Cancer genetics Flashcards
1
Q
What are cancer cells?
A
Cancers derived from mutated single cells that have acquired the characteristics of continually dividing in an unrestricted invasive manner into neighboring tissues.
Alterations in the DNA sequence of cancer gene attribute towards the abnormal manner of cancerous cells
All cancers result from changes in the DNA sequence of the genome
Genome within our cells are exposed to mutagens (UV radiation) and accumulates mistakes during replication
2
Q
What is the probability of DNA polymerase incorrectly inserting bases?
A
1 in 10,000 bases
3
Q
How many errors result per generation due to DNA polymerase incorrect base insertion?
A
2.5 x10^-8 per generation
4
Q
How does a specific mutation alter the function of a critical gene, subsequently causing cancer?
A
Provides growth advantage to the cell, over-expression of oncogenes, tumor factor genes and inhibition of tumor suppressor genes, results in increased mitotic rate
5
Q
How is a tumor from an over-proliferating cancer cell?
A
Increased mitotic rate causes tumor formation, causing it to invade surrounding tissues, leading to metastasis - secondary tumours
6
Q
What is a benign tumour?
A
A mass of well-differentiated cells that grows slowly, and is capsulated, lacking the ability to invade neighboring tissue, unable to metastasized.
7
Q
What is a malignant tumour?
A
A malignant tumor is not self-limited (evades apoptosis, causes angiogenesis), cells poorly differentiated; the ability to invade adjacent tissues and metastasis. Biopsy analyzed by a pathologist to determine tumor category
8
Q
How many steps is carcinogenesis divided into?
A
Initiation
Promotion
Progression
9
Q
What is the initiation step of carcinogenesis?
A
Irreversible genetic alteration (Tranversion, transitions or deletions in DNA)
10
Q
What is the promotion stage of carcinogenesis?
A
Expression of the genome, mediated through promoter-receptor interactions
11
Q
What is the progression stage of carcinogenesis?
A
Molecular targets during the stages of carcinogenesis include protooncogenes, cellular oncogenes, and tumor suppressor genes, alterations in both alleles of the latter found exclusively in the stage of progression.
12
Q
How does cancer develop?
A
Begin due to the accumulation of mutation involving oncogenes, tumor suppressor genes, and DNA repair genes.
13
Q
Which gene in colon cancer is a tumor suppressor?
A
APC
14
Q
How does a defect in the tumor suppressor gene, APC lead to cancer?
A
It enables excessive cell proliferation. Proliferating cells tend to acquire mutations involving DNA repair genes other tumor suppressor genes (p53) or growth-related genes (K-ras)
15
Q
What is the histology of cancer cells?
A
Abnormal, non-uniform variations in size and shape. Nucleus has a distorted appearance. Cancer cells have to distinguish histological features visible under the microscope. The nucleus is irregularly large, with cytoplasm abnormalities.
16
Q
What is melanoma?
A
Consumption of epidermis, the spread of melanocytes (melanin-forming cells), nests of melanocytes with variable size and shape. Diagnosis of melanoma accurate with biopsy, and analyzed by a pathologist.
17
Q
What is carcinoma?
A
Cancer arising from cells that cover the external and internal body surfaces. Lung, breast, and colon (epithelial)
18
Q
What is a sarcoma?
A
Cancer arising from cells found in the supporting tissues of the body (bone, cartilage, fat, connective tissue and muscle)
19
Q
What is lymphoma?
A
Cancers arising from lymph nodes and tissues associated with the immune system
20
Q
What is leukemia?
A
Cancers of immature blood cells that proliferate in the bone marrow, with the tendency to accumulate in large number within the bloodstream
21
Q
How many mutagens are approximately present within tobacco smoke?
A
60 mutagens
22
Q
Which molecules typically cause G-T mutations?
A
Polycyclic aromatic hydrocarbons (PAH), and nicotine derived nitrosamines
23
Q
How are heterocyclic amines and PAH formed?
A
Formed during the Maillard reaction at higher temperatures
24
Q
Why are PAHs and heterocyclic amines cancerous?
