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CANC380 > Module 02 - Tumourigenesis and cancer progression > Flashcards

Module 02 - Tumourigenesis and cancer progression Flashcards

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1
Q

What system do healthcare professionals use to describe the stage of a cancer?

A

TNM
Tumour
how large is the primary tumour? Where is it located?
Node
Has the tumour spread to the lymph nodes? If so, where and how many?
Metastasis
Has the cancer spread to other parts of the body? If so, where and how much?

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2
Q

What are the four TNM stages of cancer?

A

Stage 0 - In situ
Stage 1 - Localised cancer
Stage 2&3 - regional spread
Stage 4 - distant spread

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3
Q

Describe Stage 0 of the TNM system

A

“In Situ”

refers to cancer that is in the position where it started. At this stage, most cancers are highly curable. In some cases, cancers never go beyond this early stage

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4
Q

Describe Stage 1 of the TNM system

A

“Localised cancer”

Cancer being to invade neighbouring tissues. However it remains in a single lump and is localizes

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5
Q

Describe stage 2&3 of the TNM system

A

Cancer divides and grows more deeply into surrounding tissues. Cancer may have spread to lymph nodes, but not to other parts of the body

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6
Q

Describe stage 4 of the TNM system

A

Cancer has spread to other organs or parts of the body. This is referred to as distant spread or metastatic cancer

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7
Q

What are the two major stages of bladder cancer?

A

Non-muscle invasive (NMIBC)

Muscle-invasive (MIBC)

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8
Q

Describe the staging of bladder cancer

A

NMIBC
TIS - Carcinoma in situ, found only on or near the surface of the bladder (mucosa and urothelium)
Ta - Papillary tumour, meaning it extends into the lumen of the bladder. it is confined to the urothelium
T1 - Tumour extends into the submucosal connective tissue called the lamina propria, but has not invaded the muscle layer
MIBC
T2a - This is the first stage of the MIBC where the tumour has extended into the first layers of the musclaris
T2b - similar to T2a but the tumour has extended into deeper layers of the muscularis propria
T3 - tumours at this stages have grown into the perivesical fat that surrounds the bladder
T4 - Extended outside the perivesical fat and into the surrounding tissues, such as the abdominal or pelvic wall or surrounding organs. In men, this is often the prostate or seminal vesicle. In women, it is usually the cervix or vagina

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9
Q

What kinds of cancer is the TNM used to describe staging?

A

Solid tumours (eg not blood cancer)

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10
Q

What is cell differentiation?

A

Process by which less specialized cells become more specialized

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11
Q

What is one key feature of cancer cells?

A

they have different levels of differentiation as compared to the normal cells around them

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12
Q

Cancer cells are characterized by a process called what?

A

dedifferentiation

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13
Q

What is the dedifferentiation of malignant progression?

A

cancer cells lose their specializations, which means they become undifferentiated

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14
Q

What is tumour grading based on?

A

Levels of differentiation and extent of proliferation

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15
Q

How many grades of tumours are there?

A

4

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16
Q

Describe G1 tumour

A

Low grade - well differentiated
cancer cells look and behave like normal cells in the tissue of origin; cancers with well differentiated cells tend to be less aggressive and slow growing

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17
Q

Describe G2 tumour

A

Intermediate Grade - Moderately differentiated
Cancer cells look and behave somewhere between well-differentiated and undifferentiated cancer cells; most cancers have moderately differentiated cancer cells

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18
Q

Describe G3 tumours

A

High grade - poorly differentiated
cancer cells look and behave very differently from normal cells in the tissue of origin; cancers with poorly differentiated cells tend to spread more aggressively and be fast growing

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19
Q

Describe G4 tumours

A

high grade - undifferentiated
cancer cells in this grade fo not resemble the normal cells of origin at all. This is a highly aggressive form of cancer that tends to spread more readily than other grades

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20
Q

What is the grading system for prostate cancer?

A

Gleason score

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21
Q

List 4 reasons why the staging systems are important

A

1- Help healthcare professionals develop treatment plans
2- Help predict prognoses
3- help healthcare professionals communicate about the diagnosis
4- Enable the comparison of people with the same diagnosis for research purposes

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22
Q

What is the gleason score based on?

A

The sum of the grades of the two most common histological patterns (the 2 areas that make up most of the cancer)

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23
Q

How many levels are there in the gleason score?

A

5
1-2 normal tissue and not normally reported
3-5 cancerous tissue

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24
Q

What are the 6 types of tissue growth/proliferaition??

