7. Cancer IV Flashcards

1
Q

• Tumor starts as one clone, or a group of cells that have a specific mutation that allows the cell to transform to a malignant phenotype
○ Cancer is ____
• What causes transformation?
○ ____ mutation that occurs in division in absence of external stimulus
○ Causative agents
§ Chemical, radiation, viral, and microbial types

A

monoclonal

spontaneous

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Carcinogenic Agents

  • ____ Carcinogens
  • Radiation
  • ____ and Microbial
  • May act alone or in concert
A

chemical

viral

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Chemical Carcinogens
Direct-Acting
 Do not require ____
 Used as ____

Indirect-Acting
 Metabolized by ____ dependent monooxygenase
 ____ vary among individuals – personalized medicine target

• Direct-acting
	○ Alkylating agents - used to treat cancer because it causes \_\_\_\_ damage and causes cell to die
	○ Used to treat cancer because they divide faster, so they're more sensitive to damage via AA
	○ They're carcinogenic, but not strongly carcinogenic; the risk must be taken in order to remove the current cancer
	○ \_\_\_\_, chlornambucil, \_\_\_\_ are examples of anticancer drugs

• Indirect-acting
	○ Once \_\_\_\_ it becomes carcinogenic
	○ Enzymes can differ in \_\_\_\_ form one person to another - variability - due to certain AA having slight differences, no change in structure only in activity
		§ If one person has slightly higher activity, will convert the chemical faster/higher amount > higher chance to develop \_\_\_\_
		§ Personalized medicine - your risk is higher if exposed to this potential carcinogen
A

metabolism
chemotherapeutics

p450
alleles

irreversible
cyclophosphamide
nitrosurea

metabolized
activity
cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Indirect-acting Carcinogens

Polycyclic hydrocarbons
 ____
 Cigarette smoke
 ____ in meat

Aromatic Amines
 ____ dye industry
– ____ – bladder cancer

• Polycyclic hydrocarbons
	○ Benzopyrenes come from fossil fuels and cigarette smoke
• Aromatic amines
	○ Dyes that have been used in last 200 years to produce the color blue, yellow
		§ Workers that were exposed - higher rates of cancers
• These both require \_\_\_\_ activation
A

fossil fuels
broiled fat

analine
b-naphtylamine

metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Natural Indirect Carcinogens and others

 ____ – produced by Aspergillis strains found on poorly stored nuts

* Consumption of these nuts has led to increase incidence \_\_\_\_ cancer
* \_\_\_\_ plants can be a source of carcinogens
* Betel nuts - chewed that can lead to oral cancer
* Pesticides/home compounds can also lead to cancer
A

aflatoxin B1
hepatocellular
natural

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Mechanisms of Chemical Carcinogens

Initiators:
 DNA \_\_\_\_ agents
 Some target specific gene more often
 \_\_\_\_
 TP53 – “\_\_\_\_”
Promoters
 Induce cell \_\_\_\_
 Non \_\_\_\_
 Induce cell proliferation
 make mutations in initial clone cell \_\_\_\_
 Accumulation of additional mutations
 e.g \_\_\_\_, hormones, phenols
A

damaging
Ras
signature mutation

cell growth
tumorigenic
permanent
phorbol esters

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Radiation Carcinogenesis

Induces DNA damage 
 UV rays
 \_\_\_\_ dimers 
 Nucleotide Excision Repair
 Skin cancers
-- Squamous and Basal cell carcinoma– \_\_\_\_ sun exposure
-- Melanoma - Intense \_\_\_\_ sun exposure 
-- \_\_\_\_ Carcinogenesis
 Radionuclides, Ionizing radiation -
\_\_\_\_ DNA breaks 
\_\_\_\_ repair 
Non-homologous End joining
Used in therapy with \_\_\_\_ consequences to adjacent tissues
A

pyrimidine
accumulated
intermittent
field

double stranded
recombination
secondary

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

• Damage type differs between UV exposure and ionizing radiation
• UV exposure
○ Dimerized of pyrimidines that are ____ bound leading to an error
§ The nt will have to be excised via ____
□ If you have deficiencies - ____ - very sensitive to UV damage
○ Too much damage will overcome the capability of NER > carcinogenic process occurring
○ The more sunlight you’re exposed to, the more likely you’ll develop squamous/basal cell carcinoma
§ ____ people are more susceptible to sun cancer formation
○ The whole area is exposed to UV light, there will be mutations, but won’t be the same in all ____ > but the whole field has a higher chance of cancer development
§ Field carcinogenesis, also occurs in the oral cavity

