BIO 302 - Final Exam - Study Guide Flashcards
(126 cards)
1
Q
HELP HINT: study the “Take Home Messages” at the ends of each lecture slide set.
A
2
Q
Study Guide - Exam 1
A
3
Q
Cancer: The Big Picture
What is the most common class of malignant neoplasms in human beings?
A
Carcinomas.
4
Q
Cancer: The Big Picture
What is the type of carcinoma that has the highest incidence in men? In women?
A
Prostate, lung, and colorectal cancer occur the most in males, while breast, lung, and colorectal cancer are predominant in females in the United States.
5
Q
Cancer: The Big Picture
What are the top 3 most common cancer killers in the USA? What is the most common cancer killer in the world?
A
Lung (Including Bronchus)
Breast
Prostate
Colon and Rectal (Combined)
Lung (Including Bronchus)
6
Q
Cancer: The Big Picture
Is the cancer death rate in the USA going up or down? Why? What about the total number of cancer deaths?
A
Statistics show decreases in death rates for some cancers
beginning in 1992 (lung, breast, colon, prostate).
* American Cancer Society (ACS) reports that from 1991-2018 cancer death rates fell 31% .
* But the total number of cancer deaths continues to rise!!!!!
* Nevertheless, due to death rate declines, a record 18.1 million cancer survivors in the USA in January 2022 (NCI).
7
Q
Cancer: The Big Picture
What is the single most common risk factor for cancer (across all cancer types)?
A
Age.
8
Q
Cancer as Biological Entity
What is the root cause of cancer? How does cancer begin?
A
Cancer evolution = mutation + selection
* Mutated cancer cells acquire ‘fitness” with respect to competition, adaptation and survival within the body’s biological environment.
9
Q
Cancer as Biological Entity
What’s a mutation? Name 4 different types of mutation in DNA.
A
A mutation is a permanent change in the nucleotide sequence of DNA. Mutations can be of many types, such as substitution, deletion, insertion, and translocation.
Mutation may change form and/or function if it produces a mutated protein.
A mutated protein may:
* Change the functional characteristics of the protein
* Change the functioning of the cell pathway in which the protein acts
* Changes the functioning or behavior of the cell as a result
* A mutated regulatory protein (protein from a gene that controls the degree
of expression of other genes) may:
* Change the amount or function of regulatory RNA or normal protein made.
* Change the functioning or behavior of the cell as a result.
Substitution of one base for another with no change in the total number of nucleotides
The addition (insertion) of a single nucleotide
The addition of a nucleotide sequence
The deletion of a nucleotide
The deletion of nucleotide sequence
The rearrangement of entire segments of chromosomes (translocations)
10
Q
Cancer as Biological Entity
What factors cause mutations inside cells? Outside cells?
A
Mutation-production may result from dynamics or agents that are either internal or external to the body:
Internal – intrinsic to the normal organism:
* Replication error
* Damage from inflammation
* Inherited mutations
External to the normal organism:
* Radiation
* Infectious agents
* Smoking
* Exposure to mutagens (agents capable of causing mutation)
The key to normalcy is MUTATION CONTROL: repairing mutations or preventing mutated cells from replicating.
11
Q
What is a “single nucleotide polymorphism” (SNP)
A
A “single nucleotide polymorphism” (SNP) is a kind of mutation that is considered to be in the realm of normal human variation.
* A “SNP” (as compared to an analogous change called a “mutation”) is defined by convention according to frequency:
* SNP - found in >1% of the population
* Mutation – found in <1% of the population
12
Q
Cancer as Biological Entity
Are all mutations cancer-causing? What conditions must exist for a mutation to “initiate” a cancer?
A
Cancer cells exhibit a loss of proliferation control
* Sustained proliferative signaling
* Evasion of growth suppression
13
Q
Cancer as Biological Entity
Autocrine, Paracrine & Endcrine stimulation.
A
Autocrine stimulation: when the cytokine producing cell has the receptor for its own cell product on its surface.
Paracrine activation: the cytokine producing cell puts out the chemical in the environment of a nearby cell (diffusion). The other cell with a receptor will pick up the signal.
Endocrine stimulation: Thyroid creates a cytokine that stimulates a cell far away. The cytokine must get into the circulation and must be carried there to the distant cell that has the receptor.
All these processes are proto-oncogenes.
14
Q
Cancer as Biological Entity
What are the 3 key characteristics/capabilities all cancers have in common and represent aberrations of normal cell capabilities that allow cancer cells to out-compete normal cells and tissues?? With which “hallmarks of cancer” do these correspond?
A
Cancer cells:
* Utilize normal biological mechanisms in abnormal ways
* Flip biological switches inappropriately
* Activate or de-activate normal cell behaviors in inappropriate ways
* Ignore or bypass normal control mechanisms
* Cancers do not invent NEW biology, they draw on and distort normal
biological capabilities.
15
Q
Cancer as Biological Entity
What is the characteristic of cancer that causes most cancer death (i.e., what cancer characteristic is most lethal for cancer patients?)
A
Only malignant tumors are properly referred to as cancers, and it is their ability to invade and metastasize that makes cancer so dangerous.
16
Q
Cancer as Biological Entity
What is the feature of cancer that poses the biggest challenge to effective treatment and is the underlying reason for most of our treatment failures in cancer? (Hint: it is a consequence of tumor progression and repeated sub clone formation.)
A
Tumor Heterogeneity and acquired chemo-resistance.
17
Q
Cancer as Biological Entity
What is meant by “differentiation”? Why is differentiation or that lack of differentiation important in cancer biology, having implications for the cancer patient?
A
In cancer, this describes how much or how little tumor tissue looks like the normal tissue it came from. Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells.
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Q
Cancer as Biological Entity
What’s a “driver gene”?
A
Mutations in genes that contribute to the phenotype (observable behavioral characteristics) of cancer are called driver genes.
Mutations that do not contribute to the cancer cell behavioral characteristics (biologically neutral) are called passenger mutations.
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Q
Cancer as Biological Entity
What class of driver genes is the cause of all inherited cancer syndromes (like the one Angelina Jolie has)?