A 
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Anaplasia
Neoplasia
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25
What is hypertrophy?
Increase in cell size without an increase in number
26
What is hyperplasia?
Increase in the number of cells; can be physiologic or pathologic
27
What is metaplasia?
Reversible replacement of one cell type with another: adaptation to external environment
28
What is dysplasia?
Altered cell maturation, orientation, and tissue architecture; may progress to cancer or regress to normal cells
29
What is anaplasia?
"to form backward" lack of cell differentiation a hallmark of malignancy
30
What is neoplasia?
"new growth" unregulated cell proliferation as a result of genetic changes
31
What are the 2 broad mechanisms of tumour initiation?
Silencing of a tumour suppressor gene | Activation of an oncogene
32
How does the silencing of a tumour suppressor gene contribute to tumour initiation?
Tumour suppressor genes can suppress of block the development of cancer by slowing down cell division, repairing DNA or triggering apoptosis When inactivated, this can lead to cancer, usually both alleles need to be inactivated to cause cancer
33
What is the 2-hit hypothesis?
Both alleles of a tumour suppressor gene must be mutated because mutations are recessive - One can be inherited or random - Second mutation is required for cancer development
34
How does the activation of an oncogene contribute to tumour initiation?
An oncogene is a gene that has the potential to cause cancer because it directs cell growth - Proto-oncogene is the variant of an oncogene in a healthy cell, encodes proteins that help regulate cell growth and differentiation - When a proto-oncogene transform to an oncogene, the resulting transformed proteins is called oncoprotein, oncoproteins usually upregulate growth and/or inhibit apoptosis Oncogenes are dominant = only 1 allele alteration needed
35
What are the four process that lead to cell transformation?
random genetic mutations inherited genetic mutations inherited epigenetic alterations genotoxic stress
36
According to Tomasetti and Vogelstein's study, what is the risk of cancer in a tissue mainly determined by?
Lifetime number of stem cells division in the tissue, as it is the normal that DNA replication or repair error ares passed on to daughter cells. External environmental factors, eg exposure to genotoxic agents, contributes to this risk but, relative to intrinsic replication or repair errors their contribution to cancer risk is minor
37
What are 3 examples of inherited genetic mutations?
TP53 BRCA1 and BRCA2 BRAF
38
What is the most frequently altered gene in human cancers?
TP53
39
What is the function of the TP53 gene?
encodes for protein p53 which is responsible for - important for the integrity of the genome; it is known as the guardian of the genome - binding to damaged DNA and determining whether the cell will repaid the DNA or will undergo apoptosis
40
What is Li Fraumeni syndrome?
Hereditary cancer predisposition syndrome that is associated with osteosarcoma, breast cancer and soft tissue carcinoma. Caused by mutations in TP53 (75% inherited, 25% random)
41
If the TP53 mutation is in a tumour suppressor gene and therefore recessive, why is LFS considered autosomal dominant recessive?
The distinction is in the definition of LFS. Individuals with LFS have a much higher risk of cancer than those without, but they are not born with cancer. This is because they still require that second hit to generate cancer growth. As such having a recessive TP53 mutation is synonymous with having increased risk of developing cancer, making LFS dominant
42
What is the function of BRCA1 and BRCA2?
Tumour suppressor genes involved in the response to DNA damage during DNA repair, transcription, and the cell cycle. Mutations that result in defective BRCA 1/2 proteins allow DNA damage to propagate throughout the cell and can lead to further DNA mutations in daughter cells increased risk of ovarian and breast cancer and prostate and pancreatic cancer
43
What is the function of BRAF?
encodes for protein called B-RAF Involved in mitogen-activated protein kinase (MAPK) pathway. activation of MAPK pathway leads to transcription of genes that encode proteins involved in the regulation of cell proliferation and differentiation BRAF is a proto-oncogene
44
What are some form of heritable epigenetic alterations?
Methylation or acetylation of histones (increased or decreased gene expression by changin how genetic information can be accessed by transcriptional machinery) DNA methylation histone phosphorylation perturbation of epigenetic mechanisms can lead to inactivation of tumour suppressor genes
45
What are some genotoxic stress that can damage the genome?
radiation exposure to carcinogens (cigarette smoke or UV light) exposure to infection agents (oncovirus) Mostly considered second hits, except those with high association like smoking and lung cancer and UV light exposure and melanoma
46
What is genomic instability?
High frequency of changes in the genome of a cellular lineage. It can propagate cellular damage, and is one of the main mechanisms underlying tumourigenesis
47
What are the 3 main phases where processes are in place for genomic stability
Fidelity of DNA replication in S-phase Segregation of chromosome in mitosis Precise repair of sporadic DNA
48
Why are cells with already 1 hit more susceptible to genomic instability?
Faulty DNA repair and/or increased proliferative growth
49
What are some alterations cause by genomic instability?
``` Mutations (point mutations, defective nucleotide or base excision repair, or mistmatch repair) Variations (chromosome number) gross chromosomal rearrangements copy number variants hyper-recombination loss of heterozygosity ```
50
How do chromosomal abnormalities promote cancer?
Unpaired DSBs can lead to cell death or neoplastic transformation Cells deficient in DSB repair a re predisposed to chromosomal translocations, which can generate fusion genes that encode for proteins with novel properties DSBs implicated in initiation of gene amplification, can result in imbalanges in factors critical for maintaining cellular homeostasis activation of oncogens by translocation or amplification is a predominant mechanism for cellular transformation and tumourigenesis