• Ionizing radiation
	○ Can lead to \_\_\_\_, translocations and sometimes mutations (but less likely), leading to \_\_\_\_ to repair the break; or \_\_\_\_ (resulting in genomic instability)
	○ Thyroid cancer - a secondary tumor down the line can occur from treatment; can be in the same or adjacent tissue
A

covalently
NER
XP

fair-skinned
cells
deletions
recombination
non-homologous end joining
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Host Defense against Tumors: Tumor Immunity

 Tumors must evade ____ surveillance
 Immune ____ increases risk for tumors
 Challenge is finding tumor specific antigens

Targeting cytotoxic T-cells against Tumor specific antigens
 \_\_\_\_ and mutant tumor suppressors
 Viral antigens
 \_\_\_\_ proteins
 Other mutated cellular proteins
• If person is immunocompromised, risk of cancer is increased
	○ In \_\_\_\_ immunocompromised and \_\_\_\_ patients it is evident
	○ Immune suppression by \_\_\_\_ can also increase the risk for tumors
• Before we can train immune system to attack tumor, we need to train it to recognize tumor-specific antigens
	○ Categorized into these fours
• Most important cell-type in tumor immunity is \_\_\_\_
	○ Recognize antigens
A

immune
suppression
oncoproteins
overexpressed

congenital
transplant
drugs
CTL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Oncogenes and mutant tumor suppressors

 Mutations in protooncogenes and tumorsuppressors induce new antigens
 E.g. ____, ras, ____, and CDK4, her2/neu

 So far only ____ antibodies appear to be protective for breast cancer

• Normally endogenously expressed due to mutations, and now they are new:
	○ B-cat, ras, p53 and CDK4
• Her2/neu - GFR
	○ Not mutated, but it's \_\_\_\_ in breast cancers
	○ Already on the \_\_\_\_, and targeted therapy can shut down the signaling mechanism and kill the cells
A

b-catenin
p53
her2/neu

overexpressed
surface

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Other Mutated Proteins

 Genomic instability leads to mutation in numerous genes
 Altered protein products would be ____ to the cancer cells

 Diverse and varied targets, perhaps unique to each tumor
 Chemical and radiation induced changes may have “____” like p53 for aflatoxin B1

• Any gene can be mutated, so it is extremely diverse, and it would trigger an immune response
• Can be helpful: when carcinogens can induce \_\_\_\_ mutations
	○ P53, aflatoxin B1 produces a toxin that induces a mutation which can link the cancer to aflotoxin exposure
A

unique
signature mutation
specific

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Overexpression of normal proteins

 Select cell expression at low level perhaps does not induce “____”
 Now target for tumors that have deregulated these gene products

 \_\_\_\_ in melanocytes
 Cancer-Testis antigens
-- Sperm do not express \_\_\_\_
-- e.g. Melanoma Antigen 1 (MAGE1)
=== 37% of melanomas
=== Also found in subset of lung, liver, stomach an esophageal tumors
• Sometimes genes that are usually repressed, but they become activated and express their products
	○ Initially at such a low level/not expressed, so immune system was not trained so there's no \_\_\_\_
	○ An immune response is induced
		§ Tyrosinase
			□ Expressed, but in very \_\_\_\_ levels
			□ Immune system doesn't normally detect it - untrained to recognize as self
			□ Malignant melanoma - \_\_\_\_ levels increase - triggers an immune response
		§ Cancer-testis antigens
			□ Only expressed in sperm, and because it doesn't express MHCI (need it to present antigen to cell surface); the immune system has not been exposed to antigens
			□ In cancers they're not repressed, and expressed by other cells (which have MHCI) and the immune system recognizes it as foreign and targets it
			□ \_\_\_\_ and RAGE are examples
A

self-tolerance
tyrosinase
MHC class I
self-tolerance

low
tyrosinase
MAGE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Viral antigens

 ____ and EBV produce viral product kept in check by immune surveillance
 Effectiveness of Vaccine against HPV supports the role of the ____