A
Express DNA-damaging potential upon bioactivation through metabolism, through metabolism. Aryl-hydrocarbon receptor, a transcription factor activated by ligands (PAH), regulates metabolizing enzymes- enzymes cause carcinogenesis by processing the toxicants to reactive mutagen metabolites
25
What are exogenous factors?
induction events through lysogenic viruses can integrate genes into the host genome, alterations to the gene sequence of the genome can result in the expression of oncogenes
26
What are the genetic influences of cancer?
Hereditary alterations in genes can result in genetic predisposition to cancer
27
How many original hallmarks of cancer are there?
6
28
What are the 6 main hallmarks of cancer?
1) Sustaining proliferative signaling
2) Evading growth suppressors
3) Resisting cell death
4) Enabling replicative immortality
5) Inducing angiogenesis
6) Activating invasion & metastasis
29
How do cancer cells sustain proliferative signaling?
1) Self-synthesis of growth factor ligands - autocrine proliferative stimulation.
2)Transmit signals that signal normal cells within the supporting tumor-associated stroma, reciprocate by supplying cancer cells with growth factors.
3)Hyperresponseive to growth factors ligand, increased receptor proteins
Cancer cells re-regulate release of growth-promoting signals, signals are conveyed by growth factors that bind cell-surface (intracellular tyrosine kinase domains)
The latter proceeds to emit signals via branched intracellular signaling pathways that regulate progression through the cell cycle, as well as cell, growth
30
How do cancer cells evade growth suppressors?
1) Deactivation of tumor suppresor genes (Limit cell growth and proliferation)
2) Defects in the RB pathway permits cell proliferation. RB transduces growth-inhibitory signals. TP53 inputs from stress and abnormality sensors; the degree of damage to the genome is excessive. TP53 can halt cell--cycle progression. The sensation of irreparable damage can trigger apoptosis. This is circumvented
31
How do cancer cells resist cell death?
Loss of TP53 tumour suppressor function eliminates critical damage sensor from apoptosis-inducing circuitry
Tumours may increase expression of antiapoptotic regulators BD-2, BD-X or of survival signals (IGf 1.2)
32
What is the death ligand?
Fas ligand
33
What does the FAS ligand activate in terms of apoptosis?
Activates latent protease (capsizes 8 & 9) proceeds to initiate the cascade of proteolysis
34
What are the antiapoptotic regulators?
bd-2
| bd-x
35
What are the pro-apoptotic factors?
Bax, Bim, Puma
36
How do cancer cells enable replicative immortality?
Norma cell lineages can only pass through a limited number of successive growth and division cycles.
Telomerase adds telomere repeat segments to ends of telomeric DNA, expressed in immortalized cells. Extension of telomeric DNA counters telomere erosion, resistance to senescence and apoptosis
37
What is the definition of senescence?
Irreversible non-proliferative state and crisis (cell death). Beyond the stage of the cell crisis cells exhibit unlimited replicative potential
38
What is the role of telomeres?
Telomeres are involved in the capability for unlimited proliferation.
Telomeres composed of multiple tendon hexanucleotide repeats shorten progressively in non-immortalized cells (losing ability to protect the ends of chromosomal DNAs). Length correlates with the number of successive cells generations
39
How do cells induce angiogenesis?
Tumours require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic wastes and carbon dioxide. Tumor-associated neovasculature generated by angiogenesis.
Angiogenic switch activated during tumor progression causing vasculature to sprout new vessels to sustain neoplastic growths.
Angiogenic regulators include signaling proteins that bind to stimulatory cell-surface receptors displayed by vascular endothelial growth factors. These growth factors orchestrate new blood vessel growth.
40
Which molecule activated cell-cell adhesion? (Begins with E)
E-cadherin
41
What is the role performed by E-cadherins?
Forms adheren junction with adjacent epithelial cells, maintaining epithelial cell sheets. Increased expression of E-cadherin behaves as an antagonist of invasion and metastasis.
42
What happens to E-cadherin which causes intravasation of cancer cells?
Reduction of its expression through downregulation and mutations inactivation causes reduction in cell adhesion.
Enables for increased transit of cancer cells and intravasation
43
What are the four new hallmarks of cancer?
Deregulating cellular energetics
Avoiding immune destruction
Genome instability and mutation
Tumor promoting inflammation
44
Which antigens are released by tumour cells?
