Chapter 7: Neoplasia Flashcards
1
Q
What kind of tumor is derived from glands and applied to benign epithelial neoplasms?
A
Adenoma
2
Q
What benign epithelial neoplasm has visible finger like or warty projections?
A
Papilloma
3
Q
A polyp with glandular tissue is called what?
A
Adenomatous polyp
4
Q
Malignant tumors arising from solid mesenchymal tissues are called what?
A
Sarcoma
5
Q
Malignant neoplasms of epithelial cell origin, derived from any of the 3 germ layers, are called what?
A
Carcinomas
6
Q
What is the most common mixed tumor?
Capable of producing what and is designated?
A
- Salivary gland mixed tumor
- Epithelial and myoepithelial cells = pleomorphic adenoma
7
Q
What is the term applied to a heterotopic rest of cells?
i.e., a small nodule of well-developed and normally organized pancreatic tissue found in the submucosa of the stomach, duodenum, or SI.
A
Choristoma
8
Q
Lack of differentiation, or anaplasia, is considered a hallmark of?
A
Malignancy
9
Q
What refers to variation of size and shape of cancer cells?
A
Pleomorphism
10
Q
What best describes carcinoma in situ?
A
- Dysplastic changes are marked and involve the full thickness of the epithelium
- Lesions DO NOT penetrate the BM
11
Q
What malignant cancers invade early but rarely metastasize?
A
- Gliomas
- Basal cell carcinoma of the skin
12
Q
Once tumor cells breach the basement membrane they are said to be?
A
Invasive
13
Q
How is dysplasia related to malignant transformation?
Is all metastatic epithelium dysplastic?
A
- May be a precursor to malignant transformation
- Does NOT always progress to cancer
- Not all metastatic epithelium is dysplastic
14
Q
What are the 3 pathways of spread of cancer?
A
1) Direct seeding of body cavities or surfaces
2) Lymphatic spread
3) Hematogenous spread
15
Q
In direct seeding of body cavities, sometimes appendiceal carcinomas or ovarian carcinomas fill the peritoneal cavity with what?
A
Pseudomyxoma peritonei
16
Q
What is the most common pathway for the initial dissemination of carcinomas?
A
Lymphatic spread
17
Q
Where do carcinomas of the breast in the upper outer quadrant disseminate 1st to?
Inner quadrants?
A
- Axillary LNs
- LNs along internal mammary arteries
18
Q
Where do carcinomas of the lung in the major respiratory passages metastasize first to?
A
Perihilar tracheobronchial and mediastinal nodes
19
Q
Renal cell carcinoma invades what structure?
A
Renal vein —> IVC —-> right side of the heart (sometimes)
20
Q
Hepatocellular carcinoma often penetrates what?
A
Portal and hepatic radicles
21
Q
Breast carcinoma preferentially spreads to where?
A
Bone
22
Q
Bronchogenic carcinoma preferentially spreads to where?
A
Adrenals and brain
23
Q
Neuroblastoma preferentially spreads to where?
A
Liver and bones
24
Q
To avoid the considerable surgical morbidity associated with full LN dissection, which technique is often used to assess the presence of metastatic lesions in the LNs?
A
- Biopsy of sentinel nodes
*The first node in a regional lymphatic basin that receives lymph flow from the primary tumor
25
Which organs are most frequently involved in hematogenous dissemination of cancer?
Liver and lungs
26
Describe the following for **benign cancers:**
* Differentiation
* Rate of growth
* Local invasion
* Metastasis
- **Well differentiated**; structure sometimes **typical** of tissue of origin
- **Progressive** and **slow** growth
- Cohesive, expansile, **well-demarcated** masses that do not invade
- **Absent** metastasis
27
Describe the following for **malignant cancers:**
* Differentiation
* Rate of growth
* Local invasion
* Metastasis
- **Lack differentiation (anaplasia)**; structure often **atypical**
- **Erratic**, slow or rapid growth
- **Locally** invasive
- **Frequent** metastasis
28
Cancers arising in close proximity to the vertebral column often embolize through where?
This pathway is involved in the frequent vertebral metastases of carcinomas of?
- Paravertebral plexus
- Thyroid and prostate
29
What are the most common tumors in Men?
Woman?