• Immune system can be used to protect against cancer
	○ Person has a vaccine against HPV - immune surveillance set to look for HPV antigens
	○ If a cell that is transforming to cancer due to HPV > you have trained the immune system to go and kill the transforming cell
		§ Decreases incidence of HPV induced \_\_\_\_ cancer
A

HPV
immune system
cervical

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Other Targets

 Oncofetal proteins
—  ____ protein re-expressed in tumors

 glycolipids and glycoproteins

  • –  ____ specific glycolipids/proteins would be sequestered
  • –  Seen on non-____ tumors

 Differentiation specific antigens
— ____ tissue of origin for tumor

• Oncofetal proteins
	○ Initially shut down following fetus is born, and then the repression is lifted during carcinogenesis
	○ \_\_\_\_
		§ Expressed in colon/stomach cancer
	○ \_\_\_\_
		§ Expressed in liver cancer
	○ Both antigens are detected in serum, and supports the diagnosis (not the \_\_\_\_ itself!)
• Glycolipids/glycoproteins
	○ Normally not exposed to immune system due to location
		§ \_\_\_\_ - found on apical side of ductal side of breast epithelium
			□ No exposure to immune cells, and they don't know that it's endogenous protein
			□ Upon cancer losing contact and \_\_\_\_, the apical membrane becomes exposed to the immune system
• Differentiation specific antigens (CD#)
	○ Expressed on B cells, T cells and blood cells
		§ Based on the antigen expression - can categorize the \_\_\_\_
		§ In lymphoma, can deduce the cell type using this mechanism
A

fetal
ductal
polarized

delineate

carcinoembryonic antigen (CEA)
alfofetal protein (AFP)

diagnosis
mucin-1

polarity
cell type

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Anti-tumor mechanisms

Cell mediated immunity
 Cytotoxic T-cells
— ____ cells respond to viral tumors
 Natural Killer cells
— Target tumors that downregulate ____
— Diverse receptors, including ____ induced antigens

Macrophages
 ____ produced by Cytotoxic T cells and NK cells activates Macrophages

Humoral immunity
 Anti CD20 AB treats ____

• NK cells
	○ Downregulate MHCI so the cancer cells become more susceptible to NK cells (because they're killing CTL)
	○ Cancer cells under stress express antigens that are targeted by the NK
	○ Less selective than \_\_\_\_
• Macrophages
	○ Produce \_\_\_\_, other cytokines and cause death
	○ Inflammation that is seen in tumors - while it is there to control growth, it can lead to \_\_\_\_ itself - precipitating more damage
		§ Double-edged sword
• Humoral immunity
	○ NHL - cancer cells overexpress CD20 - can use ab against the CD20 antigen leading to a burst of the tumor cell
A

CD8+
MHC class I
stress

INFg

non-hodgkin lymphoma

CTL
ROS
DNA damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Immune Surveillance and Immune Evasion

 Immunodeficiency increases risk 200 fold
 ____ Immunodeficiency
 ____ patients
 ____-infection

 Immune competent host develop cancer
 Tumors must evade the immune system

A

congenital
transplant
HIV

17
Q

Mechanisms of Immune evasion

 ____ of immune system eliminate highly antigenic tumor cells
 Reduction/loss of ____ markers
 Antigen Masking – Thicker coat of ____ hides antigens

 Induction of immunosuppression
— Expression of ____
— Engagement of T-cell inhibitory receptor, ____
— Expression of ____ – apoptosis
 Downregulation of co-stimulatory molecules needed for strong ____ response

• Cancer cells will try to lose their MHC, so the immune system will not recognize the cancer cells
• Induction of immunosuppression
	○ Growth inhibition by TGF-b > the expression of TGF-b can lead to immunosuppression as well
	○  Can utilize CTLA4 that will dampen the immune response
	○ Tumor cells can express and secrete FasL, which will bind to Fas receptor and will induce apoptosis of the \_\_\_\_ cell
A

selective pressure
histocompatability
glycolipids

TGFb
CTLA4
FasL
T cell

immune

18
Q

Clinical Aspects of Cancer
 Effects of tumor on Host
 ____ of Cancer
 ____ Diagnosis

 How do we recognize cancer?