A
Nuclear tumor suppressor genes: BRCA1 and BRCA-2 DNA repair genes
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Q
Cancer as Biological Entity
What are oncogenes and tumor suppressor genes?
○ What do they do?
What happens when they are mutated? What are the consequences?
○ What steps are required to cause a functional change (gain of function) in an oncogene?
○ What steps are required to cause a functional change (loss of function) in a suppressor gene?
○ Can driver genes be “drugged” (treated by targeted therapy?) How?
A
The two classes have opposing function in normal cells. When they lose their control of function, it leads to havoc: Oncogenes and Tumor Suppressor Genes. These are mutations of your own genome that control cell division.
Oncogenes are mutated versions of genes in your stem cells called protooncogenes that control cell division. When an oncogene is mutated, it is a dominant mutation. A mutation in one allele (of 2), it becomes dominant, and that gene is off to the races. It will always be one.
Tumor suppressor genes control mutations, find and fix mutations. If they cannot fix them, its repair or die. Tumor suppressor genes, when mutated, if you mutate one (of 2) nothing happens. Its recessive. For a tumor suppressor gene to lose its function, something must happen to the opposite allele (another mutation or loss of DNA (deletion)). You allow that mutated allele to be expressed, and when it is, the gene loses its function. It can no longer control repair and die.
Oncogenes are a gain of mutation and tumor suppressor genes are a loss of contra mutation. You end up with genetic instability and different variants. All have different genomes that have been unrepaired.
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Q
Cancer as Biological Entity
What is the cell cycle? What are cell cycle checkpoints? Why are they important? What happens at checkpoints in cancer cells?
A
Cancer cells lose cell cycle checkpoint control
* Checkpoint control proteins prevent the cell cycle
from preceding when one of the following problems
is present:
DNA has been damaged and needs repair
or
Spindle assembly is incorrect and cannot support
normal chromosome attachment and segregation
* Checkpoint control Involves tumor suppressor
genes, including p53
* Cancer cells continually and inappropriately
enter and proceed through the cell cycle, by-
passing normal checkpoint controls.
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Q
Cancer as Biological Entity
What happens during cancer initiation, promotion, and progression?
○ Which of these steps involve mutation?
○ Which of these can be prevented?
A
“Initiators” (mutation-causing factors) cause mutation in a stem cell.
“Promoters” cause clonal expansion (proliferation) of initiated (mutated) cells.
“Progressors” cause additional mutations that confer additional growth-aggression advantages on expanding clones.
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Q
Cancer as Biological Entity
Describe the changes in form and function that occur during tumor progression that allow neoplastic cells to be identified under the microscope?
○ What is dysplasia?
○ What is carcinoma in situ?
○ What is invasive carcinoma?
○ What is metastatic carcinoma?
A
What is dysplasia? As genetic alterations accumulate, cells begin to look different from their normal counterparts
What is carcinoma in situ? Carcinoma in situ: cancer that has not gone through the basement membrane.
What is invasive carcinoma? Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer.
What is metastatic carcinoma? cancer that has spread (metastasized) from the original site to another part of the body.
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Q
Cancer as Biological Entity
What are the multiple capabilities that cancer cells acquire (or rather, selectively reactivate from the repertoire of abilities of normal cells) to metastasize successfully – the capabilities of the decathlon phenotype?
A
ability to locally invade cells,
ability for intravasation into blood vessels,
ability to survive in circulation under different blood pressures,
ability to exit from blood vessels,
ability to be mobile,
ability to break basement membranes using proteases/enzymes
loss of organization of epithelial cell layers
altered cell-cell adhesion
loss of basal membrane attachment
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Cancer as Biological Entity
What are the two major phenotypic changes that they undergo in the process of metastasizing? (Hint: these are the premier examples of cancer cell plasticity.)
Metastatic tumors (metastases) can occur in three ways: They can grow directly into the tissue surrounding the tumor. Cancer cells can travel through your bloodstream to distant locations in your body. Cancer cells can travel through your lymph system to nearby or distant lymph nodes
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Hallmarks of Cancer
What are the “hallmarks” of cancer exactly?? How do they provide cancer cells competitive advantages over normal cells? Does every cell in a cancer exhibit all of the hallmarks?
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Hallmarks of Cancer
Describe the key basic mechanisms that contribute to each of these hallmarks:
○ Sustaining proliferative signaling
○ Evading growth suppression*
○ Genomic instability and mutation*
■ These two are both related to tumor suppressor gene loss
of function – how are they related?
○ Resistance to cell death
○ Limitless replicative potential
○ Induction of new blood supply (angiogenesis)
○ Deregulation of cellular energetics (metabolism)
○ Ability to invade and metastasize
○ Ability to evade immune system
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■ Describe 5 ways that cancer cells avoid immune attack.
■ Can any of these be reversed or “drugged”?
■ What are the consequences of therapeutically
manipulating the interactions between cancer cells and
immune cells to increase the probability of effective
immune attack?
29
Hallmarks of Cancer
Why are these hallmarks advantageous to the cancer? How do they help cancer cells out-compete normal cells?
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BOTTOM LINE: Can you explain the step-wise process of cancer formation from the point of view of:
o Molecular changes?
o Changes in cell appearance and tissue architecture?
o Changes in cell behavior?
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Study Guide - Exam 2
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Cancer as an Evolutionary System
Describe cancer as an evolutionary system and the necessary and sufficient requirements for evolution that cancers possess: i.e., variation in the population; variation is heritable; variation affects reproduction and survival!
-Mutated cancer cells acquire 'fitness" with respect to competition, adaptation and survival within the body's biological environment.
-Mutation-production may result from dynamics or agents that are either internal or external to the body
-Internal - intrinsic to the normal organism:
*Replication error
*Damage from inflammation
*Inherited mutations
-External to the normal organism:
*Radiation
*Infectious agents
*Smoking
*Exposure to mutagens (agents capable of causing mutation)
Variation in the population Variation is heritable
Variation affects reproduction and survival
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Cancer as an Evolutionary System
What is meant by “cheating” on multicellular cooperation?
Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system.
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Cancer as an Evolutionary System
What is Peto’s Paradox?
Peto's paradox is the observation that, at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism.[1] For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales,[2] despite whales having more cells than humans. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans.