**Men** = prostate, lung, and colon
**Woman** = breast, lung and colon
30
What is responsible for a large majority of cervical carcinoma and increasing fraction of head and neck cancers?
HPV
31
What cancer is associated with benzene (i.e., light oil, paint, printing, dry cleaning, adhsives. etc.)?
Acute myeloid leukemia
32
What cancer is associated with beryllium (i.e., missle fuel, space vehicles)?
Lung carcinoma
33
What cancer is associated with cadmium (i.e., yellow pigments and phosphors; used in batteries, etc.)?
Prostate carcinoma
34
What cancer is associated with vinyl chloride (i.e., refrigerant, vinyl polymers, plastic adhesives, etc.)?
Hepatic angiosarcoma
35
What cancer is associated with chromium (i.e., metal alloys, paints, pigments, and preservatives)?
Lung carcinoma
36
What cancers are associated with nickel?
Lung and oropharyngeal carcinoma
37
What cancers are associated with Arsenic?
Lung carcinoma
Skin carcinoma
38
What is the etiologic agent of osteomyelitis?
What neoplasm?
- Bacterial infection
- Carcinoma in draining sinuses
39
What is the etiologic agent of Chronic Cystitis?
What neoplasm?
- Schistosomiasis
- Bladder carcinoma
40
What is the associated neoplasm of Sjorgen syndrome and Hashimoto thyroiditis?
MALT lymphoma
41
What is the classic example of a benign, neoplastic, precursor lesion?
Colonic *villous adenoma*
42
What are 2 examples of epigenetic modifications that contribute to the malignant properties of cancer cells?
1) **DNA methylation:** silencing of tumor suppressor genes
2) **Histone modification**
43
What are the 4 classes of *regulatory* genes that are principal targets of cancer-causing mutations?
1) Growth-promotong **proto-oncogenes**
2) Growth-inhibiting **tumor suppressor genes**
3) Genes that regulate apoptosis
4) DNA-repair genes
44
What are the **8** fundamental changes in cell physiology, which are considered the *hallmarks of cancer*?
1) **Self-sufficiency** in growth signals
2) **Insensitivity** to growth-inhibitory signals
3) **Altered** cellular metabolism
4) **Evasion** of apoptosis
5) **Limitless** replicative potential (immortality?)
6) **Sustained** angiogenesis
7) **Ability** to **invade** and **metastasize**
8) **Ability** to **evade** host immune response
45
Define Oncoprotein
A protein encoded by an oncogene that drives increased cell proliferation through one of several mechanisms
46
What is MYC known as and what are its important functions?
- The **master transcription factor** that **regulates genes** needed for **rapid cell growth** by deregulation through **chromosomal translocations**
47
90% of what type of cancer contains RAS mutations?
Pancreatic adenocarcinomas
48
What is the major function of CDK4; D cyclins?
Form a complex that **phosphorylates RB**, allowing the cell to progress through the **G1 restriction point**
49
What is the major function of the cell cycle component, RB?
- Tumor suppressive "pocket" protein that binds **E2F** transcription factors in its **hypophosophorylated** state, **prevents** G1/S transition
- Interacts with several transcription factors that **regulate differentiation**
50
What induces the cell cycle inhibitor p21?
**p21** is induced by **tumor suppressor p53**
51
What responds to growth suppressors such as TGF-B?
p27
52
What chromosome is p53 located on?
Acts mainly through what?
What negatively regulates p53?
- Chromosome **17**
- Acts mainly through **p21**
- Negatively regulated by **MDM2**
53
What inhibits MDM2 activity?
What does this do?
- p14
- Increases p53 activity
54
What specifically binds to cyclinD-CDK4, blocking CDK4/cyclin D-mediated phosphorylation of RB; thereby reinforcing the RB checkpoint?
p16
55
What occurs in the familial form of retinoblastoma?
Inherited how?
- All somatic cells inherit one mutated copy of RB gene from a carrier parent (**first hit**)
- Only one additional RB mutation in a retinal cell is required for complete loss of RB function (**second hit**)
- Autosomal dominant
56
What occurs in sporadic cases of Retinoblastoma?
- Both normal RB alleles must undergo somatic mutation in the same retinoblast (**two hits**)
- Probability of this event is low (explaining why this tumor is uncommon in th general population)
57
What is the "two-hit" hypothesis of oncogenesis as it relates to retinoblastoma?