A

grading and staging

laboratory

19
Q

Effects of Tumor on Host - Location

 Mass effects

  • - ____ or malignant tumors
  • - Block flow in ____, duct, bowel etc
  • – e.g ____ artery, liver, intestine
  • - Compress/damage normal tissue
  • – e.g ____ adenoma compression of gland
 Produce hormones
-- e.g Pancreatic b-cell tumors – \_\_\_\_
 Ulcerate surface 
-- \_\_\_\_
-- Secondary infection 
 Intussusception
-- Tumor protruding into gut lumen caught in \_\_\_\_
A

benign
vessel
renal
pituitary

hyperinsulinemia
bleeding
peristaltic pull

20
Q

• Mass effects
○ Based on ____
§ Pituitary adenoma - very small location, and the tumor is very small, but it has significant outcome:
□ Compresses the gland, and the hormones will not be secreted
§ Growth in the brain - even if small can have fatal outcomes
§ Growth in vessel wall of renal artery - and blocks flow - renal issues
§ In the liver, blocking flow of ____ will lead to digestion of liver
○ Intussusception
§ Blocking intestinal lumen > tumor protruding into the gut will interrupt the peristaltic movement leading to blockage and then ____ of local tissue
○ Production of hormones
§ Pancreatic b-cell tumor - if well differentiated > will retain some of normal function > insulin production
□ Manifest as hyperinsulinemia (low levels of blood ____)
§ Pituitary adenoma can also produce certain hormones
○ Ulcerate surface (because the vasculature is ____ in cancer)
§ More likely to occur in GI tumors, stomach tumors and colon cancer
□ Bleeding can be massive
□ Bleeding can be small, but ____ - so subtle to not be detectable by patient > can lead to ____

A
location
bile
gangrene
glucose
occult
anemia
21
Q

Effects of Tumor on Host - paraneoplastic syndromes

Paraneoplastic syndromes 
 May precede tumor
\_\_\_\_
 Differ based on tumor \_\_\_\_
 Several mechanisms
Most Common 
 \_\_\_\_
 Cushing Syndrome
 \_\_\_\_
 Nonbacterial thrombotic endocarditis
• Paraneoplastic syndrome
	○ Any symptom that is not directly to the \_\_\_\_, or the \_\_\_\_ that may be acquired by cancer (invasion of tumor into surrounding tissue)
	○ May precede tumor ID, can help the clinician diagnose the cancer
	○ Certain cancers produce certain \_\_\_\_ in paraneoplastic syndromes that can help diagnose the cancer
• Hypercalcemia
	○ If breast tumor goes to bone:
		§ Bone resorption
		§ Increase levels of Ca++ in blood
			□ These are due to \_\_\_\_ of cancer into blood, not paraneoplastic!
	○ Paraneoplastic syndrome:
		§ Production of \_\_\_\_ that will lead to increased levels of Ca++
• Cachexia
	○ Wasting
A

identification
origin
cachexia
hypercalcemia

mass effect
function

hormones
invasion
hormones

22
Q

Miscellaneous (non-specific syndrome)

Non-specific syndrome 
 \_\_\_\_
 Dysgeusia 
 \_\_\_\_ 
 cachexia

Cachexia
 Loss of ____ and ____, Weakness, Anorexia,
Anemia
 Wasting ____ than reduced food intake dictates
 Metabolism is ____, not lower
 Due to cytokines like ____ from Macrophages or tumor cells
 Only treatment is to remove ____

• Dysgeusia - fowl smelling breath
• Cachexia - very thin, very fast weight loss
	○ Non-specific
	○ Not due to \_\_\_\_, or because the tumor is using up the calories
	○ It's because of the \_\_\_\_ released by the tumor cells or the macrophages
		§ TNFa
	○ Patient may not be eating - starvation; however, metabolic rate increases (it would usually decrease)
A

fever
anorexia

fat
lean mass
faster
higher
TNFa
tumor

tumor size
cytokines

23
Q

Paraneoplastic syndromes

Clinically important because
 10-15% of cases
 Often \_\_\_\_ manifestation
 May cause significant morbidity/mortality
 May \_\_\_\_ treatment

Hypercalcemia
 ____
 Most common cause is production of ____ by tumor

• Hypercalcemia
	○ Multifactorial due to production of hormones
	○ PTHrP leads to release of \_\_\_\_
A
early
confound
multifactorial
parathyroid hormone-related protein (PTHrP)
Ca++
24
Q

