What is aneuploidy?
A state of deviation from the normal (euploid) karyotype, as seen in many cancer cells.
What is a cell clone?
Any of the mutant cells directly descended from a single progenitor cell in which the mutation originally occurred.
What is chromosomal translocation?
A form of aneuploidy in which a segment is broken off from one chromosomal arm and becomes fused to the arm of another chromosome.
What is a double minute (DM)?
A subchromosomal fragment resulting from a form of aneuploidy in which a segment is cleaved out of a chromosome, replicates as an autonomous, extrachromosomal entity, and increases to many copies per nucleus.
What is euploidy?
The state in which chromosomes are configured normally, with autosomes present in normally structured pairs and X and Y chromosomes present in the numbers appropriate for the sex of the individual carrying them.
What are genetic polymorphisms?
The inter-individual, functionally silent differences in DNA sequence that make each human genome unique.
What is a homogeneously staining region (HSR)?
A form of aneuploidy in which a segment of a chromosome is copied many times over, with the resulting extra copies fused head-to-tail in long arrays within a chromosomal segment.
What is interstitial deletion?
A type of genetic mutation in which a segment in the middle of a chromosome is discarded and the flanking chromosomal regions are joined together.
What is a neutral mutation?
A mutation resulting in an allele that is phenotypically silent; neither advantageous nor disadvantageous.
What is reciprocal chromosomal translocation?
A form of aneuploidy in which chromosomal segments are exchanged between chromosomes from different chromosome pairs.
What are 6 major types of aneuploidy often seen in cancer cells?
- Accumulation of extra copies of otherwise normal chromosomes
- Translocation (reciprocal or not)
- Gene amplification
- Deletion of growth-inhibiting genes
What is gene amplification?
An increase in the number of copies of genes carried in abnormal chromosomal segments, as seen in double minutes (DMs) and homogeneously staining regions (HSRs).
Which 2 major forms of aneuploidy result in gene amplification?
- Homogeneously staining regions (HSRs)
- Double minutes (DMs)
What condition must be met for a recently created mutant allele to be passed from an organism to its offspring?
The mutation must strike a gene carried in the genome of the sperm or egg, or in the genome of one of the cell types that are the immediate precursors of the sperm or egg within the gonads.
Approximately how many genes are in the human genome?
What are the two main broad classes of genes within mammalian cells?
- Housekeeping genes
- Tissue-specific genes
What are housekeeping genes?
Commonly expressed genes encoding proteins that are required universally to maintaing viability of all cell types or to carry out certain biological functions common to all cell types throughout the body.
What are tissue-specific genes?
Genes dedicated to the production of proteins (phenotypes) that are associated specifically with a differentiated cell.
What is pleiotropy?
The ability of a single transcription factor (or a single gene that specifies it) to elicit multiple changes within a cell or organism.
How can a malfunctioning pleotropic transcription factor lead to cancer?
It can simultaneously affect the expression of a large cohort of responder genes that together proceed to create the cancer cell phenotype.
What is a gene expression program?
The coordinated expression of multiple genes within a cell, dependent on the actions of multiple transcription factors acting in combination on large numbers of gene promoters.
What are the two broad categories of tumour, based on degree of aggressive growth?
What is a benign tumour?
A tumour that grows locally without invading adjacent tissues.
What is a malignant tumour?
A tumour that invades nearby tissues and spawns metastases.
How can benign tumours commonly cause clinical problems?
By releasing dangerously high levels of hormones, creating physiologic imbalances in the body.
What is a thyroid adenoma?
A premalignant epithelial growth in the thyroid that can cause excessive release of thyroid hormone into the circulation, leading to hyperthyroidism.
What is an adenoma?
A premalignant epithelial growth (tumour).
What is acromegaly?
A condition characterized by excessive growth of certain tissues.
How do pituitary adenomas cause acromegaly?
By releasing growth hormone into the circulation, resulting in exceesive growth of certain tissues.