Which chromosome involved?
- **Two mutations (hits)** involving **both alleles of RB** at **chromosome locus 13q14** are required to produce retinoblastoma
- In familial cases, children inherit one defective copy of the RB gene in the germline (**first hit**), and the other copy is normal. Retinoblastoma develops when the normal RB allele is mutated in retinoblasts as a result of spontaneous somatic mutation (**second hit**)
58
What are the key initiators of p53 activity following DNA damage or cellular exposure to hypoxia?
How do they act; what is p53 released from?
- ATM/ATR family
- These **kinases** phosphorylate p53, liberating it from inhibitors such as **MDM2**
59
What affect does the **active** hypophosphorylated RB in complex with E2F transcription factors have?
- Binds DNA, recruits chromatin-remodeling factors (histone deacetylases and histone methyltransferases)
- **Inhibits transcription** of genes who products are **required** for the **S phase** of the **cell cycle**
60
What phosphorylates RB (**inactivating it**)?
What occurs when RB is phosphorylated?
- Phosphorylated by **cyclin D-CDK4** and **CDK6**; also **cyclin E-CDK2**
- Causes RB to **release** E2F
- E2F is then able to **activate** transcription of **S-phase genes**
61
Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; what are these genes?
- ***RB*** (loss of function mutations)
- ***CDK4*** (gene amplifications)
* -* **Genes encoding cyclin D** proteins (gene amplifications)
- ***CDKN2A* (p16):** loss of cyclin-dependent kinase inhibitors
62
Which GFs activate Cyclins D/CDK4,6 and Cyclin E/CDK2 leading to hyperphosphorylated RB (inactive)?
EGF and PDGF
63
Explain the interaction between the E7 protein of HPV and RB, where does it bind?
Which form of HPV is higher risk and why?
- Binds to **hypo**phosphorylated form of **RB** in the same pocket which normally sequesters E2F transcription factors
- **HPV16** confers a **high risk** for development of **cervical carcinoma** and expresses E7 protein variants with **higher affinity** for RB than do lower risk viral types
- RB protein is unable to bind E2F transcription factors and is functionally inactivated by these viral oncoproteins, and the E2F factors are free to cause cell cycle progression
64
Normal GF signaling leads to RB _______ and \_\_\_\_\_\_\_\_\_\_, thus promoting cell cycle progression
Normal GF signaling leads to RB **hyperphosphorylation** and **inactivation**, thus promoting cell cycle progression
65
Tumors with wild type or mutated TP53 alleles are more susceptible to chemotherapy?
What kind of cancers?
- Wildtype
- Testicular Teratocarcinomas and Childhood Acute Lymphoblastic Leukemia
66
Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in which phase?
Causes induction of DNA repair by transcriptional upregulation of what?
- Arrest in **G1**
- Upregulation of **cyclin-dependent kinase inhibitor, *CDKN1A*** (encoding **p21**): inhibitor of CDK4/D cyclin
- Upregulation of ***GADD45 genes*** (DNA repair)
67
If DNA repair fails, what does p53 trigger?
- Apoptosis (through BAX and PUMA)
- Senescence
68
Mutated TP53 alleles are mostly resistant to chemotherapy and irradiation and include what cancers?
Lung and colorectal cancers
69
What do cells with defective p53 acquire and what does this result in?
- Mutator phenotype
- Tendency to acquire additional mutations at a higher rate
70
Rare patients with Li-Fraumeni syndrome inherit how many defective copies of *TP53?*
Inherit **one defective copy** of *TP53* and have a **very high** incidence of a wide variety of cancers
71
The majority of human cancers demonstrate ________ mutations in *TP53*
The majority of human cancers demonstrate **biallelic loss-of-function** mutations in *TP53*
72
Like RB, p53 can also be inactivated by?
Viral oncoproteins, such as the E6 protein of HPV
73
What is the "gatekeeper of colonic neoplasia?"
Functions by?
- Adenomatous polyposis coli (APC)
- Downregulates growth-promoting signaling pathways
74
Germline loss-of-function mutations involving *APC* (5q21) locus are associated with what disorder?
Inheritance pattern?