Paraneoplastic lesions

Cushing syndrome
 ____ disorder
 One cause may be ____
 Increase ____- like peptides by tumor

 Constellation of effects due to ____
 Neurologic, cardiovascular ,immunosuppression, metabolic changes (obesity/____), musculoskeletal changes, etc

• Cushing syndrome
	○ Many reasons for the disorder, cancer is one of them
		§ By itself, Cushing syndrome does not mean the patient has a \_\_\_\_
	○ Hypercortisolism
		§ Immunosuppression exacerbates the conditions in cancer patients
A
endocrine
tumor
ACTH or ACTH
hypercortisolism
moonface
tumor
25
Q

Paraneoplastic lesions

Hypercoagulability
 ____
 ____

 More will be discussed in the context of specific tumors

• Hypercoagulability leads to thrombosis in the absence of other risk factors (immobility, etc.), ultimately leading to nonbacterial endocarditis
A

thrombosis

nonbacterial endocarditis

26
Q

Mechanisms of paraneoplastic syndromes

 Produce \_\_\_\_
 Produce immunologic
response
--- \_\_\_\_ action
 Produce \_\_\_\_ molecules
 \_\_\_\_ and Infection
A

hormones
antibody
bioactive
ulceration

27
Q

Grading and Staging of cancer

 Grading
— Quantify clinical aggressiveness based on ____ presentation, number of mitoses.
— Well differentiated to anaplastic
 ____ grades (I, II, III, IV)
 ____
 Criteria vary for each form of neoplasia

 Staging
 T (1-4)- \_\_\_\_
 N(0-3) – \_\_\_\_ involvement
 M (0-1) – \_\_\_\_
 More clinically \_\_\_\_ for prognosis
• Grading
	○ Based on microscopy
	○ Not as clear cut, some personal intuition is a factor in deciding the grade
		§ Not a very quantitative way, more descriptive
• Staging (TNM)
	○ More observable gross findings
	○ Based on quantitative criteria:
		§ T - tumor size
		§ N - regional lymph node involvement
			□ \_\_\_\_ - no lymph node involvement
			□ N1-2 - lesion is on right side of salivary gland and lymph node is on the same side
			□ N3 - if lesion and lymph node are \_\_\_\_
		§ M - metastases (the most important to gauge the severity of the tumor)
			□ M0 - no metastasis
			□ M1 - \_\_\_\_
A

cytologic
4
descriptive

size
regional lymph
metastases
valuable

N0
contralateral
metastases

28
Q

Laboratory Diagnosis of Cancer

 ____ Methods
 Tumor Markers
 ____ diagnostics
 Molecular profiling of tumors

A

morphologic

molecular

29
Q

Morphologic Methods
 Benign vs Malignant is ____
 Middle ground is harder
 Other changes may mimic or masks appearance of lesion
– ____, bleeding, ____, radiation damage.

Diagnosis depends on
 ____ of specimen
 Appropriate ____ method
 Clinician ____

• Ambiguities - sometimes you see mitoses but the architecture is severely compromised
	○ Based on the clinician's skill
• Inflammation, bleeding, healing, and radiation damage can mimic/mask the cancerous changes
	○ Radiation damage may result in \_\_\_\_ damage and not lead to cancer
A

easy
inflammation
healing

quality
sampling
skill/experience

temporary

30
Q

Morphologic Methods Sampling

 Excisional/Incisional biopsy 
-- Histologic analysis
---- \_\_\_\_, Immunohistochemstiry 
-- Frozen section diagnosis
---- \_\_\_\_, less preserved architecture
 \_\_\_\_ aspirate
 \_\_\_\_ smear (papanicolaou)
 Flow Cytometry – \_\_\_\_
A
HE
faster
fine needle
cyologic
leukemia/lymphoma
31
Q

