Genetics Flashcards
Name the 2 major subdivisions of genetic changes in cancer?
- Oncogenes
- Tumor Suppressor Genes
What are the differences between a prot-oncogene and an oncogene?
A proto-oncogene is a normal gene that regulates cell cycle, growth, and promotion. (telomerase, blocks apoptosis, stimulates proliferation, increases blood supply, etc.)
An oncogene is a gain-of-function (GOF) mutation in a proto-oncogene (regulatory mutations, structural mutations, methylation of genes, loss of imprinting, etc.)
Name 3 ways Gain-of-function (GOF) mutations occur in proto-oncogenes
- **Mutation in the coding sequence **
- Gene Amplification (ie-more copies of the gene = more product)
- Chromosome Rearrangement (ie-can bring regulatory regions of one gene near the coding regions of another–> GOF)
Pediatric Neuroblastoma and certain types of breast cancer (HER2 gene) are examples of what type of mutation.
**Gene Amplification **
- Pediatric Neuroblastoma - the MYCN gene is amplified
- Breast Cancer - the epidermal growth factor receptor (HER2 gene) is amplified. More than 6 copies per nucleus.
Leukemias and Lymhomas are typically the result of what type of oncogene mutation?
Translocation (Rearrangement)
Chronic Myeloid Leukemia (CML) - translocation of chromosomes t(9;22) - Philadelphia Chromosome. This creates of fusion of the BCR and ABL gene. These genes regulate tyrosine kinase receptors.
Other examples:
- Chronic Lymphocytic Leukemia - t(11;14)
- Follicular Lymphomas - t(12;18)
- Burkitt Lymphoma - t(8;14), t(8;22), t(2;8)
- Large B-Cell lymphoma - t(3;14)
Multiple Endocrine Neoplasia 2 (MEN2) is an important inherited syndrome of oncogenes.
- What gene is effected?
- What does that gene do?
- What cancer is it associated with?
The RET proto-oncogene produces a tyrosine kinase receptor. A mutation to different domains on the receptor (extracellular, intracellular, transmembrane) can lead to varying forms of MEN2. This inherited mutation is associated with Medullary Thyroid Carcinoma.
MEN2A (Extracelluar) - leads to constitutive phosphorylation…receptor is always on which leads to constant activation of the MAP kinase cascade.
MEN2B (Intracelluar) - Only one ligand is needed to constitutively activate the receptor.
What is the knudson Hypothesis (aka - two hit theory)?
A single LOF mutatation in a tumor suppressor gene does NOT cause cancer. Only after a 2nd allele mutation (two hits), does the cell growth become unregulated.
The second muation is aquired, not inherited.
If a person never gets a second mutation, they will not get cancer and will be nonpenetrant for the disease.
What are the 3 ways the Knudson Hypothesis (aka - two hit theory) works…..what are the mechanisms of action?
- Point Muatation on 2nd allele
- Deletion of a section of the chromosome (loss of heterozygosity) - 2nd allele gene is deleted leaving only mutated genes
- Epigenetic modifications - 2nd allele is methylated
What are some differences and characteristics between herediatary cancer and sporatic cancer?
- Hereditary cancer is when an individual is born with one mutatant allele and one normal. (ie - more susceptible)
- Sporadic Cancer is when an individual is born with 2 normal alleles.
Hereditary Cancers will have the following characteristics:
- Synchronous Tumors - arise simultaneously in different parts of same tissue
- Metachronous - Aris at different times in same tissue
- Early Onset
- Multiple Tissues
Sporadic Cancers will have the following characteristics:
- Arise from a single location
- Occur due to cumulative somatic mutations
- Older onset.
Adenomatous Polyposis Coli Gene (APC) is the gatekeeper for colorectal cancer. Why?
What is disease is caused by an inherited mutation of 1 allele in the APC gene?
2 mutations (biallelic) in the APC gene is the 1st step towards colon cancer.
Familial Adenomatous Polyposis (FAP) - every cell has one muatated APC gene. Only need one more mutation to get cancer. Likelihood of cancer by age 40 is ~100%. This is a cancer susceptiblity syndrome caused by a mutation in a tumor suppressor gene.
What is Lynch Syndrome?
It is a cancer susceptibility syndrome. LOF in 1 of 4 mismatch DNA repair genes (MSH2, MLH1, MSH6, PMS2)
Most common cause of colorectal cancer..more than FAP.
- Smaller # of polyps, Early onset, 80% risk of getting CRC (colorectal cancer).
What are the diagnostic criteria for Lynch Syndrome (aka - the Amsterdam II Critera)?
- 3 relatives with Lynch Syndrome Associated tumors, 1 of whom is a 1st degree relative of the other two.
- Must involve at least 2 generations
- ONe or more cases diagnosed before the age of 50.
What is LI-Fraumeni Syndrome? What 4 types of cancer is it assocated with?
Li-Fraumeni Syndrome is cancer susceptibility syndrome caused by a mutation of the TP53 gene which is involved in DNA repair and apoptosis.
It is associated with the 4 B’s : Brain, Bone, Blood, Breast.
- 50% cancer by age 30
- 90% cancer by age 70
- 100% risk of breast cancer
What is herediatry breast/ovarian cancer syndrome?
A cancer susceptiblity syndrome caused by a mutation in the BRCA1 and BRCA2 genes.
What is retinoblastoma syndrome?
A cancer susceptibility cancer caused by a mutation to the retinoblastoma gene. This causes cancers in the retina.
Presents with a white reflex (as opposed to red) in the back of the eye. Early onset (preschool)
What does the family history look like for cancer susceptiblity syndromes? Is it dominiant or recessive phenotype?
The family history looks like a dominant phenotype, even thorugh the genetic mutation is recessive. This is because it takes 2 mutations to cause cancer.
What is a polymorphism? What is a mutation?
A polymorphism is a variant without a disease phenotype, occurs in normal population, may not necessarily produce a change in amino acid
-no change = silent/synonymous, change in a.a. = missense/nonsynonymous
“Mutation” is generally reserved to describe a change that results in a significant disruption of function.
-Missense, frameshift, nonsense, chromosomal rearrangement, splice donor/acceptor mutation, nondisjunction, copy number variants
What is a missense mutation?
A missense mutation alters the amino acid. If a missense mutation produces a >50% alteration in function of the gene product, it is clearly a mutation and harmful. If it produces a <50% alteration, it may more accurately be referred to as a nonsynonymous polymorphism, particularly if it is present in the general population.
What is a nonsense mutation?
A single base pair mutation may produce either a missense or nonsense mutation. A nonsense mutation results in a premature truncation of the gene product and is always considered harmful.
What is a splice site mutation?
A mutation at an intron/exon junction may modify a splice site consensus sequence and is usually considered harmful due to the persistence of an intron code in the final protein, or the skipping of an exon in the translation process. Deletions or duplications of large portions of a gene are also considered harmful.