51
What is the mechanism that leads to cellular transformation?
1- Cell undergoes a change that offers a proliferative advantage over other cells (eg: inactivation of tumour suppressor genes=2-hit or activation of oncogene=1 hit) 2- Defective tumour suppressor genes and oncogens can arise randomly, be inherited via genetic or epigenetic pathway, or occur in response to genotoxic stress 3- Genomic instability contributes to cellular transformation at many points - it leads to further damage such as chromosomal abnormalities - cells with a previous hit are more likely to exhibit a high degree of genomic instability, higher risk of second-hit
52
What are the 3 requirements a mutation must have to provide a selective advantage (and lead to cancer)?
1- Occur in a stem cell 2- Pass the fitness test 3- Facilitate on of the hallmarks of cancer
53
How does mutation in stem cells provide a selective advantage?
In cancer cells epigenetic modification occur such that stem cells are stuck in a self-renewing state (instead of differentiating). They then generate the clonal architecture, and are responsible for metastases and drug resistance recurrence They are the cellular drivers of cancer and are the unit of selection of cancer Mutations are only consequent when they happen in stem cells
54
What are the 3 fitness tests mutations must pass to provide a selective advantage?
1- Does it alter protein function? (if yes go to test 2) 2- Does it alter cellular phenotype endowing potential selective advantage? (if yes go to test 3) 3- Is the mutation encoding fitness advantage stably propagated? (if yes, it passes the test)
55
What are the hallmarks that must be facilitated to proved selective advantage?
``` 1- sustaining proliferative signaling 2- evading growth suppressors 3- activating invasion and metastasis 4- enabling replicative immortality 5- inducing angiogenesis 6- resisting cell death ```
56
What are the characteristics of neoplasia? (3)
1- cellular changes 2- cell membrane changes 3- metabolic changes
57
What are some cellular changes in neoplasia?
- abnormally arranged - cell division and proliferation increased - decreased response to inhibitory factors - enhanced response to hormones and growth stimuli
58
What are some cell membrane changes in neoplasia?
- Produce cell surface antigens that are immunologically distinct from the surrounding normal tissue cells - antigens are recognized as foreign by the body's immune response
59
What are some metabolic changes in neoplasia?
- May use different metabolic pathways than normal cells | - changes in pathways can lead to abnormal hormonal secretions
60
What are some examples of selective pressures?
``` oxygen availability pH Nutrient availability Other tumour cells stromal cells cells of immune system Presence of growth factors/hormones/angiogenic factors ECM composition interstitial pressure any therapy ```
61
What is the mechanism of clonal evolution?
1- Random mutation as a result of an error-prone repair mechanism and/or exposure to genotoxic agent 2- If mutation is a driver (provide selective advantage), clonal expansion ensues 3- Genomic instability of these clones increases the frequency of mutation creating sub-clones 4- Most of these subclones will fail to survive due to metabolic or immunlogoc disadvantage. Occasionally one will incur a second driver mutation which allows its progeny to become the pre-dominant subpopulation within the tumour (selective sweep) 5- The sub-clones dominates until a newly generated sub-clone outcompetes the current one
62
What is the selective sweep?
When one sub-clone population incur a second driver mutation which allows its progeny to become the pre-dominant subpopulation
63
What is the product of clonal evolution?
Tumour heterogeneity
64
How do you think tumour heterogeneity factors into the concepts of divergent and convergent evolution? Is it an example of convergent or divergent or both evolution?
Tumour heterogeneity is and example of both divergent and convergent evolution. Initially divergent evolution is the most common pattern as clones develop new mutations that make them phenotypically distinct from their parents Once subpopulations develop, clones from different lineages can start to exhibit convergent evolution patterns. they developed different mutations, but they confer similar selective advantages
65
How can the Gleason score act as a measure of tumour heterogeneity?
It measures cellular differentiation patterns in prostate cancer. Cellular differentiation is determined by a cancer cell's genome, and different patterns of cellular differentiation reflect genome differences in cell population. These genome differences can also be classified as tumour heterogeneity. Hence, the Gleason score can be a measure of tumour heterogeneity in prostate cancer
66
The article (Clona Evolution in Cancer) discusses punctuated equilibrium and gradualism as models for clonal evolution. Which on is a more accurate representation of cancer growth?
Substantial evidence indicates that cancer cells evolved via a punctuated equilibrium model. However, it is likely that there is some gradualism at the beginning of cancer development
67
How does tumour heterogeneity confer evolutionary advantages or disadvantages?
It poses a great challenge tot he management of cancer. Heterogeneity depends on the mutation rate, which varies among different cancer types, it is often higher than normal cells. The mutations can accumulate due to deficiencies in the systems that normally monitor DNA integrity and cause DNA-damaged cells to undergo apoptosis Individual subpopulations in tumours behave in a unique way in how they proliferate, invade and spread, and respond to treatment.
68
Why is early detection important?
because mutations accumulate over time and thus, early detection=less heterogeneity=easier to manage

CANC380 (6 decks)

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