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124 Cards in this Set

  • Front
  • Back
Estimated new cases of invasive cancer expected in the US in 2007
~1.4 million
Most commonly diagnosed cancer cases in the US
Lung (213,380 cases)
Breast (180,510 cases)
Prostate (218,890 cases)
Lymphoma (771,380 cases)
most of the genetic cases associated with cancer occur within what types of cells?
various non-germline (SOMATIC) cells
what are dominant oncogenes?
mutant gene that produces a protein that is inappropriately active, at the wrong time or at the wrong place.
what are recessive oncogenes?
aka Tumor suppressor genes:

can lead to cancer when their function is totally lost
what type of genes are generally involved in inherited cancer predisposition syndromes?
Tumor Suppressor genes
what is cyclin D?
important signal regulating the cell-cycle at the restriction point

complexes with Cdk to phosphorylate pRB (releasing E2F) and thereby DRIVING CELL CYCLE
how does the SV40 virus contribute to tumorgenesis?
produces T Ag, which binds to hypophosphorylated form of pRB (interfering with its sequestration of E2F), thereby inhibiting usual cell cycle- inhibition
p21 is induced by what gene?
p53 (p21 inhibits CDK4)
MDM2 counteracts action of what gene?
what happens if p19 were mutated?
MDM2 activity would go unchecked
leading to augmented expression of p53 function,
therefore less p21, resulting in a stimulus for cell proliferation
p19 and p16 are both
important cell cycle regulators
derived from the same genetic locus by a mechanism of alternative transcription and RNA splicing
analysis of cell proliferation, by exposing cells to radioactive thymidine does what?
radioactive thymidine is incorporated into DNA, thereby labeling cells in S phase

yields an estimate of the labeling index and cell doubling time
assessment of percentage of tumor cells in what phase is clinically relevant as an indicator of prognosis?
S phase

typically assessed by flow cytometry
non-small cell lung cancer cells with a doubling time of 8-10 days, probably have a tumor doubling time closer to what?
2-3 months
explain 2 explanations for disparity between cancer cell doubling time and actual in vivo tumor growth rates
1) Cell lose (by death, exfoliation or differentiation into nonliving cells)
2) not all neoplastic cells within a tumor are proliferating (many are in the Go quiescent phase of the cell cycle)
most-frequently diagnosed cancer in 2007
for men:
for women:
#1 prostate and breast
#2 lung and bronchus
#3 colon/rectum
#4 bladder (men) uterus (women)
cancer with highest mortality in 2007
for men:
for women:
#1 Lung and Bronchus
#2 Prostate (men) Breast (women)
#3 Colon/rectum (both)
#4 Pancreas (both)
v-cis is what type of gene?
oncogene (growth factor)

elaborates PDGF ligand
oncogenic changes that impact RTK pathways
1) too much GF (v-sis retroviral oncogene turns PDGF into oncogene)
2) overexpression of receptor (HER2, by amplification, can be engaged involved in growth stimulus)
3) receptor mutated, (cleaved receptor contituitively active (epidermal GFR))
4) contituitively active downstream player
TGF-beta is a ubiquitous what?
growth inhibitor, results in a decrease in the phosphorylation state of the retinoblastoma protein via regulation of cdk inhibitors
telomerase, prevalent in what type of cancer?
colorectal cancer

temolerase activity elevated in tumor cells (prevents normal degradation of telomeric sequence = a signal for cell senescence/death)
what is the Gompertzian model?
model of tumor growth
-exponential increase early, slowing over time (as growth fraction decreases and cell loss increases)
3 steps of metastatic process
1) Invasion, angiogenesis/enzymatic degradation of BM and ECM
2) Arrest and Extravasation
3) Evasion of host defenses
simultaneous inactivation by oncogenic viruses, is often seen in tumorgenesis?
esp. skin cancers
p53 and Rb
cancers that often result in mets to bone
BREAST, prostate, melanoma, lung
cancers that often result in mets to liver
Colon, melaonma, breast, lung
cancers most frequently leading to mets in brain
melanoma, lung, breast
cancers frequetly leading to mets in llung
melanoma, breast, lung/colon/prostate
TNP-470, an analogue of fumagillin is currently being tested for what potential therapeutic use?
inhibition of angiogenesis, potential to arrest primary tumor growth (noting that removal of primary tumor, may lead to upsurge in overall growth of metastatic deposits)
what causes more deaths in the US?
cancer or heart diseases?
#1 Heart Diseases
#2 Neoplasms
cancer accounts for what fraction of deaths in the US?
almost 1/4
leading types of cancer causing mortality in children
leukemia and nervous system (brain) cancers
leading types of cancer causing mortality in young adults
(breast cancer has a substantial early mortality)
predominate deaths due to cancer in older population
lung/bronchus, prostate, breast and colorectum
incidence and mortality rates for some factors vary by a factor of 20+ in high vs. low-risk countries