Tumour antigens
45
How are cancer cells eliminated by T cells?
Tumor antigens bind to antigen-presenting cels, through antigen presentation, naive T cells via TCRs bind to the presented antigen, and are activated. Activated T cells target and eliminate cancer cells
46
Which proteins downregulate and suppress T cells, promoting self-tolerance?
Programmed cell death protein 1 (PD-1) and C279, proteins on cell surface membrane that has a role in regulation in the immune system's response to the cells of the human body by downregulating the immune system
47
What happens during checkpoint pathways in terms of PD-1?
PD-1 is activated, negative signals are transmitted to the T-cell, prevents an attack
48
Which ligand is presented on cancer cells which enable them to evade immune attack?
PD-L1
49
Which therapy can be used to enable the immune system to recognize and target cancer cells?
Nivolumab (Immunotherapy)
50
When is immunotherapy typically used during cancer treatment?
Effective treatment to chemotherapy and radiation-resistant cancers (melanomas)
51
What happens during immunotherapy in terms of cancer treatment?
Activates a stronger immune response, as well as installing mechanisms for increased recognition and identification of cancer cells.
Checkpoint blockade immunotherapy, inhibits checkpoint pathways, preventing the binding action of PD-1, to PDL-1, thereby activating the T-cell to stimulate tumor degradation.
52
What is a germline mutation
A gene change in a body's reproductive cell, and subsequently incorporated into the DNA of every cell in the body of the offspring either before or during meiosis. Germ cell produce gametes and are exclusive to undergo meiosis as well as mitosis
53
Which cells do germ cells produce?
Gametes
54
What are hereditary mutations?
Inherited from parents to offspring
55
What are sporadic mutations?
Acquired/sporadic mutations are derived during mitosis in cells (non-germline tissues). Somatic mutations are not inherited; alterations in the genome can result in potential cancer
Somatic cells divide by mitosis, mutations in cancer genes accumulate over successive divisions in somatic cells until a sufficient number of accumulative errors can initiate tumor formation
The frequency of genetic events that cause cancer in somatic cells can be influenced by exposure to mutagens. Genetic events are not transmitted to future generations, considering they occur in somatic cells rather than germline variants
56
Which % of cancer are attributed to somatic mutations?
90%
57
Which cell line does cancer-predisposing mutations occur in?
germline, resulting in inheritance of cancer-causing genes.
58
Which gene leads to an increased risk of breast cancer?
BRCA-1 gene
59
Which base transversions are most common in smoking-associated cancers?
Guanine to thymine transversions, p53 mutations patterns in lung cancers are distinct between smokers and non-smokers
60
What is the % prevalence of G-T transversions in smoker' lung cancer?
30% in comparison to 12%
61
How does DNA damage caused UV radiation results in signature C>5 or G>A mutations?
UV radiation contributes towards the formation of covalent bonds between adjacent pyrimidines (cytosine, and thymine) within DNA molecule. UV-induced mutations
62
Which critical gene when subjected to change can lead to aggressive aberrant cell growth?
BRAF, development of malignant melanoma
63
What is a driver mutation?
A mutation that provides a selective advantage to a clone in its microenvironment, increasing its survival or reproduction
A minute number of mutations confers this advantage and are currently found in homozygote state
Driver genes are considered to be genes mutated in a greater proportion of cancer samples compared to the expected background mutation rate.
64
What are the two main driver gene mutations?
Inactivation of tumour suppressor genes
| Oncogenes
65
What is a passenger mutation?
Tolerance to multiple mutations by somatic cells (heterozygote state). Passenger mutations have no effect on the viability of a clone however may be associated with clonal expansion because it occurs in the same genome with a driver mutation - hitchhiker
66
Which type of mutation has a tendency to cause clonal expansion?
Driver mutations
67
What is the correlation coefficient for the lifetime of developing with how often stem cells in that tissue divide?
0.8
68
What is an oncogene?
An oncogene is a gene that has the potential to cause cancer. Tumor cells have an elevated proportion of expressed mutated oncogenes
69
What are oncogenes responsible for?
Reduction in intracellular survival signals in addition to the expression of proapoptotic factors stimulates cell crisis (apoptosis).
