The Molecular Basis of Cancer Flashcards
What are the two main characteristics of cancer cells?
- Reproduce despite normal constraints that inhibit cell proliferation and clonal expansion
- Cancer cells invade and colonize territories normally reserved for other cells
How do cancer cells look physically different to other cells?
Enlarged nucleus, changes to cytoskeleton and loss of specialised features
Tumours that remain localised and look like the tissues they came from are likely to be…
Benign
Tumours that do not resemble the tissue of origin and invade surrounding tissue are likely to be…
Malignant
Cancer cells appear different than surrounding normal cells, divide at a ______ rate, have a _____ metabolic rate and invade new tissues
Faster; high
Cancers that invade other tissues and spread to other parts of the body are said to be…
Metastatic
What is the growth factor responsible for angiogenesis?
VEGF
What are the two ways that DNA damage can be acquired?
Inherited and acquired
Why does cancer incidence increase with age?
Cumulative exposure to mutagens
DNA repair systems worsen
What are compounds or chemical that produce cancer called?
Carcinocens
How likely a mutation will lead to cancer is called its…
Penetrance
Genes that promote cancer are called…
Oncogenes
Genes that act to prevent cancer are called…
Tumour suppressor genes
Genes that repair mutated DNA are called…
Mismatch repair genes
What are the five major classes of oncogenes?
Growth factors Growth factor receptors Intracellular signalling proteins Transcription factors Cell cycle control proteins
How are proto-oncogenes altered by viruses?
Insertion of the viral gene either upstream of the proto-oncogene or within the coding sequence
Mutations of tumour suppression genes that code for cell adhesion/recognition can lead to…
cell losing their adhesion to their neighbours and spreading
Mutations of tumour suppression genes that code for enzymes in DNA repair can lead to…
production of mutant proteins that no longer repair DNA causing mutations to accumulate
Mutations of tumour suppression genes that inhibit cell division can lead to…
Mutant proteins being produces that no longer block cell division
What is the two-hit hypothesis for cancer?
In order to get cancer, both alleles of a tumor supressor gene must be mutated
What are the role of tumour supressor genes?
To prevent cells from progressing through the cell cycle - allowing repair of damaged DNA
A rare childhood tumour of the retina with high penetrance is called…
Retinoblastoma
What does hereditary retinoblastoma result in tumour in both eyes?
The mutated gene is in all cells so is therefore expressed in the retinas of both eyes
What are the six ways of losing the remaining copy of a normal tumor suppressor gene?
Nondisjunction (chromosome loss) Nondisjunction and duplication Mitotic recombination Gene conversion Deletion Point mutation
Which tumour suppressor is responsible for holding the cell at G1 checkpoint?
p53
50% of all tumour show mutations and loss of function of _____
p53
What cellular responses does p53 induce?
Cell cycle arrest
Senescence
Cell differentiation
Apoptosis
How does p53 activation inhibit cell growth?
Either through cell-cycle arrest or induction of apoptosis
What are the different types of chromosomal mutations?
Deletion of gene Chromosome loss Gain of chromosome Duplication of gene Inversion Translocation
How can chromosomal translocation lead to cancer?
Relocation of an oncogene next to a novel regulatory element
Formation of a hybrid oncogene
True or False:
Chromosomal translocation is an acquired somatic event only
True
True or False:
Chromosomal translocation is clonal
True
What techniques can be used to detect chromosomal translocation?
Karyotype
PCR
FISH
Southern Blot
What are the two types of leukemia’s and what is there untreated life expectancy?
Acute (3-4 months untreated)
Chronic (years untreated)
What cancer is produced by only one mutation?
Chronic myeloid leukemia
True or False:
Chronic Myeloid Leukemia is curable
True
What cells have the mutation in chronic myeloid leukemia?
Myeloid progenitors
What chromosomal translocation causes chronic myeloid leukemia?
Reciprocal translocation of Abl tyrosine kinase from chromosome 9 to BCR on chromosome 22. Results in a Ph chromosome (shortened chromosome 22)
The chromosomal translocation of chronic myeloid leukemia can be detected by what techniques?
