2. Characteristics of Benign and Malignant Neoplasms (Ch7) Flashcards
(309 cards)
1
Q
Neoplasia means new growth and a new growth is called a?
A
neoplasm
2
Q
Tumor originally applied to the swelling caused by inflammation but the noneoplastic usage of tumor has vanished = neoplasm. What is the study of tumors or neoplasms?
A
Oncology
3
Q
All tumors have two basic components 1) neoplastic cells that constitute the parenchyma (how they’re classified) and 2) reactive stroma made up of (growth and spread dependent on stroma)?
A
connective tissue, BVs, and cells of the adaptive and innate immune system
4
Q
In some tumors, the parenchymal cells stimulate the formation of an abundant collagenous stroma referred to as?
A
desmoplasia
Scirrhous = stony hard tumor
5
Q
What type of tumor is it when its gross and microscopic appearances are considered relatively innocent, implying that it will remain localized, will not spread to other sites and is amenable to local surgical removal?
A
Benign tumor
6
Q
benign tumors are designated using -oma- mesenchymal tumors follow this rule. What are some examples?
A
Fibroma
Chrondroma
-mesenchymal derivatives
7
Q
Benign epithelial tumors are more complex- classified on different aspects of the tumor. What is applied to benign epithelial neoplasms derived from glands- although may not have a glandular structure?
A
Adenoma
8
Q
benign epithelial neoplasms producing small visible fingerlike or warty projections are referred to as?
A
papillomas
projection on mucosal surface=polyp
9
Q
Cystademonas are those that form large cystic masses such as in the ovaries. When you combine papillary projects with cysts what do you get?
A
papillary cystadenoma
10
Q
What tumors can invade and destroy adjacent structures and spread to distinct sites to cause death?
A
malignant tumors
11
Q
Malignant tumors arising from solid mesenchymal tissues are usually called? What about when they arise from blood forming cells?
A
sarcomas
leukemias/lymphomas
12
Q
**Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers are called?
A
carcinomas
13
Q
Squamous cell carcinomas denotes cancer in which the tumor cells resemble stratified squamous epithelium and ______ denotes a lesion in which the neoplastic epithelial cells grow in a granular pattern.
A
adenocarcinoma
*sometimes tissue or organ is used in the name
14
Q
Divergent differentiation of a single neoplastic clone creastes a mixed tumor. These tumors contain epithelial components scattered within a ?
A
myxoid stroma that may contain islands of cartilage or bone
15
Q
What neoplasm has the ability to arise from a single clone capable of producing both epithelial and myoepithelial cells?
A
pleomorphic adenoma
16
Q
most neoplasms are derived from a single germ layer except ______ which contain recognizable mature or immature cells or tissues belonging to more than one germ cell layer.
A
teratoma
17
Q
Teratomas have cells that can differentiate into any cell in the body (totipotent), so it is common to see bone, epithelium, muscle, fat, nerve and other tissues. What differentiates principally along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous glands, and tooth structures?
A
Ovarian cystic teratoma
18
Q
Hamartomas are benign masses composed of cells indigenous to the involved site. What term is applied to a heterotrophic rest of cells?
A
Choristoma (pancreatic tissue nodule in stomach)
19
Q
What is the extent to which the neoplastic parenchymal cells resemble the normal parenchymal cells, both morphologically and functionally , with lack of differentiation called anaplasia-irreversible?
A
Differentiation
20
Q
In general, benign tumors are well differentiated (looks same as normal cells), in which mitoses are usually?
A
rare and are of normal configuration
21
Q
Malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that?
A
show their malignant nature
22
Q
Malignant neoplasms are composed of poorly differentiated cells are said to be anaplastic, which?
A
lack differentiation and is a hallmark of malignancy- Anaplasia is associated with many morpholigic changes
23
Q
Cancer cells display pleomorphism which is variation in size and shape, thus cells in the same tumor are not uniform, but rangle from small cells with undifferentiated appearance to?