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Cancer as an Evolutionary System
What approaches to therapy can take advantage of evolutionary principles?
Treat cancer by predicting where it's going to evolve, or use therapy in a way that it doesn't kill all the sensitive cells, but controls the growth of the cancer (adaptive therapy).
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Cancer as an Evolutionary System
What are the essential features of Darwinian evolution and how do they apply to cancer? How does this explain why cancers, as they develop, acquire greater and greater survival advantages over normal cells?
* Variation (lots of different clones with different sets of mutations -some unique to each individual clone).
* “Fitness” for survival in particular conditions or environments (like in the presence of a given therapeutic drug) conferred by different genetic traits of different clones.
* Selection of the fittest clones as conditions change.
* Adaptation to a new set of environmental conditions given the wide variety of capabilities in different clones to draw on and the survival of fit clones in the presence of selection pressures/
* Evolvability meaning that the genomic features that confer “fitness” are heritable and passed down to daughter clones allowing the entire population of cells (that is, cancer are an “organism”; cancer as “the beast”) to evolve and change over time and with shifting environmental challenges.
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Who Gets Cancer and Why
What kinds of factors alter the incidence rates of cancer?
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Who Gets Cancer and Why
What proportion of cancer is preventable?
Cancer is preventable 50-90% of the time.
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Who Gets Cancer and Why
What is a cancer risk factor?
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Who Gets Cancer and Why
Do all cancer risk factors cause mutations?
No.
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Who Gets Cancer and Why
What is relative risk?
A measure of the risk of a certain event happening in one group compared to the risk of the same event happening in another group.
0.5 - risk 50% lower than average
1.0 - average
1.5 - risk 50% higher than average
10 - 10 times higher than average relative risk
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Who Gets Cancer and Why
Name 3 risk factors for cancer that cannot be altered.
Age
Genetics
Gender
Ethnicity
Inherited mutations
Inherited immunodeficiency
Defect in detecting/destroying abnormal, mutated cells
Defect in destroying cancer-causing infectious agents
Family history
Personal history
World region
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Who Gets Cancer and Why
Name 3 risk factors for cancer that can be altered.
Chronic inflammation
Viral infections
Bacterial infection
Dietary deficiencies
Diabetes
Hormonal status
44
Who Gets Cancer and Why
What is the single most common cause of cancer in the USA??
90–95% - environmental factors
5–10% - genetics
Tobacco as a single cause (25–30%)
Diet and obesity as a category (30–35%)
Infections (15–20%)
Radiation (both ionizing and non-ionizing, up to 10%)
Environmental pollutants
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Who Gets Cancer and Why
Do we know the cause of all major cancers at this point?
Cancer is caused by a permanent alteration (mutation) of normal nucleotide sequences in the genes of normal cells. A cancer-initiating mutation occurs in a driver gene in an adult stem cell, a cell capable of undergoing mitosis and expanding the number of cells carrying that mutation.
All mutagens are carcinogens, but not all carcinogens are mutagens. Some carcinogens lack a direct effect on DNA but create or promote conditions under which DNA mutation may occur or be propagated.
Hormones are non-mutagenic carcinogens. They act a promoters that increase cell division.
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Who Gets Cancer and Why
Which factors increase risk for more than one cancer?
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Who Gets Cancer and Why
What are the most important behaviors that affect cancer risk??
(1) the susceptibility of the individual (e.g., genetic background that might increase the risk of acquiring mutations).
(2) the mode of exposure
(3) the duration and/or degree of exposure
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Who Gets Cancer and Why
Why is smoking a risk factor for multiple cancers?
Poisons in tobacco smoke can damage or change a cell's DNA. DNA is the cell's “instruction manual” that controls a cell's normal growth and function. When DNA is damaged, a cell can begin growing out of control and create a cancer tumor.
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Who Gets Cancer and Why
Why is obesity a risk factor for multiple cancers?
Obesity is associated with substantial metabolic and endocrine abnormalities:
(1) Excess production of estrogen by fat cells
(2) Increased levels of insulin and insulin-like growth factor
(3) Fat cell production of adipokines (cytokines) that stimulate cell growth, decrease apoptosis and increase inflammation (Inflammation increases production of mutation-inducing ROS).
(4) Oxidative stress (an imbalance between reactive oxygen species [free radicals] and anti-oxidants) tilts into reactive oxygen species dominating and inability to suppress them is oxidative stress.
(5) Chronic inflammation
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Who Gets Cancer and Why
Why is alcohol a risk factor for multiple cancers?
Alcohol causes different types of cancers:
Mouth & upper throat
Esophagus
Larynx
Breast
Colon
Rectum
Liver
(1) EtOH is converted to acetaldehyde in the body (mainly by the liver).
* Acetaldehyde (which also causes hangovers) causes DNA damage and blocks normal DNA repair.
* Acetaldehyde stimulates liver cell division (mitosis & ability to acquire mutations.
(2) EtOH increases estrogen production and estrogen stimulates cell division in susceptible cells (those with estrogen receptors).
(3) EtOH causes cirrhosis (via chronic inflammation); cirrhosis is a risk factor for hepatocellular carcinoma
Cirrhosis is a type of liver damage where healthy cells are replaced by scar tissue. Common causes include excessive drinking of alcohol, hepatitis B and C virus infections, and fatty liver that's caused by obesity and diabetes.
(4) EtOH increases absorption of carcinogenic chemicals from tobacco.
(5) EtOH depletes folate (needed for normal production of DNA and RNA).
(6) EtOH increases production of Reactive Oxygen Species (ROS) that directly cause DNA damage.
51
Name 9 ways to prevent cancer and explain why they work:
o No smoking
o No alcohol
o SPF to block UV radiation
o Maintain low to normal BMI
o Diet (what to eat)
o Diet (what not to eat)
o Physical exercise
o Vaccines for HPV, HbV
o Get screened for colon cancer (and cervical cancer if you haven’t been
vaccinated) at the appropriate age
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Screening
What is the rationale for cancer screening?
Testing people without symptoms - cancer has few early disease-specific symptoms.
Testing defined populations (not everyone) - usually restricted to individuals at risk for cancer.
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Screening
What proportion of cancers are found by screening?