Standard cytogenetics
FISH
PCR
True or False:
Abl tyrosine kinase is found in the cell membrane
False; it is found in the cell
What drug inhibits the activity of Abl tyrosine kinase and is therefore a treatment for CML?
STI-Gleevac
How does STI-Gleevac inhibit the activity of Abl tyrosine kinase?
It functions by blocking the binding of ATP to the bcr-abl tyrosine kinase, inhibiting its activity. In the absence of tyrosine kinase activity, substrates required for Bcr-Abl function cannot be phosphorylated and subsequenct cellular events are abrogated
How does the Bcr-Abl tyrosine kinase cause CML?
The Bcr-Abl tyrosine kinase is a constituitively active kinase which functions by binding ATP and transferring phosphate from ATP to tyrosine residues on various substrates. This causes the excess proliferation of myeloid cells characteristic of CML
What are some genes that encode for growth factors or their receptors?
PDGF
Erb-B
What are some genes that are involved in cell signalling?
K-ras
N-ras
What are some genes for transcription factors that activate genes?
c-myc
N-myc
L-myc
What is ABL?
a proto-oncogene located on chromosome 9 that encodes a tyrosine kinase. It is negatively regulated by its SH3 domain and deletion of the SH3 domain turns ABL into an oncogene. The t(9;22) translocation results in the head-to-tailfusionof theBCRandABLgenes, leading to afusion genepresent in many cases of chronicmyelogenous leukemia
Define angiogenesis
the growth of new blood vessels that tumours need to grow. This process is caused by the release of chemicals by the tumour and by the host cells near the tumour
Define anti-angiogenics
drugs that prevent the growth of new blood vessels and therefore restrict the size that a tumour can grow
Define ATP-competitive inhibitors
a molecule that binds to an enzyme and decreases its activity
Define benign
referring to a tumour that does not invade surrounding tissue or spread to other parts of the body
Define BRC1
a human tumour suppressor gene that encodes a protein that is responsible for repairing DNA. Point mutations or larger deletion and duplication mutations can result in the protein being dysfunctional, and leads to a high penetrance for breast and ovarian cancer
Define cancer
A term for diseases in which abnormal cells divide without control and can invade nearby tissues
Define carcinogen
any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes
Define cell-cycle arrest
when a cell stops at a cell cycle checkpoint after detecting defects in the DNA. This prevents the accumulation of mutations and development of cancer
Define chemotherapy
a type ofcancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardizedchemotherapy regimen
Define chromosomal translocation
achromosomeabnormality caused by rearrangement of parts between nonhomologouschromosomes. A gene fusion may be created when thetranslocation joins two otherwise-separated genes, it is detected on cytogenetics or a karyotype of affected cells
Define chronic myeloid leukemia
a cancer of thewhite blood cells. It is a form ofleukemia characterized by the increased and unregulated growth of predominantlymyeloid cells in thebone marrowand the accumulation of these cells in the blood. It results from a chromosomal translocation where parts of chromosome 9 and 22 swap, creating the BCR-ABL gene, which codes for tyrosine kinase, and the Ph chromosome
Define clonal expansion
The explosive increase in the number of lymphocytes, both B cells and T cells
Define cell proliferation
An increase in the number of cells as a result of cell growth and cell division
Define cytogenic remission
a molecular response that occurs in CML patients undergoing treatment where the cells no longer have the Ph chromosome
Define DNA virus
avirusthat hasDNAas its genetic material and replicates using aDNA-dependent DNApolymerase.
Define familial aggregation
the clustering of certain traits, behaviours, or disorders within a givenfamily.Family aggregationmay arise because of genetic or environmental similarities
Define FISH
Fluorescence in situ hybridization (FISH) is atestthat “maps” the genetic material in a person’s cells. This testcan be used to visualize specific genes or portions of genes.FISH testingis done on breast cancer tissue removed during biopsy to see if the cells have extra copies of the HER2 gene.