Morphologic Methods Sampling

• Frozen section diagnosis
	○ Faster, you take in the OR, freeze immediately and look under the scope
	○ \_\_\_\_, but important initial diagnosis
		§ Useful in \_\_\_\_, to see if you removed the tumor; check the tissue next to the tumor region
	○ Still have to follow it up with a regular \_\_\_\_ analysis
• \_\_\_\_ tumors - biopsy
• Fine needle aspirate
	○ Tumors that have lost \_\_\_\_, or cavities where the cells may be shedding into
	○ i.e: \_\_\_\_ tumors
• Papanicolaou (cyologic smear)
	○ Cells on the \_\_\_\_ may be brushed away
		§ Place on slide and stain them
		§ Normal epithelial cells have nice structure, but cancerous cancer (right): different size, hyperchromatism, mitotic cells and some inflammatory cells
	○ Pap smear - reduction in the incidence of \_\_\_\_ cancer
	○ Two photos illustrate this process
• Flow cytometry (most \_\_\_\_ - more quantitative assessment!)
	○ Leukemia/lymphoma
	○ Utilizes staining of blood cells
		§ For \_\_\_\_ that recognizes markers that tells us which cell is a lymphocyte, NK cell, monocyte, etc.
		§ Based on \_\_\_\_ protein expression
A
preliminary
surgery
histological
solid
cells
breast
epithelium
cervical
accurate
antibodies
CD
32
Q
Tumor markers
 Biochemical Assays for
biomarkers
--- \_\_\_\_ activity
--- \_\_\_\_ level
--- Other protein in blood
 Useful for screening, prognosis, response to therapy, recurrence
 Prostate specific antigen (PSA)
 Example of successful tumor marker for \_\_\_\_
 Also elevated with \_\_\_\_
 No PSA doesn’t mean no \_\_\_\_. 
 Specificity and sensitivity are \_\_\_\_ 
 Useful for \_\_\_\_ and therapy
• Using antigens are more \_\_\_\_
• Normally protein levels should be below a cutoff value, but if there's an increase that suggest a cancer that is overexpressing that protein
	○ Increased levels of PSA in blood may indicate prostate cancer
	○ No change in PSA doesn't mean no cancer - the testing may not be sensitive enough
	○ Has low specificity and low sensitivity; but good for surveillance and response to therapy
		§ But can follow levels in changes over time in a person who you know has cancer - allows you to get a \_\_\_\_ reading, and after treatment the levels may go down
		§ If increase in levels - shows that there's a recurrence, but there's also carcinoembryonic antigen, where you can follow levels
• Not perfect - not specific to cancer
	○ If benign prostatic hyperplasia - PSA levels may also increase
A
enzyme
hormonal
prostatic adenocarcinoma
BPH
cancer
low
recurrence

quantitative
basal

33
Q
Molecular Diagnosis
 Diagnosis of Malignancy
 Prognosis and behavior
 Detection of \_\_\_\_ disease
 Diagnosis of predisposition to cancer
 Therapeutic decision making
Arsenal of molecular methods
 \_\_\_\_
 Fluorescent In situ
hybridization
 \_\_\_\_ activity 
 Deep sequencing
• PCR
	○ Can \_\_\_\_ any gene of interest and determine if there's a deletion/mutation within the gene
• Fluorescent in situ hybridization (FISH)
	○ Using dyes to stain \_\_\_\_
	○ Can deduce if \_\_\_\_, deletion or presence of \_\_\_\_
		§ Philadelphia chromosome
• Enzyme activity
• Deep sequencing (most \_\_\_\_)
	○ Sequence the entire \_\_\_\_ of a cancer growth - gives us the most comprehensive picture of all the genetic alterations
A
minimal residual
PCR
enzyme
amplify
chromosomes
translocation
double minutes
advanced
DNA
34
Q

Molecular Diagnosis

Diagnosis of Malignancy
 \_\_\_\_ tumors
 PCR distinguishes
--- Polyclonal \_\_\_\_ rearrangements
--- \_\_\_\_ rearrangements
--- \_\_\_\_ translocation, common
 FISH
--- \_\_\_\_ sarcoma, rarer \_\_\_\_

Prognosis and behavior
 Poor Prognosis/treatment  ____ – breast cancer
 ____ - neuroblastoma

• Lymphoid tumors
	○ Philadelphia chromosome - can look for translocation that causes the bcr/abl fusion - will give you the diagnosis
• FISH
	○ Ewing's sarcoma - chromosome defect
• Her2/neu overexpression
	○ If can look via PCR to see if relative expression is higher than normal
	○ If overexpressed, it's associated with \_\_\_\_ outcomes, so you can be more aggressive in treatment
	○ Same principle for N-myc
A
lymphoid
IgG
monoclonal
BCR:ABL
Ewing's
translocations