What are epithelia?
Sheets of cells that line the walls of cavities and channels or, in the case of skin, serve as the outside covering of the body.
What type of cancer cells are responsible for approximately 90% of all deaths from cancer?
Metastases spawned by malignant tumours.
What is the basal lamina (or basement membrane)?
A layer of cells separating the epithelial cells from the underlying layer of supporting connective tissue cells (the stroma), assembled from proteins secreted largely by the epithelial cells into a specialized type of extracellular matrix.
What is the stroma?
The layer of supporting connective tissue cells underlying the epithelia, separated from the epithelia by the basal lamina.
What are endothelial cells?
Cells that form the inner linings of capillaries and larger vessels, resting on a specialized basement membrane that separates them from an outer layer of specialized smooth muscle cells.
What is the most common class of human cancers?
The carcinomas (tumours arising from epithelial tissues).
What are carcinomas?
Tumours arising from epithelial tissues; the most common group of human cancers.
What are the three primitive cell layers found in the early vertebrate embryo?
Which epithelia are derived from the endoderm?
The epithelia of the gut and derived outpouchings, including lung, pancreas, and liver.
Which epithelia are derived from the ectoderm?
The epithelia of the skin and nervous system.
Which epithelia are derived from the mesoderm?
The epithelia of connective tissues, including bone, muscle, and blood-forming cells.
What are the 2 most common categories of carcinomas?
- Squamous cell carcinomas
What are squamous cell carcinomas?
Tumours arising from epithelial cells that function to seal the cavity or channel that they line and to protect the underlying cell populations (e.g. skin, esophagus).
What are adenocarcinomas?
Tumours arising from specialized epithelial cells that secrete substances into the ducts or cavities that they line, often to protect the epithelial cell layers from the contents of the cavities that they surround (e.g. mucus-secreting lung/stomach epithelial cells).
What are sarcomas?
A major class of nonepithelial tumours arising from various connective tissues throughout the body.
What are mesenchymal cells/tissues?
Cells/tissues derived from the mesoderm, including fibroblasts (and related collagen-secreting connective cell/tissue types), adipocytes, osteoblasts, and myocytes.
What are fibroblasts?
Connective tissue cells that secrete collagen, forming the major structural component of the extracellular matrix of tendons and skin.
What are adipocytes?
Mesenchymal cells that store fat in their cytoplasm.
What are osteoblasts?
Mesenchymal cells that assemble calcium phosphate crystals within matrices of collagen to form bone.
What are myocytes?
Mesenchymal cells that assemble to form muscle.
What is an angiosarcoma?
An uncommon type of tumour that arises from precursors of the endothelial cells.
What are hematopoietic malignancies?
Nonepithelial cancers arising from various cell types that constitute blood-forming tissues, including the cells of the immune system.
What are leukemias?
Malignant derivatives of hematopoietic cell lineages that move freely through the circulation and are nonpigmented.
What are lymphomas?
Tumours of the lymphoid lineages (B and T lymphocytes) that aggregate to form solid tumour masses, most frequently found in lymph nodes.
What are neuroectodermal tumours?
A group of nonepithelial tumours arising from cells that form various components of the central and peripheral nervous system.
What are the 3 major groupings of nonepithelial tumours?
- Hematopoietic malignancies
- Neuroectodermal tumours
What are melanomas?
Tumours derived from melanocytes (pigmented cells of the skin and retina).
What is transdifferentiation?
The switching of tissue lineage and resulting acquisition of a new set of differentiated characteristics (relative to the differentiation lineage determined for the same cell during embryogenesis).
What is epithelial-mesenchymal transition (EMT)?
A shift in cell phenotype in which epithelial cancer cells change shape and gene expression programs to take on attributes of nearby stromal cells of mesenchymal origin; found at the borders of many carcinomas.
What kind of transdifferentiation is seen in small-cell lung carcinomas (SCLCs)?
