MBB 446 Lecture 5 Flashcards
What was the 1970’s theory regarding viruses and cancer? Problem?
- theory that DNA and RNA tumor viruses could infect tissue, cause transformation of infected cells, and lead to cancer (based on observations in rodent and chicken cells)
- most types of human cancer did not spread like infectious disease; “clusters” (mini-epidemics) of cancer cases were hard to find; attempts to isolate viruses from human tumors were unsuccessful
- Exceptions: cervical carcinomas and hepatomas (liver cancer); linked to specific viral causative agents
How did most of the endogenous retroviral genomes present in the human genome come about?
result of germ-line infections that occurred 5 million years ago;; proviruses sequences mutated and could no longer encode infectious retroviral particles
% of human genome that derives from endogenous retroviral genomes?
Up to 8%
Retroviruses can lead to cancer by deregulating genes at their sites of ______ (insertional mutagenesis) in animal models------but no evidence in humans
integration
_______ have comparable incidence rates
_______ highly variable incidence rates
Pediatric tumors have comparable incidence rates
Skin cancer – highly variable incidence rates
Define incidence
of new cases of disease; can be reported as a risk or as an incidence rate; frequency with which a disease occurs or is diagnosed in a population
Define prevalence
of existing cases of a disease, at a particular point in time
How can incidence be low but prevalence high? Giveexample
In slow progressing diseases e.g. incidence of pancreatic neuroendocrine tumors is low, but the prevalence is relatively high
What environment/lifestyle factors are etiologic for human cancers?
- Diet
2. Tobacco
What were Katsusaburo Yamagiwa two main findings
- Directly implicated chemicals in cancer causation
2. Demonstrated that cancer can be induced in lab animals
Define carcinogen
Cancer-causing
Define mutagens
mutates DNA; many carcinogens can act as mutagens
Define oncogenes
- a gene capable of transforming a normal cell into a tumor cell
- a gene that causes cells to grow in an uncontrolled manner
- oncogenes are mutant forms of normal functional genes (called proto-oncogenes) that have a role in cell proliferation
- proto-oncogenes have the intrinsic potential to induce cancer
How could the oncogenes be detected/found?
Transfection = gene transfer technique (to detect oncogene activity)
SHOWING mouse tumor transforming mouse cells
- Take chemically transformed mouse fibroblasts and isolate DNA
- Transfection using calcium phosphate co-precipitation procedure. Ca-P facilitates uptake of DNA into normal cells
- Inject into normal mouse fibroblasts
- Formation of a focus of morphologically transformed cells if transforming gene (oncogene) present in DNA
- Injection of morphologically transformed cells into mouse host
- Tumor formation
Could the same group of cellular proto-oncogenes be activated by retroviruses (e.g. by insertional mutagenesis) in one context and by non-viral mutagens in other contexts? OR are there two distinct groups of cellular proto-oncogenes?
N/A
What are the 6 main products of oncogenes? The one new “non-coding” class?
- Transcription factors
- Chromatin remodelling
- Growth factors
- Signal transducers
- Growth factor receptors
- Apoptosis regulators
And one “new” non-coding class: miRNAs
What are the 4 mechanisms of oncogene activation? How do they induce changes
- Gene amplification
- Chromosome rearrangement
- Mutation
- Post-transcriptional modification by miRNAs
- Cause increase or deregulation of expression
- Cause alteration of oncogene structure
Example of each of the 4 mechanisms of oncogene activation?
- Gene amplification
- Amplification of HER2 in human breast cancer - Chromosome rearrangement
- chromosomal translocation: formation of bcr-abl oncogene. “Philidelphia chromosome; reciprocal translocation of 9 and 22”
3. Mutation: H-ras proto-oncogene - Expression and structure appeared same - DNA sequence analysis showed a single base substitution in which guanosine was substituted by thymidine; this single point mutation converted a normal gene into a potent oncogene (Glycine to Valine change) - Ras Val12
- Post-transcriptional modification by miRNAs
Describe the circos plot of genetic variation in liposarcoma
Inner-most circle contains validated structural rearrangements of fusion genes with translocations indicated in purple, and intra- chromosomal rearrangements indicated in orange. The middle ring contains the aCGH plot with copy number loss indicated in green and copy number gain in red;; each orange ring corresponds to a log2 value of 1. The outer-most ring indicates validated, damaging single nucleotide variants.
How is abl-bcr fusion protein targeted by therapies?
fusion protein has tyrosine kinase activity that is targeted by therapies
Different breakpoints in Bcr are associated with distinct ______
leukemias
How does translocation affect post-transcriptional regulation by miRNA? Example?
Translocation relieves miRNA-mediated suppression of translation. Translocation serves to liberate a proto-oncogene from neg regulation. E.g. HMGA2
What is a OncomiR?
- a microRNA associated with cancer
- either fxn as oncogene or tumor suppressors
- Involved in many cellular processes that are altered in cancer such as differentiation, proliferation and apoptosis
Example of a oncomiRNA?
microRNA-21 (miR-21) is an miRNA overexpressed in many tumors