Her2/neu
N-myc

poor

35
Q
Molecular Diagnosis
Detection of minimal residual disease
 After \_\_\_\_
 Increased Sensitivity of \_\_\_\_ methods
 Detect changes in small number of cells
 \_\_\_\_ for CML
Diagnosis of predisposition to cancer
 \_\_\_\_ – Breast Cancer
 Implement Aggressive Screening protocols
 \_\_\_\_ Surgery
 Genetic counseling 
 Patient and offspring
• After treatment, can use sensitive molecular methods to detect residual disease
	○ May not be obvious in form of mass effect/paraneoplastic syndrome
• BRCA1 mutation - more prone to develop breast cancer
	○ Patient must be \_\_\_\_ to undergo screening at an earlier age using more refined methods
	○ And undergo \_\_\_\_ surgery
A

treatment
PCR
BCR:ABL

BRCA1
prophylactic
counseled
prophylactic

36
Q

Therapeutic Decision Making

 Recognized that some mutations cross diagnostic criteria or even ____ types
 Tailored therapeutics
– B-RAF
—- 60 % of ____
—- % of colon, thyroid, and Hairy cell leukemia, Langerhans cell histiocytosis

 Distinct morphologies
 Different Tissues
 Same oncogene

• B-RAF
	○ Downstream from Ras pathway (activates two arms):
		§ PI3K
		§ RAF
	○ Mutation in B-RAF > can be targeted by a specific \_\_\_\_
		§ Run molecular diagnostics > can give patient a specific drug targeting the molecule
• Maybe should categorize cancers on \_\_\_\_ lesion, not the location
	○ B-RAF mutated, Ras mutated, etc
A

tissue
melanomas
drug
genetic

37
Q
Molecular Profiling
Expression profiling
 Gene chip or micro array
 compare thousands of \_\_\_\_ levels
 Has shown differences in \_\_\_\_ expression in tumors from the same category
• Silica plates where you have your target \_\_\_\_
• Tumor tissue > isolate \_\_\_\_; control tissue > isolate RNA
• Convert to \_\_\_\_, and tag with fluorescent molecules and mix
	○ Normal tissue: green, tumor: \_\_\_\_
• Lay on silica plate, and the DNA should bind to targets that are genes (each dot)
• If there is a gene that is present in mixture against gene that you're look at > bind
	○ If expression of gene is same in tumor and normal > \_\_\_\_
	○ If more of gene (oncogene) in the tumor > \_\_\_\_
	○ If less in tumor tissue > \_\_\_\_
• Can use a \_\_\_\_ piece of tumor tissue and look for relative expression of genes of interest
	○ 5-10,000 genes at same time
• Shows differences in RNA levels of tumors
	○ Looking at oncogenes and TSG's
A
mRNA
mRNA
gene/probe
RNA
DNA
red
yellow
red
green
small
38
Q

Molecular Profiling - Next generation sequencing

 a.k.a. Deep Sequencing
 Decreased \_\_\_\_ and cost
 Revealed
--- Childhood tumors -\_\_\_\_
changes,
--- Adult tumors 100s – \_\_\_\_
 Reveal all mutations in a tumor
- Driver mutations
-- \_\_\_\_ mutations
-- Lead to \_\_\_\_ of cancer
- \_\_\_\_ mutations
 Refocus therapy from tissue of origin to \_\_\_\_ lesion
• Deep sequencing (more comprehensive view)
	○ Not limited by number of genes you can look at on plates; can look at the entire genome
	○ More \_\_\_\_ - sequences the genome repetitively
• Childhood tumors require few changes in order for the tumor to arise, adults require more
• Driver mutations
	○ Recurrent mutations occur across different patients that lead to hallmarks of cancer
		§ \_\_\_\_, p53
• Passenger mutations
	○ More random, not that \_\_\_\_
A
time
few
1000s
recurrent
hallmarks
passenger
molecular

accurate
Ras
critical

39
Q

• Need to target many ____ of cancer in order to be successful
• Require an ____ approach
○ Personalized therapy has become the forefront of cancer

• Signature mutation - a specific mutation that is caused by a specific \_\_\_\_ agent that helps you link the \_\_\_\_ agent to the cancer
A

aspects
individualized
chemical
causative