- Familial Adenomatous Polyposis = Autosomal Dominant
- Individuals born w/ one mutant allele develop thousands of adenomatous polyps in the colon during their teens or 20s
75
What is the role of APC in regulating the stability and function of β-catenin in both resting and WNT activated colonic epithelial cells?
Forms what?
What does β-catenin do?
- In **resting** colonic epithelial cells (**not exposed to WNT**), β-catenin forms **macromolecular complex** containing the APC protein. This complex leads to **destruction** of β-catenin, and intracellular levles are low
- When **stimulated by WNT**, the ***destruction complex*** is **deactivated**, β-catenin degradation does not occur, and cytoplasmic levels increase
- **β-catenin** translocates to the nucleus, where it **binds to TCF**, a TF that **activates genes** involved in **cell cycle progression** and **proliferation**
76
Germline loss-of-function mutations of the von Hippel-Lindau (VHL) gene on chromosome 3p are associated with what?
- Hereditary renal cell cancers
- Pheochromocytomas
- Hemangioblastomas of the CNS
- Retinal angiomas
- Renal cysts
77
When APC is mutated or absent, as frequently occurs in colonic polyps and cancers, what happens to β-catenin?
How do they cells behave?
- The destruction of β-catenin **cannot** occur.
- β-catenin translocates to nucleus and coactivates genes that promote entry into the cell cycle and cells behave as if they are under **constant** stimulation by the **WNT** pathway
78
VHL encodes what, which is reponsible for?
How does this function in oxygen rich and hypoxic enviornments?
- Encodes a component of a **ubiquitin ligase** that is responsible for the **degradation** of **hypoxia-induced factors (HIFs)**
- In **presence of oxygen**, HIF1α is **hydroxylated** and binds to VHL, leading to its ubiquitination and degradation
- In **hypoxia** the hydroxylation rxn does **NOT** occur and HIF1α escapes recognition by VHL and accumulates in nuclei of hypoxic cells turning on genes encoding **VEGF, PDGF, and GLUT1**
79
In *chronic myelogenous leukemia (CML)* and some *acute lymphoblastic leukemias (ALL)*, which translocation occurs?
What does this fusion create?
- **ABL** gene is translocated from **chromosome 9 to chromosome 22** where it **fuses** with the **BCR** gene
- Encodes a constituitively active, **oncogenic *BCR-ABL tyrosine kinase***
80
Which portion of the *BCR-ABL* fusion has the tyrosine kinase activity?
What is the function of the other gene?
- ***ABL*** has **tyrosine kinase** activity
- ***BCR*** drives self association of *BCR-ABL* and unleashes activity of *ABL*
81
What 6 ways are tumor cells able to evade cell death by apoptosis?
1) **Loss of p53** --\> **r****educed**function of pro-apoptotic factors such as**BAX**
2) **Reduced** egress of **cytochrome c** as a result of **upregulation** of **anti-apoptotic** factors such as **BCL2, BCL-XL, and MCL-1**
3) **Loss** of apoptotic peptidase activating factor 1 **(APAF1)**
4) **Upregulation** of inhibitors of apoptosis (**IAP**)
5) Reduced **CD95** level
6) **Inactivation** of death-induced signaling complex **FADD**, needed for Fas-FasL
82
Which pathway of apoptosis is most commonly affected in cancer cells?
Intrinsic (mitochondrial)
83
In \>85% of follicular B-cell lymphomas, what gene is overexpressed?
Due to what translocation?
- Anti-apoptotic gene *BCL2*
- (14;18) translocation
84
What are the most common general category of tumor in adults?
Children?
**Adults =** Carcinomas
**Children** = Acute Leukemia and distinctive neoplasms of CNS
85
What is an abundant collagenous stroma called?
How can this also be described?
- Desmoplasia
- Scirrhous
86
What chromosome is the RB gene located?
How is it inherited?
- Chromosome 13
- Autosomal dominant
87
What cancer is specific to a mutation in BRCA2?
Chronic lymphocytic leukemia
88
What is the function of GADD45?
What induces it?
- DNA repair
- p53
89
What does CDKN2A activate?
p16 and p14
90
What is a novel gene expression assay that is being used to predict prognosis and treatment response in cancer patients?