but when all cancers are considered together variation in total cancer incidence or mortality variation is...
3-fold at most
most important cancer risk factor in the united states
tobacco probably accounts for about what % of cancer mortality
Alcohol probably accounts for what % of cancer mortality
radiation probably accounts for what % of cancer mortality
Cancer sites with direct association to tobacco use
Larynx, lung/bronchus
oropharynx, esophagus, pancreas
stomach, myelocytic leukemia
Cancer sites with direct association to alcohol use
oropharynx, larynx, esophagus
Cancer sites with direct association to ionizing radiation
leukemia, thyroid, female breast (pre age 40 exposure)
lung, stomach, colon, esophagus, bladder, ovary, myeloma
cancer sites with direct association with UV radiation
melanoma, non-melanoma skin
Cancer sites with direct association with infections
Liver (Hep B)
cervix (HPV)
Hodgkin's disease (EBV)
Burkitt's lymphoma (EBV)
bladder (schistosomiasis)
nasopharyngeal (EBV)
stomach (H. pylori)
drug that may be protective against cancers (esp. GI)
autonomous cell proliferation
malignancy of epithelial cell origin
malignancy of mesenchymal cell origin
histologic criteria of malignancy
characteristics of Malignant Neoplasms
rapid growth
locally invasive
irregular growth, no capsule
capable of metastasis
variable histological differentiation
glandular cell

benign neoplasm:
malignant neoplasm:

squamous cell
benign neoplasm:
malignant neoplasm:

squamous cell carcinoma
transitional cell
benign neoplasm:
malignant neoplasm:
transitional cell carcinoma
fibrous tissue
benign neoplasm:
malignant neoplasm:

benign neoplasm:
malignant neoplasm:

skeletal muscle
benign neoplasm:
malignant neoplasm:

adipose tissue

benign neoplasm:
malignant neoplasm:

benign neoplasm:
malignant neoplasm:


benign neoplasm:
malignant neoplasm:

totipotential or multipotential tumors:
germ cell tumors, leukemias, lymphomas
increase in cell # (prostate, endometrim, breast)
replacement of one normal cell type with another normal cell type (squamous metaplasia, glandular epi in lung, cervix)
non neoplastic, disorganized proliferation (potentially reversible of cells within epi

disorganized growth with cellular pleomorphism, abnormal mitoses and nuclear hyperchromasia

degrees of dysplasia: mild, moderate and severe
intraepithelial neoplasia
dysplasia (all degress) involving specific sites (cervix CIN, vulva VIN, vagina VAIN, prostate PIN and pancreas PanIN)
non-reversible dysplastic change, involving the entire epithelial thickness

no invasion into the underlying tissue, therefore no risk of metastasis
Carcinoma in situ
poorly differentiated cells characteristic of malignant neoplasms
a malignant neoplasm of epithelial cell origin
malignant neoplasm of mesenchymal cell origin
non-neoplastic lesion

benign tissue in the correct place
non-neoplastic lesion

benign tissue in the wrong place
malignant testicular tumor
malignant tumor derived from plasma cells
indicates degree of differentiation of the tumor (cytology and architecture)
grade I tumors are generally...
well differentiated "low grade," grow more slowly
high grade tumors are characterized by...
poor differentiation

generally rapidly growing, poor prognoses
cancer "STAGE" is based on
clinical assesment, based on pathological findings (size and spread)
TMN staging
Tumor SIZE
Tumor Antigens, useful in Dx of neoplasms:
hepatocellular carcinoma
PSA (prostate)

Alpha-fetoprotein (hepatocellular carcinoma)

Beta-HCG (choriocarcinoma)
specimin types, used in gross examination of neoplastic tissue
Exfoliative and brush cytology
fine needle aspiration
specimin type used to examine cervical spears and body fluids
exfoliative and brush cytology
technique frequently used to provide specimins for gross examination of suspected neoplasms in breast, thyroid, lymph nodes, pancreas and kidney
fine needle aspiration
biopsies are frequently used to Dx what types of neoplasms?
resection is often used to examine suspected neoplasms in
stomach and thyroid
gross characteristics useful in examination of suspected neoplastic specimens
histologic feature diagnostic of neuroendocrine tumors
neurosecretory granules
histologic feature diagnostic of melanoma
histologic feature diagnostic of epithelial tumors
technique whereby, use Abs or substrate detection to id cell products and surface markers
immunohistochemistry is particularly useful in:
categorization of undifferentiated tumors and lymphomas/leukemias