A
Giant cells many times larger than their neighbors
24
Q
Abnormal nuclear morphology is seen with anaplasia- characteristically, the nuclei are disproportionately large for the cell, with a nuclear to cytoplasm ratio that may approach?
A
1:1 instead of the normal 1:4
shape is irregular, chromatin clumped and distributed along membrane-darkly stained
25
Unlike benign tumors, in undifferentiated tumors- many cells are in mitosis reglecting high proliferative activity of parenchymal cells. What is important for malignancy?
atypical, bizarre mitotic figures with tri/quad/multipolar spindles
26
In addition to cytoogic abnormalilites, the orientation of anaplastic cells is markedly disturbed- tumors grow in unorganized fasion. Often, rapidly growing malignant tumors develop?
centers of ischemic necrosis d/t lack of blood supply
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*well differentiated* benign tumors and carcinomas reflect the tissue theyre in so they secrete hormones characteristic of their origin. Anaplastic, undifferentiated lose their?
resemblance to the normal cells in which they arose- sometimes they form random things not associated with the tissue normally
28
Metaplasia is defined as replacement of one type of cell with another due to damage/repair /regeneration (barretts esophagus). What is dysplasia (reversible)?
Disordered growth encountered in epithlia and is characterized by a loss of uniformity of the individual cells as well as a loss in their architectural orientation
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Dysplastic cells often contain larger hyperchromatic nuclei with a high nuclear to cytoplasm ratio. The architecture is usally?
disorderly
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What is the grading scale for differentiation?
- Well differentiated: looks a lot like the parent tissue. ** best
- Moderately differentiated: can identify features of the original tissue, but it is not the dominant pattern and there is additional atypia present.
- Poorly differentiated: a small number of cells have features of the parent tissue and is associated with cellular anaplasia.
- Undifferentiated: tissue of origin cannot be discerned and is always associated with anaplasia **worst
31
An example is in dysplastic squamous epithelium, the normal progessive matuartion of tall cells in the basal layer to flattened squames on the surface may fail in part or entirely leading to replacement of the epithelium with?
basal-appearing cells with hyperchromatic nuclei with mitotic figures in all cells
32
When dysplatic changes are marked and involve full thickness of the epithelium, but the lesion does not penetrate the basement membrane, it is considered to be?
a pre-invasive neoplasm and is referred to as carinoma in situ
(dysplasia to in situ to invasive)
33
**Although dyplasia may be a precursor to malignant transformation, it does not?
always progress to cancer
| *if the basement membrane is not involved, dysplasia is reversible)
34
What is accompanied by progressive infilitration, invasion, and destruction of the surrounding tissue, whereas nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and lack the capacity to infiltrate, invade or metastasize to distant sites?
Growth of CANCERs
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Benign tumors usually grow slowly and form a fibrous tissue around them called a capsule which consists of ECM deposited by fibroblasts. What does this capsule allow?
creates tissue that is discrete, palpable and moveable (non-fixed)
36
In contrast, malignant tumors are poorly demarcated from the surround normal tissue and are without a welldefined tissue border. What kind of image is common among cancers that penetrate adjacent structures?
Crablike picture (pattern of growth)
37
What is the most reliable feature that differentiates between cancers and benign tumors?
Metastasis
| -invasiveness is the second best characterization of a malignant cancer vs. benign growth
38
What is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor, and unequivocally marks a tumor as malignant as by definition benign neoplasms do NOT metastasize?
Metastasis
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Most malignant tumors metastisize but some hardly ever do including gliomas (malignant glial cells of CNS) and what of the skin?
Basal cell or squamous cell carcinomas
40
Approximately 30% of solid tumors present with metastasis, strongly reduced the chance of cure. What is in the blood and usually disseminated at diagnosis?
leukemias and lymphomas - derived from blood forming cells that travel to distant sites
41
Pathways of speed: dissemination of cancers may occur through on of the 3 pathways 1) direct seeding of body cavities or surfaces 2) lymphatic spread 3) ?