- Expression of CEN/KT (centromere and kinetochore) genes
- Centromere and kinetochore gene expression score (CES) signature
91
How does the Warburg effect work (3 signaling mechanisms)?
1) PI3K/AKT signaling
2) RTK activity
3) MYC
92
What opposes the actions of the Warburg effect via blockage of PI3K/AKT signaling?
PTEN
93
Mutation of PTEN results in what?
Located on what chromosome?
- Cowden syndrome
- Chromosome 10
94
Hypoxia triggers angiogenesis through the actions of?
**HIF1α** on the transcription of the **proangiogenic** factor **VEGF**
95
How does p53 regulate angiogenesis?
RAS, MYC, and MAPK?
- **p53** Induces synthesis of the angiogenesis **inhibitor thrombospondin-1**
- **RAS, MYC, MAPK** all upregulate **VEGF expression** and **stimulate** angiogenesis
96
Invasion of the ECM, a hallmark of malignancy, occurs in what 4 steps?
1) Loosening of cell-cell contacts
2) Degradation of ECM
3) Attachment to novel ECM components
4) Migration and invasion of tumor cells
97
Via which enzymes and factors are tumor cells able to degrade the basement membrane and interstitial CT during the second step of invasion?
- Tumor cells may secrete proteolytic enzymes themselves
- May induce stromal cells (i.e., **fibroblasts and inflammatory cells**) to elaborate proteases, such as **MMP, Cathepsin D,** and **U****rokinase plasminogen activator**
98
What is loss of adhesion to the BM called?
Triggers what?
- Anoikis
- Apoptosis
99
Solid tumors and normal T lymphocytes is use what to spread to LNs and other metastatic sites?
- Binding of **CD44** to **hyaluronate** on **high endothelial venules**
- Solid tumors express CD44, which appears to enhance their spread to LNs and other metastatic sites
100
What mechanisms may account for the organ tropism exhibited by tumor cells and why metastasis sometimes occurs in locations unrelated to the initial site of the tumor?
- Tumor cells may have **adhesion molecules** whose ligands are expressed preferentially on the endothelial cells of the target organ
- Chemokines may play an important role. Some breast cancer cells express the chemokine receptors **CXCR4 and CCR7**
- In some cases, the target tissue may be a nonpermissive enviornment - **"unfavorable soil"**
101
The prolonged survival of micrometastases without progression (dormancy) like in breast cancer metastases to bone is accomplished how?
- Breast cancer cells secrete **PTHRP**, which stimulates osteoblasts to make **RANKL**
- RANKL activates osteoclasts, which degrade the bone matrix and release GFs embedded within, like **IGF** and **TGF-B**
- GFs help make the metastatic site habitable for the cancer cells.
102
What protein is often found overexpressed in drug-resistant cancers?
MCL-1
103
What areas of the body rarely have metastasis?
Why?
- Spleen and Skeletal muscle
- Represent "unfavorable soil"
104
What are the main pro angiogenic factors?
GOF mutations in what may upregulate them?
- VEGF, bFGF
- GOF mutations in *RAS* or *MYC*
105
What are the oncofetal antigens whose expression at high levels serve as markers that aid in tumor diagnosis and clinical management?
- CEA (carcinoembryonic antigen)
- AFP (α-fetoprotein)
106
The first step in invasion of the ECM by tumor cels involves loss of?
E-cadherin function
107
Where do most metastasis occur?
What organs?
- First capillary bed available
- Lung and liver
108
Which oncogene products and tumor suppressor gene products may enter MHC class I and class II for detection by the immune system?
**Mutated** RAS, p53, and BCR-ABL
109
Which overexpressed and aberrantly expressed cellular proteins may lead to detection of tumor cells by the immune system?
**Overexpressed:** tyrosinase, gp100, MART in melanomas
**Aberrantly** **expressed:** cancer-testis Ags (**MAGE, BAGE**)
110
Which T lymphocytes have a clear protective role against virus-associated neoplasms and increased number of these cells correlates with a better prognosis in a variety of cancers?
CD8+ CTLs
111
Which immune cells may collaborate in anti-tumor reactivity?
T cells, NK cells, and Macrophages
112
Which cytokines activate NK cells and what is their effect on tumor cells?