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Screening
What is pre-clinical vs. clinical disease?
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Screening
What are the major challenges to effective screening for cancer?
What is a false positive test? What are the consequences?
What is a false negative test? What are the consequences?
* False positive tests lead to over-diagnosis, over-treatment
and needless burden for patient and healthcare system
* False negative tests lead to under-diagnosis and missed
opportunity for life-saving early treatment.
* Possible goal: Maximize true positives, minimize false positives
* The trade-offs for the choice of the DT depend on the consequences of wrongly classifying an individual in the context of the test use.
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Screening
What is positive predictive value? Why is it important?
What is negative predictive value? Why is it important?
Positive predictive value (PPV): the probability that those with a
positive test actually have the disease.
PPV = TP / TP + FP
As false positives go up, the predictive value of the test declines.
Negative predictive value (NPV): the probability that those with a negative test don’t have the disease.
PPV = TN / TN + FN
As false negatives go up, the predictive value of the test declines
57
Screening
What is a “diagnostic threshold” (DT) for a series of test results? How is it used by physicians administering the test to a patient (individual person)?
When everyone in a population is tested, those with and without disease will have a spectrum (bell curve) of results due to human variation; the curves usually overlap.
* In the overlapping range, people with or without disease may have the same test rest;
the more the curves overlap, the less the discriminatory power of the test.
* The DT will always miss some true positives and includes some false negatives.
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Screening
What is a receiver-operator characteristic (ROC) curve and how it it used in the development of a diagnostic test? What does the “area under the (ROC) curve” (AUC) tell you about the test?
Page 142-143
Discrimination Threshold (DT): value above which the test result would be positive and below which it will be deemed negative. it sorts out the test population into two groups: sick and healthy. The accuracy of a screening test refers to how well it distinguishes the sick from the healthy.
In general, AUC values are interpreted as follows: 0.5-0.6 (failed), 0.6-0.7 (worthless), 0.7-0.8 (poor), 0.8-0.9 (good), > 0.9 (excellent).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218006/
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Screening
Why is it impossible to screen for rare cancers?
Assume a sensitivity of 100% (perfect) and specificity of 95%
(very good)
* This rare cancer affects 1 in 10,000 individuals
* Test 10,000 people
* The test WILL identify the person with the cancer – that is,
the person with the cancer WILL have a positive test
* However, 5% of those without the disease will have a
positive test too – that’s 500 people!!!
* HUGE burden for those misdiagnosed and huge burden on
the healthcare system to rule out the presence of disease.
Assume a sensitivity of 95% (very good) and specificity of 100%
(perfect)
* This rare cancer affects 1 in 10,000 individuals
* Test 10,000 people
* The test WILL identify the 9,999 people WITHOUT the cancer – that is, all those without the cancer will have a negative test
* However, the one person with the cancer may be missed (test sensitivity is only 95% not 100%) and have a negative test too!!!
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Screening
What is the United Stated Preventive Services Task Force (USPSTF)? What does their grading system for screening tests tell you?
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Screening
Name the 2 screening modalities that have been definitively demonstrated to reduce cancer deaths and have gotten an A grade from the USPSTF.
Cervical and Colon Cancer.
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Screening
Name major cancer killers for which the causal risk factors are unknown.
Breast, prostate, pancreas
63
Screening
What is lead-time bias? Why is it important?
What is over-diagnosis bias?
How do these biases affect the understanding of the benefit of cancer screening?
Two kinds of bias mislead physicians into thinking screening saves lives:
Lead Time Bias
* Early Dx and Rx doesn’t change the ultimate outcome for some cancers (we don’t have effective Rx)
* A 5-year-survival would appear to improve spectacularly, but patient dies of disease at same age
* Depends on the cancer biology and the available treatments
Over-Diagnosis Bias
* Not all cancer is aggressive and progresses
* Depends on the cancer biology irrespective of treatment
* Lumping all cancers together is misleading and associated with over-treatment (breast; prostate)
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Screening
What are the most common patient and physician misconceptions about cancer screening?
A 2013 survey of patients showed that most patients who underwent
cancer screening were not told about over-diagnosis and over-treatment.**
* The large number of uninformed patients is related to the large
number of uninformed clinicians
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Pediatric Cancer
What are the most common cancers in children?
The childhood leukemias are acute leukemias.
* ACUTE LEUKEMIA 30%
* BRAIN AND SPINAL CORD 26%
* NEUROBLASTOMA 6%
* WILMS TUMOR 5%
LYMPHOMAS
* NON-HODGKIN LYMPHOMA 5%
* HODGKIN LYMPHOMA 3%
* RHABDOMYOSARCOMA 3%
* BONE 3%
* RETINOBLASTOMA 2%
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Pediatric Cancer
How do they differ from adult cancers?
Malignant clonal proliferation of mutated precursor cells with reduced
capacity to differentiate (cell division at the expense of differentiation)
* Myeloid precursors: acute myelogenous leukemia (AML)
* Lymphoid precursors: acute lymphocytic leukemia (ALL)
* Maturation arrest occurs at an immature (“blast”) stage
* In chronic leukemia, arrest occurs at a more mature stage of development
* Blast cells don’t mature, don’t function normally, and don’t die
* Normal bone marrow becomes completely replaced by blast cells
* Bone marrow suppression ensues causing:
* Anemia
* Immunosuppression and infection
* Thrombocytopenia (low platelets → clotting problems → hemorrhage
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Pediatric Cancer
Is the incidence of pediatric cancer going up or down? Do we know why?
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Pediatric Cancer
Are deaths from pediatric cancer going up or down? Do we know why?
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Diagnosis and Assessment
What is involved in a “work-up” of a cancer patient? WHAT is done and WHY? What principles guide the steps involved in a cancer work-up?
ACTIONS IN THE CANCER “WORK-UP”
Physical examination
* Physical examination /palpation – oropharynx, breasts, testes, thyroid, abdomen, digital rectal exam, digital prostate exam, lymph nodes.