Hematogenous spread
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Seeding of body cavities and surface occurs when malignant neoplasm penetrates into an open field- commonly the peritoneal cavity. This seeding is characteristic of?
carcinomas of the ovaries
*tumor is only on surface and does not penetrate inside- fills cavity with pseudomyxoma peritonei (gelatinous mass)
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Transport through the lymphatics is the most common pathway for the initial spread/dissemination of?
carcinomas
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Sometimes used by sarcomas, carcinomas use near by lympathics to spread. This usually leads to metastasis at ?
the regional lymph nodes
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Breast cancers in the upper outer quadrants go to axillary LN while inner quadrants drain to LN in the?
internal mammary arteries
46
What is often used to asses the presence or absence of metastatic lesions in the lymph nodes, which is defined as the first node in a regional lymphatic basin that receives lymph flow from the primary tumor?
Sentinel nodes (biopsy of)
47
Sentinel node mapping is done by injecting radiolabeled tracers or colored dyes and examination of frozen section of the sentinel LN performed during surgery can guide the surgeon to the appropriate therapy- what is this commonly used for?
metastasis of melanoma, colon and other cancers
48
Hematogenous spread is typical of ____ but is also seen with carcinomas.
sarcomas
49
Arteries with thicker walls are less commonly penetrated than veins are. When the cells spread via veins, where do they end up?
in the first capillary bed they find which is generally the liver and lungs
50
Nodal enlargement can be one of two things, including?
dissemination of the cancer to the LN OR reactive hyperplasia of the T cells fighting off the cancer inside
51
Arterial spread occurs when tumor cells pass through pass through the pulmonary capillary beds, pulmonary arteriovenous (AV) shunts, or ?
when the pulmonary tumor give rise to additional tumor emboli in the blood
52
Thryroid and prostate commonly mestatsize to vertebral column via paravertebral plexus. There are certain carcinomas that have a propensity for invasion of veins including? 2
```
Renal cell carcinoma (renal vein to IVC in heart)
Hepatocellular carcinoma (portal/hepatic veins)
```
53
Anatomical location and path of veins does not always explain the distributions of metastasis, for example breast carcinoma spread to bone, etc. What two areas are rare sites of secondary deposits?
skeletal muscles and spleen event though they receive alot of blood
54
In 2008, it was estimated that there were about 12.7 million new cancer cases worldwide, leading to 7.6 million deaths (21,000 deaths per day). Due to increasing population size and age, by 2030 it is projected that the number of cancer cases and cancer related deaths world wide will?
increase to 21.4million cases and 13.2 million deaths
55
The most common tumors in men are prostate, lung and colorectal and in female are breast, lung and colorectal. What cancers have the highest mortality?
LUNG cancer (no screening for this :/)
breast/prostate (have screen for these)
colorectal
56
Although genetic and environmental factors contribute to the development of cancer, environmental influences appear to be?
the dominant risk for most cancers
57
Environmental risk factors for cancer include infectious agents like HPV, smoking, alcohol consumption, diet, obesity, and what other two things?
```
reproductive history (estrogen - breast/ endometrial ca)
environmental carcinogens
```
58
Age has an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur in the latera years of life as in?
>55 years
59
Cancer is the main cause of death among women 40-79 and men 60-79, the decline in deaths after age 80 is due to?
low number of individuals who reach this age
60
What is the explanation of increased age with increased cancer?
accumulation of somatic mutations associated with the emergence of malignant neoplasms
(decline in immune competence may contribute as well)
61
10% of all deaths in children younger than 15 is due to cancer, however, the type of cancer affecting children is different than adults. How so?
Carcinomas are most prev. in adults
In children, leukemia, CNS neoplasms are most common. Along with small rough blue cell tumors (neuroblastomas), wilms tumors Rb, and rhabdomyosarcomas
62
Acquired condition that predispose to cancer can be divided into chronic inflammations, precursor lesions and?
Immunodeficiency states.
63
What can be defined as localized morphologic changes that are associated with a high risk of cancer, all arising in epithelial surfaces/ associated with increased risk of various forms of carcinoma?
Precursor lesions
64
Chronic inflammation increases the pool of tissue stem cells which may be susceptible to transformation. Aditionally, activated immune cells produce ?