Oncogenes can evade designated apoptosis, resulting in successive proliferation. The predecessor of oncogenes are proto-oncogenes (functional genes involved in cell growth and proliferation, or inhibition of apoptosis).
70
What type of mutation causes oncogene formation?
Mutations can upregulate genes for promoting cellular growth (gain of function mutations), and will predispose the cell to cancer and thus termed oncogenes.
71
What are acquired mutations?
Cancer-causing mutations involving oncogenes are acquired. Mutations activate oncogenes by chromsome rearrangements, gene duplication or mutation
72
Which chimeric gene translocation causes chronic myeloid leukemic?
BCR-ABL
73
How are proto-oncogenes activated?
Mutation within proto-oncogene or within promoter region results in altered sequence of mRNA, thereby alteration in the protein structure; either causing an increase in enzymatic activity or loss of regulation. Increase in protein concentration can be caused by an increase in protein expression through mis-regulation an increase of protein (mRNA) stability, prolonging its existence and thus activity
74
Which chromosomes are involved in a Philadelphia chromosomal translocation?
Chromosomes 9 and 22
75
Which gene encodes for non-receptor tyrosine kinase ABL?
ABL1 gene
76
How is the ABL gene activated?
In response to growth factors, cytokines, cell adhesion, DNA damage, oxidative stress and other signals
77
What happens upon ABL activation?
Cell proliferation or differentiation, survival, or death retraction or migration
78
Which activity is associated with the BCR gene?
Serine/threonine kinase activity, and is a guanine nucleotide exchange factor for RHo family GTPase including RHoA
79
What does the product of the BCR-ABL gene lead to?
Has elevated tyrosine kinase activity, relocated to the cytoskeleton and phosphorylates multiple cellular substrates.
80
What do RAS proteins control?
Control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation.
81
Which class of proteins are RAS proteins associated with?
GTPases
82
How are RAS proteins activated?
In response to various extracellular stimuli. Activated receptors transfer the signal to intracellular RAS protein. RAS is a small G-protein upon signal, RAS protein binds to GTP-activation into the signal-emitting mode.
83
What is the main role performed by RAS proteins?
Function as binary molecular switches that control intracellular signaling networks. KRAS is a gene that behaves as an activator/deactivator in cell signaling - functionally controls cell proliferation.
84
Which mutation renders the GTPase domain of Ras insensitive to inactivation by GAP?
Residue G12 in the ploop and the catalytic residue Q61. Glycine to valine mutation at residue 12 renders the GTPase domain of RAS insensitive
85
What is GAP in terms of GTPase?
GTPase activating proteins
86
What are GAPs?
Regulatory proteins that bind to activated g-proteins and stimulate their GTPase activity, with the result of terminating the signaling event
87
How is RAS inactivated?
By GAP activity
88
What does GTPase convert?
GTP to GDP
89
What is the result of GAP insensitivity?
Results in increased and continued intracellular signaling & transcription due to secondary messengers within the cell cycles
90
Which residue is responsible for stabilizing the transition state for GTP hydrolysis?
Residue 61
91
What is MEN2?
Multiple endocrine neoplasia type 2 caused by an inherited mutation in the gene RET- Patients affected by syndrome develop medullary cancer of the thyroid
92
What does the RET proto-oncogene encode for?
A receptor tyrosine kinase (Dominant gain of function) concerns uncontrolled proliferation, impaired differentiation and unrestrained survival of the cancer cell
93
What type of tumors arises from an inherited mutation in KIT?
Hereditary gastrointestinal stromal tumours
94
What type of cancers arises from inherited mutations in MET?
Hereditary papillary renal cancer
95
What type of cancers arises from CDK4 inherited mutations?
Malignant melanomas
96
What is a tumor suppressor gene?
Is a gene that regulates a cell during cell division and replication. The gene encodes for a protein that controls cell growth, preventing the excessive proliferation
97
What are the results from mutated tumor suppressor genes?
Results in a reduction or loss of function, thereby alterations in the base sequence will inhibit mRNA transcription of the functional gene, and the cell regulator proteins cannot be translated.
A combination with other genetic mutations enables the cell to grow aberrantly in an unrestrained manner. mutations attributed to hallmarks of cancer
98
What are the four main functions of tumour suppressor genes?