Define fusion protein
proteinscreated through the joining of two or more genes that originally coded for separateproteins
Define gene amplification
an increase in the number of copies of agene without a proportional increase in othergenes. This can result from duplication of a region of DNA that contains agenethrough errors in DNA replication and repair machinery as well as through fortuitous capture by selfishgeneticelements
Define growth factors
molecules that typically act as signalling molecules between cells. Examples are cytokines and hormonesthat bind to specific receptors on the surface of their target cells. They often promote cell differentiation and maturation, which varies between growth factors
Define haematological remission
a molecular response that occurs in CML patients undergoing treatment where BCR-ABL gene can no longer be detected in the blood
Define karyotype
the number and appearance of chromosomes in the nucleus of a eukaryotic cell
Define malignant
A term for diseases in which abnormal cells divide without control and can invade nearby tissues
Define metastasis
the development of secondary malignant growths at a distance from a primary site of cancer
Define mismatch repair genes
a gene that encodes proteins responsible for regulating DNA mismatch repair. Mutations can be inherited or sporadically and result in the inability to regulate DNA replication resulting in the accumulation of mutations
Define mutagen
a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level
Define MYC
a family of regulatorgenesand proto-oncogenes that code for transcription factors. In cancer, c-myc is often constitutively expressed resulting in increased expression of cell proliferation genes
Define oncogene
a gene that has the potential to cause cancer. In tumor cells, they are often mutated and/or expressed at high levels
Define p53
a tumor suppressor gene that plays a role in apoptosis, genomic stability and inhibition of angiogenesis.
Define PCR
a technique used inmolecular biologytoamplify a single copy or a few copies of a segment ofDNAacross several orders of magnitude, generating thousands to millions of copies of a particularDNA sequence
Define penetrance
the proportion of individuals carrying a particular variant (orallele) of agene(thegenotype) that also express an associated trait (thephenotype)
Define Ph chromosome
Philadelphia translocation(Ph) is a specific genetic abnormality inchromosome 22ofleukemia cancercells (particularlychronic myeloid leukemia(CML) cells). This chromosome is defective and unusually short because ofreciprocal translocation of genetic material betweenchromosome 9and chromosome 22, and contains afusion genecalledBCR-ABL1.
Define proto-oncogene
A normal gene which, when altered by mutation, becomes anoncogenethat can contribute to cancer.Proto-oncogenesmay have many different functions in the cell. Someproto-oncogenesprovide signals that lead to cell division. Otherproto-oncogenesregulate programmed cell death (apoptosis)
Define Ras
A family of proteins that are involved in transmitting signals with in cells. Mutations inrasgenes can lead to the production of permanently activated Ras proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals. Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead tocancer
Define retinoblastoma
a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye
Define RNA virus
avirusthat hasRNA(ribonucleic acid) as its genetic material. This nucleic acid is usually single-strandedRNA(ssRNA) but may be double-strandedRNA(dsRNA)
Define southern blotting
a method used in molecular biology for detection of a specific DNA sequence in DNA samples.Southern blottingcombines transfer of electrophoresis-separated DNA fragments to a filter membrane and subsequent fragment detection by probe hybridization
Define spontaneous mutation
a DNA mutation that can
arise from a variety of sources, including errors inDNAreplication, spontaneous lesions, and transposable genetic elements
Define STI-Gleevac
a medication used to treat CML that works by stopping the BCR-ABL tyrosine kinase. This can slow growth or result in programmed cell death of certain types of cancer cells
Define transcription factors
DNA-binding proteins that regulate the expression of an array of target gene that usually have transactivation domains that activate or repress genes)
Define tumour supressor genes
agenethat protects a cell from one step on the path to cancer. When this genemutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other geneticchanges
Define tyrosine kinase receptors
the high-affinity cell surfacereceptorsfor many polypeptide growth factors, cytokines, and hormones
Define VEGF
vascular endothelial growth factor; a signal protein produced by cells that stimulates the formation of blood vessels (angiogenesis)