* Focused on system referable to complaint, but not exclusively
Procedures
* Upper or lower endoscopy, bronchoscopy, colposcopy, cystoscopy, sigmoidoscopy (or full colonoscopy), endoscopic retrograde pancreaticoduodenoscopy
Imaging
* x-ray (CT), ultrasound, MRI, nuclear medicine
Cell/tissue sampling
* Excisional biopsy (skin, breast), forceps biopsy, needle biopsy
Blood tests
* CEA (colon), PSA (prostate), Ca-125 (ovarian) - tumor biomarkers
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Diagnosis and Assessment
What is meant by cancer diagnosis and how is it achieved?
DIAGNOSIS (DX)
* Identification of the illness through a process of evaluation
* Assessment of a person with symptoms (or an abnormality
found on screening)
* A working list of diseases with similar signs and symptoms,
called the “differential diagnosis”, must be narrowed down
* Diagnostic “work up” proceeds from most informative but
least “invasive” or expensive test until correct diagnosis is
reached
* For definitive diagnosis of cancer, histo- or cyto-pathological
examination is the gold standard
Prognosis is a future prediciton, whereas a diagnosis is a present fact (identification of a condition).
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Diagnosis and Assessment
What is the difference between disease signs and disease symptoms?
A symptom is a manifestation of disease apparent to the patient himself, while a sign is a manifestation of disease that the physician perceives.
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Diagnosis and Assessment
What is a differential diagnosis
A working list of diseases with similar signs and symptoms,
called the “differential diagnosis”, must be narrowed down.
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Diagnosis and Assessment
What imaging technologies are used in the work-up of a cancer and how do they work?
o Flat films (x-rays)
o Computed axial tomography (CAT or CT scans)
o PET scans
o Nuclear medicine scans
o MRI
o Ultrasound
Ionizing radiation
* Any type of particle or electromagnetic wave that can transmit enough energy to ionize or knock electrons out of outer shells atoms.
* Examples used in diagnosis:
* X-rays (standard flat films; CT scans; mammography)
* Gamma radiation from radioactive decay (nuclear imaging; PET scans).
TECHNIQUES USING IONIZING RADIATION
* Mammography (low energy x-rays)
* X-ray (“flat films” – 2-dimensional)
* High-energy, very short wave length (between UV and gamma rays)
electromagnetic radiation passes through materials opaque to light
* Energy is deferentially absorbed or blocked as it passes through
* Air is black; bone is white; soft tissues are shades of gray
* Computed tomography (CT scan – 3-dimensional)
* Series of x-rays taken from many different angles that are
reconstructed by computer to create cross-sectional images.
TECHNIQUES USING RADIOACTIVE ISOTOPES
* Nuclear medicine scans
* Positron Emission Tomography (PET) scans:For cancer: fluorine-18 isotope is attached
to glucose (fluorodeoxyglucose / FDG) and
used for FDG-PET imaging
* Glucose is taken up by cancers with high
metabolic activity
* Gamma rays (ionizing high-energy
photons) are emitted by positrons from the
decaying radioactive isotope and are
detected by sensors that encircle the body
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Diagnosis and Assessment
What are the advantages and disadvantages of imaging modalities??
Imaging = primary method of assessing tumor stage.
Any imaging technology can be used:
* Ionizing radiation
* Fluoroscopy (continuous, movable x-ray image)
* Mammography
* CT
* No ionizing radiation
* Ultrasound
* MRI
TECHNIQUES WITHOUT IONIZING RADIATION: MAGNETIC
RESONANCE IMAGING (MRI)
* Uses rotating magnetic fields and radio waves to create detailed images
* A strong homogenous electromagnetic field is created by passing an electric
current through wire loops (an electromagnetic coil).
* Another coil sends and receives radio waves.
MRI
Advantages
* Produces high resolution contrast among different soft tissues (CT can’t)
* NO IONIZING RADIATION is involved!
* No long-term side effects
Disadvantages
* More complicated and costly instrumentation
* Scan takes much longer
* Very noisy (rapid on-off of gradient magnets)
* Claustrophobia-inducing
* Expensive (average scan = $2,611; CT is half that)
* Incompatible with metallic objects in body (e.g., pacemaker, drug
pumps, aneurysm clips, cochlear implants)
Ultrasound - (sonogram) - superficial penetration
Oscillating high frequency sound waves with a frequency greater
than the upper limit of the human hearing range reflect off body
tissues and are picked up by a handheld transduce
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Study Guide - Exam 3
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76
Do cancer cells do anything (have behaviors) that normal cells cannot ever do????
Do cancer cells have molecular features that normal cells never have????
What are the key differences between cancer cells and normal cells?
Normal cells follow a typical cycle: They grow, divide and die. Cancer cells, on the other hand, don't follow this cycle. Instead of dying, they multiply out of control and continue to reproduce other abnormal cells.
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What causes cancer?
What’s a mutation?
A mutation is a permanent change in the nucleotide sequence of DNA. Mutations can be of many types, such as substitution, deletion, insertion, and translocation.
Mutation may change form and/or function if it produces a mutated protein.
A mutated protein may:
* Change the functional characteristics of the protein
* Change the functioning of the cell pathway in which the protein acts
* Changes the functioning or behavior of the cell as a result
* A mutated regulatory protein (protein from a gene that controls the degree
of expression of other genes) may:
* Change the amount or function of regulatory RNA or normal protein made.
* Change the functioning or behavior of the cell as a result.
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What causes cancer?
Name some ways of causing a mutation.
Duplication (gene amplification), deletion, single nucleotide substitution, translocation, inversion of a nucleotide sequence, insertion of a new sequence (viral)
Substitution of one base for another with no change in the total number of nucleotides
The addition (insertion) of a single nucleotide
The addition of a nucleotide sequence
The deletion of a nucleotide
The deletion of nucleotide sequence
The rearrangement of entire segments of chromosomes (translocations)
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What causes cancer?
Mutation types – what are driver gene mutations??
Mutations in genes that contribute to the phenotype (observable behavioral characteristics) of cancer are called driver genes.
Mutations that do not contribute to the cancer cell behavioral characteristics (biologically neutral) are called passenger mutations.
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What causes cancer?
What is the epigenome?
- DNA methylation and gene silencing – a Rx target?
- Epigenetic silencing of tumor suppressor genes is reversible by therapy.
The current definition of epigenetics is ‘the study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence’.