1) Repression of genes that are essential for continuing of the cell cycle. Lack of genic expression will result in cell cycle disruption a cell division is inhibited
2) Coupling the cell cycle to DNA damage: Damaged DNA sends intracellular survival signals to stimulate DNA repair, senescence or apoptosis. Reparable DNA will enable cell cycle continuation
3) Proteins involved in cell adhesion prevent tumor cells from dispersing block loss of contact inhibition, and inhibits metastasis. Proteins considered as metastasis suppressors
4) DNA repair proteins
99
What is contact inhibition in terms of cancer cells?
The process of arresting cell growth when cells come in contact with each other, normal cells stop proliferation, forms monolayer.
100
What are the three main DNA repair proteins?
MEN1, HNPCC, & BRCA
An increased mutation rate from decreased DNA repair (ligases) leads to increased inactivation of tumor suppressor and activation of oncogenes
101
What does the two-hit hypothesis of cancer state?
The Knudson hypothesis concerns that most genes require two mutations to cause a phenotypic change.
Used to explain the early onset at multiple sites in the body of hereditary retinoblastoma
102
Which case bilateral or unilateral cases are always heritable, in terms of tumour suppressor protein?
Bilateral cases
103
Describe the age of onset distribution of bilateral cases
Consistent with the presence of a single mutation
104
What is the general inheritance pattern for loss of function mutations that occur in tumor suppressor genes?
Recessive
105
What is the first event of the two-hit hypothesis?
Inherited germline copy of mutated gene heterozygous insufficient to become cancerous
106
What is the second hit in the two-hit hypothesis?
Deleterious mutation to a functional gene within the gene pair occurring somatically -producing cancer
107
What does the two-hit hypothesis state in terms of mutation probability?
The hypothesis predicts that the chances for a germline mutation carrier to get a second somatic mutation at any multiple sites in one body cells are much greater than for a non-carrier to get two hits in the same cell
108
What are the main functions of P53?
Has a plethora of functions including DNA repair, inducing apoptosis, transcription and regulating the cell cycle. P53 activates transcription of proteins involved in DNA repair
109
What is the role performed by p53 in terms of Mdm2?
Regulates the expression of Mdm2 and the genes involved in growth arrest
110
Which syndrome is associated with the inheritance of the p53 gene?
Li-Fraumeni Syndrome (LPS) - inheriting one functional copy of the TP53 gene.
111
Why are cancer cells genetically unstable?
Stop cell cycling to allow time for DNA repair (p53R2); carry out efficient DNA repair, or undergo apoptosis (Bax, Apadf-1 , PUMA, & NoxA)
112
What is the function of DNA repair genes?
Code for proteins that correct mitotic errors and mistakes that may arise during DNA semi-conservative replication prior to cell division
113
What factors is the rate of DNA repair dependent on?
Dependent on a plethora of factors, including cell type, cellular age, and the extracellular environment
114
What are the three potential states of cellular dysfunction?
1) Irreversible state of dormancy
2) Apoptosis
3) Unregulated cell division and proliferation leading to the cancerous tumor
115
What is the role of the BRCA1 gene?
Is phosphorylated by ATM, and CHK2 in response to double-stranded DNA breaks (ionizing radiation potential cause). Phosphorylation results in the activation of molecules
BRCA1 binds to BRCA2 which interacts with RAD51 to form a DNA-repair complex.
116
What are the two categories of cancer viruses?
DNA & RNA viruses.
117
How does the lysogenic pathway of viruses lead to cancer?
Through the lysogenic pathway, viral DNA is integrated into the host's genome, viral gene triggers intracellular changes, resulting in cellular proliferation and growth. Integration into host cell chromosomal DNA, stimulate mutations and chromosomal rearrangements that predispose to cancer
Insertion of viral promoter sequence adjacent specific host genes leads to ectopic gene expression resulting in neoplasia
Contain oncogenic strains carrying oncogenes that encode for transforming proteins - influence cell proliferation and differentiation
118
Which virus typically causes cervical cancer?
```
Human papillomavirus (HPV) , causes cancer of cervix and genital warts
99.7% of cervical cancer
```
119
Which pathogen causes stomach ulcers?
H.Pylori