Lung epithelial cells shed some of their epithelial characteristics and take on many attributes of neurosecretory cells, secreting biologically active peptides (often in response to neuronal signalling).
What major biological principle governing most cancers allows pathologists to classify tumours and assign a tissue of origin?
While cancer cells deviate substantially in behaviour from their normal cellular precursors, they almost always retain some of the distinctive attributes of the normal cell types from which they arose.
What is an anaplastic tumour?
A tumour in which the cells have shed virtually all of the tissue-specific, differentiated traits of their normal precursor tissues, making it impossible to use histopathological criteria to identify the tissue of origin.
What are dedifferentiated cells?
Cells in an anaplastic tumour that have shed virtually all of the tissue-specific, differentiated traits of their normal precursor tissues.
What are hyperplastic growths?
Abnormal cell masses that contain cells that deviate only minimally from those of normal tissues, but are abnormal in that they contain excessive numbers of cells.
What is metaplasia?
An abnormal cell growth in which one type of normal cell layer is displaced by cells of another type that are not normally encountered in that site within a tissue.
Where is metaplasia most frequently found?
In epithelial transition zones, where one type of epithelium meets another.
What is leukocytosis?
Benign leukemia, characterized by uncontrolled proliferation of white blood cells.
In the context of the immune system, what is resolution?
Successfully fighting off an infection or cancer and returning the tissue to its normal state.
What is the leading cause of death in Canada?
What is the leading cause of death (surpassing cancer) in many developing countries?
What are 3 major factors driving the increased risk of cancer with age?
- More time to be exposed to carcinogens
- Greater chance for DNA mutations and failure of DNA repair
- Telomere degradation
What phenomenon has been observed in people immigrating to the US from Japan?
In Japan, stomach cancer is more common than colon cancer, but Japanese immigrants to the US develop colon cancer more frequently (which is more common in the US than stomach cancer).
What country has the highest frequency of leukemia?
What country has the highest frequency of colon cancer?
What country has the highest frequency of cervical cancer?
What country has the highest frequency of lung cancer?
What country has the highest frequency of liver cancer?
What country has the highest frequency of stomach cancer?
What country has the highest frequency of skin cancer?
What 3 causes of cancer are clearly indicated by geographical variation in cancer types and frequencies?
- Environmental causes
- Genetic causes
- Behavioural causes
What 3 characteristics define a tumour?
A mass of cells that...
- Exceeds the bounds of the surrounding tissue
- Is uncoordinated with normal tissue
- Keeps growing even after initial growth stimuli are removed
What is the most common site of metastasis for prostate cancer?
What is the most common site of metastasis for small cell lung cancer?
What is the most common site of metastasis for neuroblastomas?
What is the most common site of metastasis for breast cancer?
What types of cancers are more likely to affect the young?
Cancers with some genetic cause.
What 3 proteins interact with p53 to promote growth arrest?
What regulatory protein depends on p53 as a transcription factor?
How does p53 regulate itself in a negative feedback loop?
By acting as a transcription factor to increase expression of Mdm2, which can form a complex with p53 that promotes the ubiquitylation and degradation of p53.
What happens to p53 in the cell when there is no DNA damage?
Unphosphorylated p53 promotes expression of Mdm2, which is (later) phosphorylated; phosphorylated Mdm2 forms a complex with p53, targeting p53 for ubiquitylation and degradation.
What happens to p53 when there is DNA damage in the cell?
p53 is phosphorylated so that it cannot form a complex with Mdm2, so it is not targeted for ubiquitylation and can instead go on to activate other growth arrest and pro-apoptotic proteins.
What is the role of ATM kinase in DNA repair?
ATM kinase is activated when DNA damage is detected; it phosphorylates p53 to keep it from being bound by Mdm2 so that it cannot be targeted for ubiquitylation and degradation (and can instead go on to activate other proteins in the repair/apoptosis pathway).
What happens to ATM kinase when DNA damage is successfully repaired?