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STAGE: GENERAL CLASSIFICATION FRAMEWORK
Stage 0 - early form
Stage 1 - localized
Stage 2 - early localized advanced (spread to regional lymph nodes)
Stage 3 - late localized advanced (spread to regional lymph nodes)
Stage 4 - metastasized
Stage is more clinically useful in classifying patients
Deciding on the right treatment strategy for a given patient
Comparing treatments to evaluate differences
Comparing outcomes in different populations
Comparing outcomes in different hospitals (quality measure)
Comparing outcomes for patients of different gender, race, etc.
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Two classes of Tumor Suppressor Genes
1. Gatekeepers
* Act through cell cycle to stop cell proliferation
* Loss of function mutations lead to excessive proliferation
* Example: p53
2. Caretakers
* Function in DNA repair and chromosome sorting
* Includes “spell checkers” that repair normally-occurring
replication errors (i.e., DNA polymerase errors)
* An error normally occurs once per every 10 billion base pairs
* Loss-of-function mutations contribute to genomic instability
* Examples: BRCA1, MLH1
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Name the Hallmarks of Cancer – what’s their basis??
Sustained proliferative signaling – what are oncogenes?? Cell surface through nucleus and cell cycle (positive regulators like cyclins).
o Increasing growth factor production/utilization
o Producing it’s own growth factors
o Increasing the number receptors on cell surface
o Utilizing mutated receptors
o Activating downstream proteins in the growth pathway
o Stimulating normal cells to produce more growth factors
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Name the Hallmarks of Cancer – what’s their basis??
Evading Growth suppression – what are tumor suppressor genes?
o Caretakers: damage detection and repair enzymes
o Gatekeepers: DNA damage cell cycle checkpoint control: repair or die
o Why is tp53 tumor suppressor gene so important? It REGULATES THE CELL
CYCLE and is the primary gatekeeper – it is called “the master tumor
suppressor gene” and is the most commonly mutated tumor suppressor gene
in cancer
o p53 is also known as “the guardian of the genome” because it is responsible
for detecting DNA damage in the genome and eliminating cells with damaged
genomes
o p53 also promotes normal aerobic metabolism so its loss pushes the cancer
cell to anaerobic metabolism
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Name the Hallmarks of Cancer – what’s their basis??
Invasion and metastasis: Describe the steps required for metastasis.
What is EMT?
What happens during this process and what abilities does it confer on the cancer cell?
What is MET?
What happens during this process and what abilities does it
confer on the cancer cell?
Is metastasis an efficient process (i.e., do most cancer cells
have all the capabilities needed for successful metastasis?
EMT IS CHARACTERIZED BY LOSS OF MOLECULAR ANCHORS BETWEEN CELLS
* Loss of organization of epithelial cell layers
* Altered cell-cell adhesion
* Loss of basal membrane attachment
* Degradation of the basal membrane
* Acquired motility
EPITHELIAL TO MESENCHYMAL TRANSITION (EMT)
* Allows an epithelial cell to assume a mesenchymal cell phenotype
* Results in enhanced migratory capacity, invasiveness
* Completes when underlying basement membrane is degraded and the
mesenchymal cell can migrate away from the epithelial layer
MET: reverse process of EMT after traveling to a distant site.
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Name the Hallmarks of Cancer – what’s their basis??
Resisting cell death: apoptosis = normal way to eliminate defective or senescent cells and maintain cell balance in body; the cancer cell increases cell death apoptosis) inhibitors (like Bcl2) and decreases cell death activators (like Bax);
mutated cells escape cell death!
o P53 here again
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Name the Hallmarks of Cancer – what’s their basis??
Replicative immortality
o Telomeres
o No damage consequence (p53 again)
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Name the Hallmarks of Cancer – what’s their basis??
Angiogenesis: inducing growth of new blood vessels for a private blood supply
o VEGF, FGF, PDGF etc. – growth factors from tumor and cells in environment
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Name the Hallmarks of Cancer – what’s their basis??
Avoiding immune destruction
o Multiple mechanisms: immune suppressive cytokines; checkpoint inhibitor
over-expression; eliminating neoantigens (mutated proteins) from their cell
surfaces, etc.
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Name the Hallmarks of Cancer – what’s their basis??
Deregulating cellular energetics
o Cancer cells use glycolysis (anaerobic metabolism) and lactate production in
the presence of oxygen instead of aerobic glycolysis – called the Warburg
effect (normal cells use anaerobic glycolysis only when oxygen is absent)
o Less ATP produced but many other beneficial effects for the cancer cell result
o Glycolysis leads to increased lipid and nucleotide production to support cell
proliferation
o Lactate stimulates mitosis, invasiveness in cancer cells
o Some tumor cells can even utilize lactate as fuel
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Name the Hallmarks of Cancer – what’s their basis??
Enabling characteristics:
- Genomic instability and mutation
- Tumor-promoting inflammation: what is the tumor microenvironment?? Cytokines,
chemokines, proteases produced by normal cells in the stroma surrounding the tumor cells that enable tumor cells’ growth and survival.
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Describe cancer as an evolutionary system and the necessary and sufficient requirements
for evolution that cancers possess: variation in the population; variation is heritable;
variation affects reproduction and survival (“fitness”)!
* What is meant by “cheating” on multicellular cooperation?
* What approaches to therapy can take advantage of evolutionary principles?
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Name 8 ways to prevent cancer (lower risk of getting cancer):
- No smoking
- No alcohol
- Maintain low body weight (no obesity)
- Regular physical exercise
- Protection from UV radiation (SPF to block UV)
- Proper diet (what to eat, what not to eat)
- Vaccines for oncogenic viruses like HPV, HBV
- Get screening colonoscopy and cervical screening (Pap tests)
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What are the major challenges to effective screening for cancer?
- Challenge of developing effective tests
What is a false positive test? What are the consequences?
What is a false negative test? What are the consequences?
- The prevalence of the cancer
* False positive tests lead to over-diagnosis, over-treatment
and needless burden for patient and healthcare system
* False negative tests lead to under-diagnosis and missed
opportunity for life-saving early treatment.
* Possible goal: Maximize true positives, minimize false positives
* The trade-offs for the choice of the DT depend on the consequences of wrongly classifying an individual in the context of the test use.
