypes
Cytogenetic studies allow us to differentiate between cancers that have the same genetic cause such as AML type 2 and CML (both can occur from a 9,22 translocation, but have different prognosis and effective treatments) |
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Inherited Rentinoblastoma |
Rare malignant childhood cancer - 1:20,000
40% are inherited (autosomal dominant)
Large # of primordial retinoblasts and high rate of proliferation
Since one allele is already mutated, another mutation will leave the patient without any gene product which will often times lead to oncogenesis - this manifests itself in the presence of bilateral tumors
Penetrance is 90%
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Familial Adenomatous Polyposis Coli (FAPC) |
Mutation in Adenomatous Polyposis Coli (APC) gene located at 5q21-q22
Incidence = 2-3:100,000
Accounts for <1% of all colon cancers, but somatic mutations in APC present in >80% of sporadic colorectal cancers
Causes >100,000 benign polyps of the colon
Patients with APC mutations are only predisposed
Non-penetrance is rare |
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Inherited Breast Cancer |
Accounts for ~5% of breast cancer cases
20-70% have mutations in BRCA1 and/or BRCA2
Early onset and bi-lateral breast cancer indicative of inherited form
BRCA1 lifetime risk: 50-80% breast, 20-50% ovarian, modest increase in colon and prostate cancer
BRCA2 lifetime risk: 50% breast, 10-20% ovarian |