determination of origin of metastatic tumors

detection of prognostic/therapeutic markers
may present as:
apple core tumor
cauliflower tumor
colonic adenocarcinoma
malignant neoplasm of smooth muscle
malignant neoplasm of bone
osteogenic sarcoma
metastatic carcinoma in liver is most likely what primary origin
metastatic carcinoma in lung is most likely from what primary origin
grade of neoplasm is provided by
(degree of differentiation)
technique used to detect cell surface antigens and DNA content of tumor cells
flow cytometry
-clonality and lymphoma/leukemia typing
-placental molar lesions (tri/diploidy)
-nuclear DNA ploidy and cell cycle proliferation indices and tumor prognostic markers
Molecular Diagnostic techniques useful in refining histological diagnoses
PCR, W. Blotting
Hematopathology is useful in:
1) Dx: gene rearrangements in lymphoma
2) minimal residual disease
3) therapeutics (responder, vs. non-responder, mutation)
Molecular Diagnostics are useful in infectious diseases related to neoplasms
1) difficult to culture organisms, strain typing
2) quantitative analysis, genotyping
3) resistance testing
4) rapid TAT
fundamental changes in cell physiology, to become malignant
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Evasion of apoptosis
4) Defects in DNA repair
5) limitless replicative potential
4) sustained ANGIOGENESIS
5) ability to INVADE and METASTASIZE
3 well-establisehd models for the morphologic evolution of carcinoma in the brest
1) normal, non-prolif epi --> proliferative disease -->
atypical hyperplasia (evasion of apoptosis, loss of growth inhibition, genome instability in form of LOH)
2) atypical hyperplasia progressing to carcinoma in situ)
3) carcinoma in situ --> invasive carcinoma
cDNA fragments or oligonucleiotides are spotted on slide/support (gene chip hybridized to probes of tumor and control samples)
cDNA synthesis from tumor tissue labeled red
red spot= expression of gene is higher in tumor
green = expression higher in normal tissue
black or yellow = no difference in gene expression bt normal and tumor specimen
used to obtain expression profiles of proteins contained in tissues, serum or other body fluids

ICAT (isotope-coding affinity tags) labels proteins with light vs. heavy isotopes, can be IDs by mass spec
potential promise of gene and protein expression analysis
1) predict metastatic potential
2) predict prognosis
3) predict response to Tx
4) reveal gene expression patterns dpdt on the mutation of a single oncogene
5) analyze effects of hormones and enviro agents on cancer dvpt
LiFraumeni Snydrome shows what type of inheritance pattern?
autosomal dominant

(caused by TP53 gene)
90% penetrance by age 70
50% penetrance by age 30
??% mutations are sporadic
??% mutations are germine
60% sporadic
40% germline
gene involved in Familial retinoblastoma
autosomal dominant
90% penetrance
de novo mutations are common in what disease?
Familial adenomatous polyposis (FAP) ~30% of cases

Multiple endocrine neoplasia 2B ~50% of cases

Hereditary retinoblastoma ~50% of cases
(i.e. no family history, but germline mutation)
Autosomal recessive inheritance cancer syndromes are much less common, some examples
Ataxia telangietasia (Lmyphoma)
Bloom syndrome (solid tumors)
Xeroderma pigmentosa (skin)
Fanconi anemia (AML)
APC gene is associated with what Cancer syndrome
Familial adenomatous polyposis
MLH1 and MSH2, MSH6, PMS1, PMS2 are associated with what cancer snydrome
BRCA1 and BRCA2 are associated with what inherited cancer syndromes
Breast (both)
Ovarian (BRCA1 moreso)
Breakdown of CRC (colorectal) causes
65% sporadic
10-30% familial
FAP 1%
rare CRC syndromes <0.1%
caused by mutations in APC tumor suppressor gene on chromosome 5q

up to 30% of patients have a de novo germline mutation

most families have unique mutations

most mutations are protein truncating mutations

genotype/phenotype relationships emerging
FAP (familial adenomatous polyposis)
no clear pattern of inheritance

onset at same age as sporadic CRC

multiple causes persumed

few or no adenomas
Familial CRC
also known as Lynch syndrome
HNPCC (aka cancer family syndrome)
early and variable age of onset
tumors in PROXOIMAL colon
Amsterdam criteria
clinical diagnostic creteria of HNPCC
3 -- 3 family members, one of which is a FDR of the other two (lynch pin).
2 -- spanning 2 generations.
1 -- 1 person diagnosed by the age of 50.
0 -- Familial Adenomatous Polyposis ruled out.
Knudsen's Hypothesis
2 Hit hypothesis
According to the ‘two-hit’ model, an individual with an inherited predisposition to cancer (the sister on the left) receives one mutated version of an important tumor suppressor gene (in this case, from her father) and one normal copy of the gene. Because of this, every cell in her body has ‘taken the first hit’ and has only one remaining functional copy of the gene. Later, as an adult, a subsequent mutation in that normal copy within a susceptible cell type (such as a cell from a duct in her breast) sets in motion the development of cancer.
predominant technique used to allelotype genome
microsatellite repeats (repetitive non-protein coding, non-regulating sequences)

used to hunt for Tumor suppressor genes, detect loss of heterozygosity
what might LOH from a tumor cell gene indicate
a mutation of a tumor suppressor gene!
microsatellite instability found when LOH was expected
results in new alleles, that may also contribute to cancer
multi-step process involved in genetic testing for cancer susceptibility
1) ID at-risk individual
2) provide counseling
3) provide informed consent
4) disclose results
5) provide post-test counseling and provide medical follow-up