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Name the 3 screening modalities that have been demonstrated definitively to lower the number of deaths from the cancer being screened for:
* Pap smears (cervical cancer),
* Colonoscopies (colorectal cancer),
* Spiral CT scans for heavy high-risk smokers (lung cancer)
* Debated (with recently revised/conflicting recommendations): PSA (for prostate cancer) and mammography (breast cancer).
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Name 2 major cancer killers for which the actual cause is unknown:
breast and prostate.
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What cancer causes the most cancer deaths in the USA?
Lung cancer!
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What is the most common cancer in men? In women?
Prostate. Breast.
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What is involved in a “work-up” of a cancer patient? WHAT is done and WHY?
Actions in the Cancer “work-up”
Physical examination
Physical examination /palpation – oropharynx, breasts, testes, thyroid, abdomen, digital rectal exam, digital prostate exam, lymph nodes
Focused on system referable to complaint, but not exclusively
Procedures
Upper or lower endoscopy, bronchoscopy, colposcopy, cystoscopy, sigmoidoscopy (or full colonoscopy), endoscopic retrograde pancreaticoduodenoscopy
Imaging
x-ray (CT), ultrasound, MRI, nuclear medicine
Cell/tissue sampling
Excisional biopsy (skin, breast), forceps biopsy, needle biopsy
Blood tests
CEA (colon), PSA (prostate), Ca-125 (ovarian) - tumor biomarkers
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How is a definitive diagnosis made? What are the different options for doing this?
How is a clinical stage of disease determined? What are the different radiological imaging options for doing this and how do they differ?
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What is GRADE?? – why is it important?? What does it signify?
What is STAGE?? - why is it important? What does it signify?
While a grade describes the appearance of cancer cells and tissue, a cancer's stage explains how large the primary tumor is and how far the cancer has spread in the patient's body.
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What is multidisciplinary cancer care? Why is it important?
A multidisciplinary team (MDT) in oncology is defined as the cooperation between different specialized professionals involved in cancer care with the overarching goal of improving treatment efficiency and patient care.
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What are the different classes of risk factors for cancer treatment:
patient-related, tumor-related, treatment environment related? Name 3 examples in each category.
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Name 3 different types of GOALS for cancer treatment? (cure is not the only one!)
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What is palliative care and when should it be used?
The term "palliate" means to remedy or lessen without curing. it is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psycho-social and spiritual.
Also known as supportive care, with the aim to provide relief from the many stresses that life-threatening diseases poses.
Modern palliative care is delivered alongside disease-specific treatment from the time of diagnosis until such time as the anticancer treatment ceases to show benefit or is no longer desired by the patient.
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What is local therapy? Name 3 kinds of local therapy, when they are appropriate and what needs to be considered when using them.
Local therapy is directed only to a specific part of the body with a clinically detectable tumor mass and delivered using highly specialized techniques and sophisticated technologies.
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What is systemic therapy?
Systemic therapy is any form of treatment that is delivered to the entire body all at once. It is used when the patient has regional or metastatic cancer (TNM Stage III or IV) or when adverse prognostic factors associated with a high risk of developing metastatic disease are present (lymphatic or venous invasion by tumor at the primary site) in local disease (TNM stage II).
Primary treatment of Leukemias and Lymphomas (systemic from the outset).
Neoadjuvant therapy prior to cancer-directed surgery.
Neoadjuvant therapy prior to radiation therapy.
Secondary treatment for recurrent cancer following primary therapy.
Delivered via the bloodstream to cancer cells or masses located anywhere in the body by intravenous transfusion.
Only about a quarter to a third of advanced cancers respond to any therapy.
Goals of Systemic Therapy
* Achieve a curative outcome for the patient.
*Prolong life if cure cannot be achieved.
* Reduce or eliminate symptoms of the cancer.
* Minimize damage to normal cells, tissues, and organs.
* Extent / duration of therapy is limited by patient tolerance.
* No systemic therapy is free of toxicity.
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Name 3 kinds of systemic therapy, when they are appropriate, and what needs to be considered when using them.
Cytotoxic chemotherapy: Most chemotherapeutic drugs kill cancer cells and are known as "cytotoxic" (cell-killing) agents.
*Cytostatic drugs will stop the growth of cancer cells but do not kill them. Cytotoxic agents act by causing injury during the cell cycle that leads to the death of the proliferating cell. They can cause direct DNA injury that cannot be repaired. Since cancer cells often have impaired ability to repair DNA due to caretaker tumor suppressor gene mutation and loss of function, they are disproportionately sensitive to these DNA-damaging agents compared to normal cells.
Hormonal therapy: Does not kill cancer cells. It is used in combination with other chemo-therapies that do kill cancer cells.
* Sex hormones are used to block either the production of natural hormone or binding of natural hormone to receptors on the cancer cell (Prostate blocks androgen production and breast block estrogen action).
* Corticosteroids reduce inflammation, swelling, boost appetite, and relieve side effects of other chemotherapies.
Immunotherapy:
Vaccines
Immune stimulation (cytokines, etc.)
Cell-based (T cell) therapies (in vitro manipulations of various sorts including genetic engineering)
Checkpoint inhibition
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Activated (immune) cell therapy (ACT)
“Living drugs”
Capture, expand and re-infuse unmodified tumor-infiltrating lymphocytes (TILs), which are cytotoxic lymphocytes (killer T cells) that target cancer cells
Also called “T cell transfer therapy”
Problem: Getting a sufficient quantity of tumor tissue and TILs
Genetically Engineered Killer T Cells:CAR-T therapy
Killer T cells harvested from cancer patients are genetically engineered in vitro to express chimeric antigen receptors (CARs) that recognize tumor antigen(s)
These receptors don’t exist in nature
Called “chimeric” because they combine both an antigen-binding (extracellular) and T-cell activating domain (intracellular) into a single receptor.
The TCR/CAR genes are delivered by viral vectors or crisper technology
Time- and labor-intensive: CAR-T therapy is custom made for each patient
Challenge of creating TCR/CARs for diverse neoantigens
High cost and complexity of this type of ‘individualized’ therapy
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What is adjuvant therapy / neo-adjuvant therapy? When and why are they used?