- IL-2 and IL-15
- NK cells can lyse a wide range of human tumors, including many that seem to be nonimmunogenic for T cells
113
What mode of inheritance is hereditary nonpolyposis colon cancer (HNPCC)?
Defect in what?
Genome shows what?
- Autosomal dominant
- Mismatch repair system
**- Microsatellite instability (hallmark)** = changes in length of short repeats throughout the genome
114
Antibodies against which transmembrane protein expressed on the surface of all normal B-cells have been used in the treatment of B-cell lymphomas and leukemias?
What are these antigens called?
- CD20
- Differentiation antigens
115
Which mutations leading to genomic instability are important causes of lymphoid neoplasms?
Mutations in **lymphoid cells** due to expression of gene products that induce genomic instability (**RAG1, RAG2, AID**)
116
What leads to anemia in patients with advanced cancers?
Inflammation-induced sequestration of **iron** and downregulation of **EPO** production
117
What has been shown to decrease the incidence of colonic adenomas and are now approved for **tx of patients with familial adenomatous polyposis**?
COX2 inhibitors
118
What mucins are expressed on ovarian carcinomas?
CA-125
CA19-9
119
Which gene responsible for nucleosome positioning/chromatin remodeling is mutated in 100% of Malignant rhabdoid tumors?
*SNF5*
120
Which genes responsible for histone methylation are seen in 90% of Acute leukemia in infants and Follicular Lymphomas?
* MLL1 **=*** Acute leukemia in infants
* MLL2* = Follicular lymphoma
121
In the molecular model for the evolution of colorectal cancers through the adenoma-carcinoma sequence what are the steps?
What are the "first hit" and "second hit"?
**"First hit" = loss of APC** tumor suppressor genes at **5**q21
**"Second hit"** = methylation abnormalities; **APC -- β-catenin**
- Activation of **RAS**
- Loss of **TP53** at **chromosome 18**
122
Where is MUC-1 expressed?
Ovarian and breast carcinomas
123
What is expressed on T cell lymphomas and Hodgkin lymphomas and antibodies to it may be used as treatment?
CD30
124
People with xeroderma pigmentosum are at increased risk for what?
Defect in what?
- Cancer of skin due to UV radiation --\> **pyrimidine dimers**
- Nucleotide excision repair (NER)
125
Mutations in what genes account for 30% of HNPCC?
MSH2 and MLH1
126
Defects in the homologous recombination DNA repair system results in what 3 disorders?
1) Bloom syndrome
2) Ataxia-Telangiectasia
3) Fanconi anemia
127
Infiltrating cancers invoke chronic inflammatory states with what classic symptoms?
- Anemia
- Fatigue
- Cachexia
128
What miR is believed to be important in invasiveness and metastasis?
MiR-200
129
What miR is overexpressed in B cell lymphomas and upregulates MYC?
miR-155
130
Deletions of what miRs lead to CLL?
Their deletion upregulates what?
- miR-15 and miR-16
- BCL-2
131
Defects in DICER lead to what cancers?
Rare Ovarian and Testicular tumors
132
Which genotype seen in 10% of the white population increases the risk of developing lung cancer in light smokers nearly 7-fold?
*CYP1A1*
133
What carcinogen does Aspergillus make?
Causes what cancer?
- Aflatoxin B1
- Hepatocellular carcinoma in Africa and the Far East
134
Aflatoxin B1-associated hepatocellular carcinomas have which particular mutation in *TP53*?
G:C --\> T:A **transversion** in codon **249** producing an **arginine --\> serine** substitution in the **p53 protein**
135
What is responsible for the induction of cutaneous cancers?
Due to the formation of?
What wavelength?
- UV**B**
- Formation of **pyrimidine dimers** in DNA (**NER**); particularly adjacent **thymidine** residues in the same strand of DNA
- 280-320 nm
136
What are the most frequent radiation-induced tumors?
- Myeloid leukemias, Thyroid cancer (only in the young)
- **Intermediate category:** breast, lungs, and salivary gland cancers
137
What sites are relatively resistant to radiation-induced neoplasia?
Skin, bone, and GI tract
138
What is the main oncogenic RNA virus?
What does it cause?
Endemic where?
HTLV-1
Adult T-cell leukemia/lymphoma (ATLL)
Japan, Caribbean, South America, Africa
139
What protein is responsible for the transforming activity and essential for viral replication in HTLV-1?