ROS that are genotoxic as well as inflammatory mediators that promote cell survival (bad)
65
Chronic epithelial damage causes metaplasia, change of one cell to another for better adaption. However this can lead to potential?
oncogenic mutations to survive leading to cancer
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Many precursor lesions arise in chronic inflammation and can be recognized by metaplasia, examples? 4
* Barrett Esophagus: gastric and colonic metaplasia of the esophageal mucosa in the setting of gastric reflux
* Squamous Metaplasia of the Bronchial Mucosa in response to smoking
* Squamous Metaplasia of the bladder in response to schistosomiasis infection
* Colonic metaplasia of the stomach in the setting of pernicious anemia and chronic atrophic gastritis
67
Other precursor lesions are noninflammatory hyperplasia with one of the most common being endometrial hyperplasia which is caused by?
sustained estrogenic stimulation of the endometrium
(another is leukoplakia - thickening of squamous epithelium that may occur in oral cavity or on penis/vulva giving rise to squamous carcinoma)
68
the final group of precursor lesions is benign neoplasms that are at risk for malignant transformations. The classic example is clonoic villous adenoma which if left untreated?
progresses to cancer 50% of the time
****Note: MOST benign tumors transform RARELY such as uterine leiomyomas and pleomorphic adenomas
69
Immunodeficient (especially T cell immunodeficient) patients are at increased risk for cancers espcially those caused by oncogenic viruses such as lymphomas. Why?
CD8Tcells recognize tumor antigen in the context of MHC class I and kill tumor cells (if you're deficient you cant do that)
70
Sporadic malignant neoplasms = 95% of cancers in the US. 5% of cancers can be ascribed to germline mutations in a tumor suppressor gene. Cancer is the most common in?
adults over the age of 60 and the variation that occurs geographically is likely due to environmental reasons
71
There are many genomic themes in carcinogenesis such as nonlethal genetic damage which allows the cell to proliferate and survive, which is then able to undergo?
colonal expansion of the single cell
**needs genetic damage
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There are four classes of normal regulatory genes- the growth promoting proto-oncogenes, growth inhibiting tumor suppressor genes, and what other two?
genes that regulate programmed cell death (apoptosis) and genes inolved in DNA repair
*all these are principle targets of cancer causing mutations
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Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time. Malignant neoplasms have several phenotypic attributes referred to as cancer hallmarks such as? 3
excessive growth, local invasivness, and the ability to form distant metastases which stem from the genomic alterations that change the expression and function of key genes.
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What are the mutations that contribute to the development of the malignant phenotype?
driver mutations
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the first driver mutation that starts a cell on the path to malignancy is the initiating mutation, however it is required that the initiated cell aqcuires?
many driver mutations, each helping to develop cancer
*cancers arise from 'cancer stem cells'
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Loss of function mutations in genes that maintain genomic integrity appear to be a common early step on the road to malignancy, particularly in?
solid tumors
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Mutations that lead to genomic instability increase the likelihood of acquiring driver mutations, and also greatly increase the frequency of mutations that have no phenotypic consequences, called?
passenger mutations - more common than driver
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Tumors evolve under the pressure of selection - survival of the fittest. Early on all the tumor cells are the same- coming from one parent cell. By the time the tumor comes to clinical attention (1gm mass) it has gone through a minimum of?
30 cell divisions*** for clinical presentation
79
During tumor evolution, there is competition among tumor cells for nutrients, and subclones with the capacity to overgrow their predecessors tend to win the dawinian contest and dominate the tumor mass. This tendancy of tumors to becomes more agressive is known as?
tumor progression
*at clinical presentation, tumor cells are extremely heterogenous
80
One of the most profound selective pressures that cancer cells face is effective chemotherapy or radiotherapy. Tumors that recur after therapy are almost always found to be?
resistant if the same treatment is used again
81
Epigenetic modifications also contribute to the malignant properties of cells. These modifications include DNA methylation which silences gene expression and what other modification?
histone modification - enhances or suppresses gene expression
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Together, both DNA methylation and histone modification are expressed together, which determines which genes are expressed and in turn determines?