Neo-adjuvant therapy
Chemotherapy or radiation BEFORE surgery
Aim: “Shrink” tumor to improve technical probability of successful removal of all disease and biological probability of reducing tumor viability
Adjuvant therapy
Chemotherapy or radiation AFTER surgery
Aim: Kill tumor cells left behind – detectable or not
Radiation if tumor cells are present at the surgical resection margin
Chemotherapy if systemic risk of recurrence (metastatic disease appearing after surgery) is high
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What is targeted therapy?? How is it used? What is a companion diagnostic test for a targeted therapy?
Agents that are directed against specific molecular aberrations in cancers, most often mutated or over expressed oncoproteins. Heterogeneous in terms of the type of molecule that is targeted and the biological effect that is created.
Monoclonal antibodies that are used to deliver a tumoricidal payload such as a toxic agent, drug, or radioactive molecule, which is coupled to the antibody. These antibody-drug conjugates (ADCs) are sometimes called "smart bombs."
A more common strategy for targeted therapy is to use antibodies or small molecules directed against growth factor receptors on tumor cell surfaces in order to block the docking of the corresponding growth factors and abolish their growth signal initiation function.
They are products of oncogenes and are either constitutively active or over expressed. Mutated or overexpressed growth factor receptors are particularly attractive targets because they can be powerful driver of tumor growth and also may be capable of activating more than one signaling pathway. Their location on the surface of the cell makes them much more accessable to therapeutic agents like monoclonal antibodies compared to molecular targets inside a tumor cell.
Targeted therapies do not work for all types of cancers or all cancers of a given type.
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What are the different forms of immunotherapy? How do they work?
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What is the biggest challenge for any systemic therapy and why do systemic therapies fail??
Heterogeneity of clones within the tumor (in primary and metastatic sites) and resistance
(new or pre-existing)
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What is an IRB and what does it do?
Institutional Review Board (IRB) insures compliance with federal standards for experimental animal care and use, as well as those of the National Institute of Health (NIH) if NIH funding is involved. For each participating institution in a clinical trial, full IRB review and approval of the protocol is required before the trial can open in that institution. This includes a careful analysis of the consent form proposed for the study.
The levels of IRB review is determined by the level of risk posed to the research participants.
Exempt: Less than minimal risk (de-identified records or autonomous surveys).
Expedited Review: Not greater than minimal risk.
Full Board Review: More than minimal risk (interventions involving physical or emotional discomfort; research involving sensitive data).
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The Belmont Report: Essential Ethical Principles for Clinical Research
Respect for persons: individuals must be treated as autonomous agents who enter research voluntarily and that researchers must be truthful about the experiment to which the research participants are consenting.
Beneficence: individuals must be protected from harm (i.e. the risk must be minimized and the benefits must be maximized).
Justice: there must be a fair distribution of the risks, benefits, and costs for research participants.
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The Ethics of Human Experimentation
The Declaration of Helsinki
World Medical Association declaration of recommendations. for physicians involved in research involving human subjects
Consent should be in writing.
Interests of science should never take precedence over well- being of the patient.
The Nuremburg Code
Developed in reaction to Nazi atrocities of WWII.
Human experimentation is justified when the results are for the good of society and cannot be procured by other means.
Must satisfy moral, ethical and legal concepts.
Voluntary consent of human subject is absolutely essential.
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What are the phases of clinical trials and what is the goal of each phase??
Phase 1 clinical trials: sole purpose is to evaluate safety in humans.
Phase 2 clinical trials: purpose is to establish the optimum dosage for efficacy,
Phase 3 clinical trials: purpose is to prove efficacy & safety statistically.
Phase 4 clinical trials: monitor safety of the approved drug with real-world use.
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What must be demonstrated to the FDA for approval of a new therapy??
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What is required in order to test new therapies on cancer patients?
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What is informed consent for human research and what are its 3 basic requirements?
* Disclosure of information (all relevant information): procedures, risks, benefits, alternatives, conflicts of interest.
* Comprehension: information explained in terms that are consonant with the research subject’s capability.
* Voluntarism: decision to participate must be free of coercion and undue influence.
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THE TARGET: CANCER “DRIVER” GENES
Oncogenes
* Gain-of-function mutations
* Antagonist Rx (therapy blocks activity)
* Wide range of Rx design options – base of targeted therapy!
Tumor Suppressor Genes
* Loss-of-function mutations
* Agonist Rx (therapy restores function)
* Far more difficult Rx design (very few examples in any therapeutic area)
* Demethylation of the promoter of a normal gene is one exception – only success!
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What are the steps that are required to generate a new cancer therapy? What is the overall success rate of cancer drug development? How long does it take? How much does it cost?
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What is drug discovery: rational design vs screening?
What is pharmacokinetics? Movement and fate of drugs within the body. Why important?
absorption, distribution, metabolism, excretion
Pharmacodynamics? The effect of drugs and their actions in the body. Why important?
Pharmacokinetics is the study of how the body processes a drug ( i.e. how the drug is distributed in the body; where, how and how fast it is metabolized; where, how, and how fast it is eliminated from the body). This knowledge is required for calculating dosing schedules that will maintain effective drug levels in the system during treatment.
Pharmacodynamics refers to the effects of the drug on the body, both therapeutic and toxic, as increasing doses of the agent are given. Helps to determine the effective and optimal doses of the drug for treatment, as well as safety of the drug at different dosages. Also gives information about the does ranges at which the drug is lethal.
Pharmacogenetics: Impact of genetic variation in drug metabolism enzymes Slow, intermediate and fast metabolizers. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached. In others, metabolism may be so slow that usual doses have toxic effects.
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What is pre-clinical development? Does it accurately predict activity in humans – Efficacy? Toxicity??
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What is the track record for new cancer therapies in terms of amount of overall amount of additional life conferred on patients who are treated with them?
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What are the future challenges for cancer medicine?
* Spiraling costs
o Who will pay for treatments with extraordinary costs?
o How will costs of survivorship be covered?
o How can drug prices be controlled?
* Limitations of use (fruitless) anti-cancer treatment in terminal stages of
disease
* Increasing focus and investment in prevention.