ATM kinase is inactivated (resulting in dephosphorylation of p53, which can then be bound by Mdm2 and targeted for ubiquitylation and degradation).
Where are p53 and Mdm2 synthesized?
On the rough ER.
What is p21?
A cyclin-dependent inhibitor of Cdk2 and Cdc2; when activated by p53, it inhibits Cdk2 so that the cell cannot enter S phase, and Cdc2 so that the cell cannot enter M phase.
What is GADD45?
A stress protein, upregulated and activated by p53 in the event of environmental stress leading to DNA damage; it inhibits Cdc2 so that the cell cannot enter M phase.
What is 14-3-3σ?
A protein, activated on DNA damage by p53, that inhibits Cdc2 so that the cell cannot enter M phase.
How does Bax promote apoptosis?
It forms ion pores in the outer mitochondrial membrane that allow the release of cytochrome c, which goes on to trigger other pro-apoptotic enzymes.
Which caspase is activated by cytochrome c in the intrinsic apoptotic pathway?
Which downstream caspase is the final (terminator) caspase common to both intrinsic and extrinsic cell death pathways?
How does p14 Arf help to promote DNA repair and/or apoptosis?
It sequesters Mdm2 so that it cannot bind p53 and trigger the ubiquitylation and degradation of p53.
Why is it important to have p14 Arf as a braking mechanism to control Mdm2 activity during DNA repair?
p53 acts as a transcription factor for Mdm2 as part of its normal activity, so increased damage leads to increased levels of both p53 and Mdm2; without p14 Arf sequestering Mdm2, p53 and Mdm2 would just increase together and p53 would be bound and destroyed at the same rate as if it were at lower levels.
Which member of the Bcl2 protein family is the only anti-apoptotic protein?
Are Bax proteins (of the Bcl2 family) pro- or anti-apoptotic?
Is Bcl2 (of the Bcl2 protein family) pro- or anti-apoptotic?
Are BH3-only proteins (of the Bcl2 protein family) pro- or anti-apoptotic?
What protein family do Bax, Bad, and Bid belong to?
The Bcl2 protein family.
What function do members of the Bcl2 protein family have in common?
They are all pore-forming proteins that control the permeability of the mitochondrial outer membrane to cytochrome c, which has an important role in intrinsic apoptosis.
Why does overexpression of Bcl2 protein lead to increased risk of cancer?
Bcl2 is anti-apoptotic, so overexpression can block apoptosis (a hallmark of cancer).
What is ER stress?
A condition in which cellular damage is indicated by accumulation of unfolded proteins at the smooth ER; the smooth ER is then targeted by Bcl2 proteins to initiate apoptosis.
What chemical messenger is stored in the smooth ER and can be released when the ER is targeted by pore-forming Bcl2 proteins during apoptosis?
Which caspase is activated by death receptors (Fasr) to initiate apoptosis?
Is caspase-9 associated with the extrinsic or intrinsic pathway of apoptosis?
Is caspase-8 associated with the extrinsic or intrinsic pathway of apoptosis?
Is caspase-3 associated with the extrinsic or intrinsic pathway of apoptosis?
Yes - both (can be activated by caspase-8 or caspase-9).
What Bcl2 protein allows cross-talk between the extrinsic and intrinsic pathways of apoptosis?
Bid: when converted by caspase-8 (extrinsic) to active t-Bid, it can interact with other Bcl2 proteins in the intrinsic pathway to form channels in the mitochondrial membrane for release of cytochrome c and activation of caspase-9 (intrinsic).
What is blebbing?
The packaging of an apoptotic cell into many small vesicles for easier removal by resident macrophages.
What characteristic of cells that have undergone blebbing allows us to determine whether chemotherapy is successful?
Microcells resulting from blebbing keep the epitopes marking them as belonging to their parent tissue; if microcells with epitopes from the tumour site are present in the blood, it means cells from that site have undergone apoptosis.
In what 2 ways does blebbing help to avoid an inflammatory response to apoptotic cells?