the lingeage comittment and differentiation state of both normal and neoplastic cells
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Epigenetics has made a new path for cancer treatments because unlike DNA mutations, epigenetic alterations are ?
reversible by drugs that inhibit DNA or histone modification
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All cancers display 8 fundemental changes in cell physiology which are considered hallmarks of cancer. What hallmark is that tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation?
self-sufficiency in growth signals
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Tumors may not respond to molecules that inhibit proliferation of normal cells, usually because of inactivation of tumor suppressory genes that encode components of these growth inhibitory pathways... Which cancer hallmark?
insensitivity to growth inhibitory signals
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What are the other 6 hallmarks of cancer?
1. altered cellular metabolism (warburg effect)
2. evasion of apoptosis
3. limitless replicative potential (immortality)
4. sustained angiogenesis
5. Ability to envade and metastasize
6. Ability to evade the host immune repsonse
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The aqcuisition of the genetic and epigenetic alterations that confer the 8 hallmarks of cancer may be accelerated by what two things?
genomic instability and cancer promoting inflammation
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What are created by mutations in protooncogenes and encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth promoting signals?
Oncogenes- freed from normal checkpoints so can proliferate excessively
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What is the most frequently mutated oncogenic pathway in human neoplasms?
receptor tyrosine kinase pathway
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Pro-growth oncoproteins endow cells with self-sufficiency in growth. The factors that have the greatest impact on malignant phenotype is RAS and its two signaling arms downstream...?
mitogen activated protein kinase (MAPK) and phosphoinositidyl-3kinase (PI3K/AKT) pathway are important in promoting cell growth
91
Cancer cells acquire the ability to release GFs for their receptors, creating an autocrine cell signaling loop. What are three situations in which GF are over expressed, creating this loop of activation?
PDGF-B-overexpression = astrocytoma
TGFA- overexpression = astrocytoma
*normally signal transducer is activated compared to GF production
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Most oncogenes encode GFreceptors which are mainly receptor tyrosine kinases. They are activated without GF binding to the receptor, hence delivering?
continuous mitogenic signals to the cell (even without a signal)
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What protooncogene encodes the epidermal growth factor receptor (EGFR) which is involved in point mutations in certain cancers?
ERBB1 (EGF receptor fam)
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Of greatest clinical significance are several different ERBB1 point mutations that are found in a subset of? These mutations result in activation of EGFR tyrosine kinase.
lung adenocarcinomas
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What protooncogene encodes a RTK family- HER2, and instead of mutation, the gene is amplified in _______ carcinomas, leading to overexpression?
ERBB2 gene
(EGF receptor fam)
amplified in breast carcinomas
**Note treatment by blocking HER2 is proven
96
Gene rearrangements occur to activate RTKs as well, such as tyrosine kinase ALK. For example a deletion on chr 5 fuses ALK with another gene _____ in which carcinomas? Leading to?
ALK fuses with EML4 in lung adenocarcinomas resulting in a chimeric protein that is constituitively active
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RTKs stimulate RAS, MAPK and PI3K/AKT downstream. In what cancer is it seen where there can be a RAS mutation that does NOT need the RTK to be activated in order for signaling and growth to occur?
lung adenocarcinomas
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What is the most common type of abnormality involving proto-oncogenes in human tumors?
Point mutations of RAS family genes (HRAS, KRAS, NRAS)
99
The RAS family genes were discovered in transforming retroviruses. 15-20% of all cancers contain RAS mutations. 50% of colon,endometrial, and tyroid cancers, 30% of lung adenocarcinomas and myeloid leukemias and 90% of?
pancreatic adenocarcinomas and cholangiocarcinomas
100
RAS is a G protein that binds GDP to make GTP which stimulates MAPK and PI3K/AKT. These phosphorylate and activate a number of cytoplasmic effectors as well as several?
transcription factors for rapid cell growth
*note GAPs (GTPase activating proteins) terminal RAS signaling, preventing uncontrolled signaling- some RAS mutations get around this
101
Disabling mutations of neurofribromin 1, a GAP encoded by NF1 gene are associated with inherited cancer syndrome ?