Tax
140
How does the protein Tax produced by the HTLV-1 virus contribute to increased pro-growth signaling and cell survival?
- Interacts with **PI3K** and thereby stimulates **AKT**
- Directly upregulates expression of **cyclin D2** and represses function of **CDK inhibitors**
- Activates the TF **NF-kB**
141
What are the high-risk DNA viruses associated with squamous cell carcinomas of the cervix, anogenital region, and head/neck?
HPV **16** and **18**
142
What binds to and mediates the degradation of p53?
What does it stimulate?
Polymorphism of Arg72 in p53 leads to what?
- **E6** protein
- Stimulates expression of **TERT**, catalytic subunit of **telomerase**
- Cervical carcinomas
143
What binds RB protein and displaces E2F?
What can it inactivate?
What can it activate?
- **E7** protein
- Inactivates **CDK inhibitors p21** and **p27**
- Activates **cyclins E** and **A**
144
HPV itself is not sufficient for Carcinogenesis, what else does it need for full malignant transformation?
Co-transfection with mutated **RAS**
145
What are the most common EBV associated tumors?
- Those derived from B cells (i.e., **African Burkitt Lymphoma** and **B-cell lymphomas**)
- Nasopharyngeal carcinoma
146
What does EBV use to infect B cells?
Complement receptor 2 **(CR2, CD21)**
147
What does EBV use as an oncogene?
How does it act?
- **LMP-1**
- Behaves like a **constituitively active CD40 receptor** = stimulates B cell growth
- Activates **NF-kB** and **JAK/STAT** signaling pathways and promotes B cell survival and proliferation
- Prevents apoptosis by activating **BCL2**
148
What is the most common childhood tumor in central Africa and New Guinea?
Burkitt lymphoma (EBV related)
149
In the case of Burkitt lymphoma it seems that EBV is not directly oncogenic, but instead acts how?
Acts as a **polyclonal B-cell mitogen** setting the stage for acquisition of the (**8;14**) **translocation** and other mutations that ultimately produce full-blown cancer
150
Which tumor is endemic in Southern China, some parts of Africa, and in the Inuit population?
Association with what virus?
- Nasopharyngeal carcinoma
- EBV
151
While the oncogenic effects of HBV and HCV are multifactorial, what is the dominant effect in the development of hepatocellular carcinomas?
Immunologically mediated **chronic inflammation** and **hepatocyte death** leading to regeneration and, over time, genomic damage
152
Which key molecular step within hepatocytes blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations characteristc of HBV induced hepatocellular carcinoma?
Activation of NF-kB pathway
153
Which protein of HBV and the HCV core protein can activate signal transduction pathways that may contribute to carcinogenesis?
Where is HBV endemic?
- HBx protein
- **Endemic in**: Far East and Africa (highest incidences of **hepatocellular carcinoma**)
154
*H.pylori* causes what cancers?
What associated gene is present?
- **Gastric adenocarcinoma** and **MALT (gastric) lymphomas**
- ***CagA****,* stimulates growth factor pathways
155
Chronic *H.pylori* infection leads to polyclonal B-cell proliferations that may give rise to a?
**Monoclonal** B-cell tumor (**MALT lymphoma**) of the stomach
156
What is characteristic of neoplasms in the gut and urinary tract?
Melena (blood in stool) and Hematuria
157
Cancer cachexia is associated with what 3 events?
1) **Equal** loss of both **fat** and **lean** **muscle**
2) **Elevated** BMR
3) Evidence of **systemic inflammation** (i.e., increase in acute phase reactants)
158
Grading of tumors is based on what?
Cytologic appearance; based on idea that behavior and **differentiation** are related
159
What are the 3 things staging is graded on?
**T** - size of primary lesion
**N** - extent of spread to regional **LNs**
**M** - presence or absence of blood-borne **metastases**
160
T0 means what?
Indicative of **In situ lesion**
161
What are the major forms of underlying cancer associated with Cushing Syndrome?
Small-cell carcinoma of **lung**
**Pancreatic** adenoma
**Neural** tumors
162
Lung cancer patients with Cushing syndrome have elevated serum levels of?
- POMC
- Corticotropin
163
What are the 2 general processes involved in cancer-associated hypercalcemia?
