Exam 4: Intro to Cancer Genetics Flashcards
Define cancer as a genetic disease
Cancer is often referred to as a genetic disease because it results from mutated gene products or abnormally expressed genes.
Cancer is caused by mutations generally in somatic cells, only 5% are associated with germline mutation
Describe Knudson’s multi-hit cancer model and its relation to cancer as a progressive disease.
Alfred Knudson studied sporadic and inherited retinoblastoma.
He noted that inherited retinoblastoma occurs at a younger age and more often resulted in tumor formation in both eyes compared to the sporadic disease.
Knuson hypothesized that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the underlying predisposition is caused by a first insult inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited
retinoblastoma, two “hits” had to take place before a tumor could develop, explaining the age difference.
First Hit (Germline Mutation): Individuals inherit one mutated copy of a tumor suppressor gene from one of their parents. This germline mutation is present in every cell of their body.
Normal Cell (One Functional Copy of the Tumor Suppressor Gene): In the early stages of life, the individual’s cells have one normal (functional) copy of the tumor suppressor gene and one mutated copy. At this point, there’s no apparent impact on cell behavior.
Second Hit (Somatic Mutation): A somatic mutation, or a random mutation, occurs in the other copy of the tumor suppressor gene in a specific cell. This second hit results in the loss of function of the tumor suppressor gene in that cell.
Loss of Tumor Suppressor Function: With both copies of the tumor suppressor gene now mutated (loss of heterozygosity), the cell loses the normal regulatory control over cell division. This loss of tumor suppressor function allows the cell to start dividing uncontrollably, leading to the development of a tumor.
Compare and contrast proto-oncogenes and tumor suppressors.
Proto-oncogenes: Normally produce factors that STIMULATE cell division. Tend to be dominant, so only one copy required to produce excessive cell proliferation. When a proto-oncogene undergoes a mutation that leads to its overactivity, it becomes an oncogene. This can result in uncontrolled cell growth.
Tumor Suppressor: Normally produce factors that INHIBIT cell division. Mutant alleles are recessive, so both must be mutated to produce excessive cell proliferation (this goes back to the two-hit hypothesis). They regulate processes like DNA repair, cell cycle checkpoints, and apoptosis to prevent the formation of cancerous cells. (Ex: p53, RB, etc)
Describe clonal evolution of cancer cells and how it relates to cancer as a progressive disease.
Clonal Evolution: tumors arise from normal cells that mutate and generate abnormal offspring that also mutate, ultimately forming a mass of genetically varied cancer cells.
Evidence of Clonal origin
-Every patient with Burkitt lymphoma carries a reciprocal translocation between chromosome 8 and either chromosome 2, 14, or 22.
-X-inactivation is the same within cancer cells of a female individual.
Discuss the behaviors of cancer cells that may differentiate them from normal cells.
-Uncontrolled cell growth
-Disregard for cell cycle check points
-Resistance to inhibition factors
-Evading apoptosis (programmed cell death…..)
-Telomere maintenance
Benign vs malignant tumors
Benign: Results from unregulated cell growth that forms a multicellular mass. Removed by surgery, causing no serious harm.
Malignant: Result from metastasized cells invading other tissue and causing life-threatening problems.
Explain how cancer is a multistep process that requires multiple mutations.
-No single mutation is tumor forming
-Incidence of most cancers rises exponentially with age
-Cancer formation is delayed from carcinogen exposure
-Independent and random mutations are necessary for a cell to become malignant.
-Cancer develops from accumulation of several mutagenic events in the cell.
Cancer cell evolution: monoclonal vs. polyclonal
Monoclonal evolution means that the cancer cells within a tumor originated from a single cell, often referred to as a single “ancestor” cell. All cells in the tumor share a common set of genetic mutations. Monoclonal evolution is common in certain types of cancers, such as leukemias and some lymphomas. Targeted therapies may be more effective in treating monoclonal tumors because the entire tumor mass shares a common set of vulnerabilities.
Polyclonal evolution means that the cancer cells within a tumor have multiple independent origins, arising from different mutated cells. Polyclonal evolution is common in solid tumors, such as breast cancer and colorectal cancer. The presence of multiple cell populations can contribute to intratumoral heterogeneity, making the tumor more challenging to treat as different subpopulations may respond differently to therapies.
Explain cancer stem cell theory
The first malignant cell, that gives rise to the tumor, is often labeled a cancer stem cell.
The theory assumes that there is a small population of cells in the tumor that exhibits stem cell-like properties and have the ability to give rise to a variety of cells in tumor tissue, self-renew indefinitely, and upon transfer can form new tumors.
According to the hypothesis, cancer stem cells are the only cells capable of tumorigenesis – initiation of a new tumor.
Even if the majority of cancer cells are eliminated through therapy, the survival of CSCs may lead to tumor recurrence and resistance to treatment.
These cells are thought to be responsible for the heterogeneity observed within tumors, as they can generate a diverse range of cell types.
CSCs are often considered more resistant to conventional cancer treatments, such as chemotherapy and radiation therapy.
Describe what a gain-of-function mutation is and how it could be harmful.
A gain-of-function mutation is a type of mutation in which the altered gene product possesses a new molecular function or a new pattern of gene expression.
When a mutation occurs in a proto-oncogene, it becomes permanently activated. The gene then starts making too much of the proteins that code for cell growth. Cell growth occurs uncontrollably. This is called a gain-of-function mutation because the cell takes on a new purpose. This is harmful in this case because it causes cancer.