familial neurofibromatosis type 1
NF1 is an example of a tumor suppressor gene that acts through negative regulation of RAS signaling
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BRAF mutations, a RAF family, have been detected in 100% of what cancer? As well as 60% of melanomas, and 80% of benign nevi.
hairy cell leukemias
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BRAF is a serine protein kinase that sits at the top of the cascade of MAPK. Mutations in BRAF stimulate downstream activation and transcription factors, however downstream from BRAF mutations uncommonly cause cancer.. what does this suggest?
mutations affecting factors near the top of the RAS/MAPK cascade produce significant pro-grow signals
104
PI3K and its antagonist PTEN are commonly mutation. PI3K activations a cascade of serine/threonine kinases including AKT. What are the main things AKT activates? 2
mTOR (stims protein and lipid syn)
| BAD (pro-apoptotic)
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30% of breast carcinomas have a GOF mutation in the alpha-isoform of _______. when the function of PTEN is lost
PI3K
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Alteration in nonreceptor tyrosine kinases normally localize in the cytoplasm- not on the membrane and usually take form as chromosomal translocation sor rearrangments, forming?
fusion genes encoding active tyrosine kinases
107
In chronic myelogenous leukemia** CML and acute lymphoblastic leukemias, the ABL gene is translocated from its normal chromosome 9 to?
chromosome 22 (translocation)
108
On Chr 22 ABL fuses with BCR gene, making an active BCR-ABL tyrosine kinase. The most important contribution of the BCR moiety is that ?
it promotes self association of BCR-ABL = activation
109
What occurs in which tumor cells are highly dependent on the activity of one or more oncogenes?
oncogene addiction (best example is CML inhibition of BCR-ABL)
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What protooncogene is expressed in all eukaryotic cells (organisms with nucleus inclosed in a membrane) and belongs to the immediate early response genes which are induced by RAS/MAPK?
MYC (transcription factor)
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MYC activates expression of genes that are involved in cell growth, like D cyclins involved in cell cycle progression. It is a TF that can act together to reprogram somatic cells into pluripotent stem cells and in some contexts MYC can upregulate?
expression of telomerase
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In what type of B/T cell lymphoma is the MYC oncogene on chromosome 8 translocated to chr 14, causing increased MYC protein and expression of pro-growth genes?
Burkitt Lymphoma
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NMYC and LMYC are genes that are amplified in neuroblastomas and small cell cancers of the lung, respectively. IN many other instances, oncogenic mutations involving components of upstream signaling pathways elevated MYC protein levels by?
increasing MYC transcription, enhancing MYC mRNA translation or stbailizing MYC protein
114
GFs tranduce signals that induce progression of cells through the cell cycle mainly via what, which are activated by binding to cyclins?
Cyclin dependent kinases CDKs
*CDKInhibitors regulate cell cycle when CDKs are active
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What are the main two cell cycle checkpoints, each of which is tightly regulated by a balance of growth promoting and growth supressing factors?
G1/S and G2/M transitions
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G1/S defects are more important in cancer. gain of function mutations in what are oncogenes that promote G1/S progression?
GOF mutations in cyclin D and CDK4
*CDK4 is seen in melanomas, sarcomas, glioblastomas
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The other group that affects the G1/S checkpoint is loss of function mutations in?
tumor suppressor genes that inhibit G1/S progression such as CDKIs (CDK4/Dcyclin inhibitor)
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Activation of JAK 2 tyrosine kinase by a point mutation can cause what kind of cancer?
myeloproliferative disorders
119
Tummor suppressor genes apply the breaks to cell proliferation and abnormalities in these genes leads to?
failure of growth inhibition - hallmark or carcinogenesis
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Retinoblastoma gene what the first tumor suppressor gene discovered. 40% of retinoblastomas are familial with the predisposition to develop the tumor being transmitted?
autosomal dominantly
10,000 fold increase in developing Retinoblastoma
121
What hypothesis is used to explaint the retinblastoma mutations?
a two-hit hypothesis of oncogenesis in which in familial inheritance there is one Rb gene defective and the chance of a sporadic mutation is high = bilateral Rb
in sporadic cases you need 2 mutations on the same gene= very less likely = unliateral Rb
122
What is known as the governor of proliferation, which is a key negative regulator of the G1/S cell cycle transition and is directly or indirectly inactivated in most human cancers?