Which of the 2 is considered to be paraneoplastic?
1) **Osteolysis** induced by cancer
2) Production of **calcemic humoral substances** by extraosseous neoplasms (only one considered **paraneoplastic**)
164
Which factors have been causally implicated in the hypercalcemia of malignancy?
Which is the most important?
- PTHRP = **most important**
- IL-1
- TGF-α
- TNF
165
Which tumors are most often associated with paraneoplastic hypercalcemia?
- Squamous cell carcinoma of lung
- Breast carcinoma
- Renal carcinoma
- Adult T-cell leukemia/lymphoma
166
What are the 2 major forms of underlying cancer seen in *Myasthenia*?
1) Bronchogenic carcinoma
2) Thymic neoplasms
167
What is the major form of underlying cancer seen in disorders of the CNS and PNS?
Breast carcinoma
168
What are the 3 major forms of underlying cancer seen in patients with *Acanthosis nigricans*?
Due to what?
- Gastric carcinoma
- Lung carcinoma
- Uterine carcinoma
- Due to **EGF secretions**
169
What are the 2 major forms of underlying cancer seen in patients with Hypertrophic osteoarthropathy and clubbing of the fingers?
1) Bronchogenic carcinoma
2) Thymic neoplasms
\*Also seen in Myasthenia syndromes
**B**ig **T**en **H**ype
170
What are the 2 major forms of underlying cancer seen in patients with *Migratory thrombophlebitis (Trousseau phenomenon)*?
1) Pancreatic carcinoma
2) Bronchogenic carcinoma
171
*Disseminated intravascular coagulation* is most commonly associated with what 2 cancers?
1) Acute promyelocytic leukemia
2) Prostatic adenocarcinoma
**DICAP**-itated
172
What screening technique is used for carcinoma of the cervix, endometrial carcinoma, lung carcinoma, bladder and prostatic tumors, etc
Cytologic smears
173
What technique is used for assessment of breast, thyroid, and LN cancer?
Fine needle aspiration (FNA)
174
Presence of cytokeratins, detected by immunohistochemistry points to?
An epithelial origin (**carcinoma**)
175
What does presence of ALK in a immunohistochemical stain indicate?
Lung cancer and lymphomas
176
Flow cytometry is mainly used to identify cellular antigens expressed by what kind of tumors?
- "Liquid" tumors, those that arise from blood-forming tissues
- **B- and T-cell lymphomas** and **leukemias**, as well as **myeloid neoplasms**
177
HCG is a marker for what tumors?
- **Trophoblastic** tumors
- Testicular tumors
178
CA-125 is a marker for what?
- Ovarian tumors
- *Immunoglobulin* in multiple myeloma
179
Alpha-fetoprotein (AFP) is a marker for what?
- Hepatocellular carcinomas
- Embryonal cell carcinomas (yolk sac tumors)
180
Neuron specific enolase is a marker for what 2 tumors?
1) Small-cell cancer of lung
2) Neuroblastoma
181
*TP53, APC, RAS* mutants in stool and serum used as marker for what cancer?
Colon cancer
182
Chronic Inflammatory Bowel disease increases the risk for what cancer?
Colorectal carcinoma
183
What is one major differenc between Burkitt Lymphomas and Nasopharyngeal carcinomas associated with EBV?
- **Burkitt lymphomas** associated with EBV do **NOT** express **LMP-1**
- **Nasopharynheal carcinomas** associated with EBV **DO** express **LMP-1**
184
What are the 2 major forms of underlying cancers associated with Dermatomyositis?
1) Bronchogenic carcinoma
2) Breast carcinoma
185
What is the major form of underlying cancer associated with Red cell aplasia?
Thymic neoplasms
186
Hypertrophic osteoarthropathy is characterized by what 3 abnormalities?
1) Periosteal new bone formation, primarily at **distal ends of long bones, metatarsals, metacarpals, and prox. phalanges**
2) **Arthritis** of the **adjacent joints**
3) **Clubbing** of the digits
187
Advances mucin-secreting adenocarcinomas often show lesions of the heart where?
Known as?
- Often **left-sided** heart valves
- *Nonbacterial thrombotic endocarditis*
188
CA-15-3 is used as a marker for what cancer?
Breast cancer