RB
* active HYPOphosphorylated state in quiescent cells
* inactive HYPERphosphorylated state in cells passing thru cell cycle
123
High levels of CDK4/cyclin D,etc lead to hyperphosphorylation=inhibition of RB, releasing E2F transcription factors that drive progression of cell cycle. Germline and somatic LOF mutation of the RB gene is assocaited with what two cancers?
Retinoblastoma and osteosarcoma
124
Mutational activation of cyclin D/CDK4 or mutational inactivation of CDKinhibitos favor cell proliferation by faciliting?
hyperphosphorylation and inactivation of RB (so its almost like having an RB LOF)
125
Loss of normal cell cycle control is central to malignant transformation and at least one of key regulators of the cell cycle (p16/INK4a, Cyclin D, CDK4, RB) is?
dysregulated in the vast majority of human cancers
126
The transforming proteins of several oncogenic animal and human DNA viruses also act by neutralizing growth-inhibitory activities of RB. What virus protein binds to the hypophosphorylated form of RB, inactivating RB?
HPV- E7
binds in same place E2F would bind, causing lack of hyperphosphorylation = cell cycle progression
127
```
NOTE
Growth inhibitors TGF-B/p53 stimulate CDKinhibitors like p16/INK4 which inactivate CyclinD/CDK4 causing hypophosphorylation of RB = NO PROGRESSION CELL CYCLE = TRANSCRPTION BLOCK
Growth factors (EGF/PDGF) activate cyclinD/CDK4 which phosphorylate and hyperphosphorylate RB causing EF2 TF to be released and bind DNA where it ALLOWS PROGRESSION THROUGH CELL CYCLE
```
***
128
What is known as the guardian of the genoome, a tumor suppressor that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis **most frequently mutated gene in human cancers?
TP53
Chr17p13.1
129
In most cases TP53 mutations are present in both alleles and are acquired, not inherited. What occurs in Li fraumeni syndrome?
Rare inheritance of mutated TP53 allele - 25fold greater chance of developing malignant tumor by 50
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What are the most common types of cancers associated with Li-fraumeni syndrome?
sarcomas, breast cancer, leukemias, brain tumors and carcinomas of the adrenal cortex
131
What are two things that can degrade p53, causing lack of p53 and cell cycle monitoring?
MDM2 upregulation degrades p53
| Viral E6 HPV bind and promote p53 deg.
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In normal cells, p53 is undetectable because it is degraded by MDM2, but in stressed/damaged cells what occurs?
p53 is released from inhibitory MDM2 via 2 mechanisms depending on the nature of stress
133
The key initiators of p53 activation following DNA damage or d/t hypoxia are ataxia-telangiestasia mutated ATM and?
ataxia-telangiectasia and Rad3 related ATR
134
Once ATM and ATR are signaled via DNA damage or hypoxia, they stimulate phosphorylation of proteins including?
p53 and MDM2, these postranslational modifications allow MDM2 and p53 to separate and p53 to accumulate
135
Oncogenic stress is the other way MDM2 and p53 binding is released via MAPK/PI3K AKT, cellular stress signals lead to increase expression of p14/ARF which is encoded by which tumor suppressor gene?
CDKN2A (binds MDM2 and allows p53 accumulation)
136
What are the three way that activated p53 diconstinues neoplastic transformation?
transient cell cycle arrest
senesence (permanent cell cycle arrest)
apoptosis
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For transient p53-induced cell cycle arrest, p53 induces production of CDK inhibitor p21, which inhibits CDK4/D cyclin complexes, maintaining hypophos of RB = pausing cell cycle. What does p53 recruit to help with DNA repair?
GADD45
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If the DNA damage can not be repaired p53 directs the transcription of several pro-apoptotic genes such as what?
BAX and PUMA which induce intrinsic apoptosis pathway
139
What occurs with loss of p53?
DNA damage goes unrepaired, driver mutations accumulate in oncogenes and other cancer genes and the cell marches blindly along a dangerous path leading to malignant transformation
140
What tumor suppressor gene is known as the gatekeeper of colonic neoplasia, a member of the class of tumor suppressors that function by downregulation growth promoting signaling pathways?
Adenomatous polyposis coli APC
141
Germline loss of function mutation of APC is associated with familial adenomatous polposis an autosomal dominant DO in which ?
someone with the mutation develops thousands of adenomatous polyps which gains more mutations and forms colon cancer
*(note: 70-80% of nonfamilial colon cancer show acquired APC mutations)
142
APC is a component of which pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embyonic development?
WNT signaling pathway
143
WNT signals via FRZ and stimulates Bcatenin and APC. APC regulates B-catenin activity. When signaling occurs from WNT it blocks APC , allowing B catenin to do what?
allowing it to translocate from cytoplasm to nucleus
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Once in the nucleus B-catenin forms a complex with TCF (DNA binding factor) which promotes growth of colonic epithelial cells by increasing ?
transcription of MYC, cyclin D1
**Thus mut APC allows Bcatenin to cause progrowth signals like it is being activated by WNT
145
The importance of APC/Bcatenin pathway is that B catenin is commonly mutated which prevents APC dependent destruction allowing the mutant protein to accumulate in the nucleus and?
stimulate transcription
146
Tumors with wild type TP53 alleles are more likely to be killed by what therapy as opposed to tumors with mutated TP53alleles?
(WT = testicular teratocarcinomas/ acute lymphoblastic leukemias)
irradiation
| Conventional chemotherapy
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Tumors such as lung cancers and colorectal cancers which have TP53 MUTATIONS (not wild type WT) are usually?
resisitant to irradiation and chemotherapy
148
Individuals who inherit one mutant allele of the NF1 gene develop numerous benign neurofibromas and optic nerve gliomas as a result of inactivation of the second copy of the gene.... known as?
Neurofibromatosis type1
| NF is a GTPase domain which stops RAS signaling, when gone = RAS active
149
Germinline mutations in the NF2 gene develop benign bilateral schwannomas of the acoustic nerve, what is this dz known as?
neurofibromatosis type 2
150
LOF mutations in WT1 gene on chr11p13 is associated with the development of?
a pediatric kidney cancer: wilms tumor
151
WT1 protein is a transcriptional activator of genes involved in renal and gonadal differentiation- what is its deficiency closely related to?
differentiation of genitourinary tissues
152
In many adult cancers, WT1 is overexpressed (leukemias/breast cancer) and functions as a oncogene even though?
it is a tumor suppressor gene in children
153
What is a tumor suppressor gene that encodes a cell membrane protein called PATCHED1 which are negative regulatos of the hedgehog signaling pathway?
PTCH1
154
In normal conditions, hedgehog binds PATCH receptors to relieve the negative regulation and activates the pathways which?
stimulates downstream TFs
155
In the absence of patched1 membrane protein, there is unopposed hedgehog signaling that increases expression of many progrowth genes such as? 2
MYC / CyclinD
156
Germinline loss of function in PTCH1 cause gorlin syndrome and inherited condition known as?
nevoid basal cell carcinoma syndrome (inc risk of skin BCC and medulloblastomas of the cerebellum)
157
What is a germline loss of function mutation on chromosome 3p that is associated with hereditary renal cell cancers*, pheochromocytomas, hemangioblastomas of the CNS, retinal angiomas and renal cyst?
VHL - von hippel-lindau gene
158
The VHL protein is a component of a ubiquitin ligase to promote degredation via proteasomes. What is a critical substrate for VHL ubiquitin ligase?
HIF1A (hypoxia inducible factor)
159
In the presence of O2, HIF1A binds VHL and is degraded. Under hypoxic states, HIF1A evades VHL and accumulates in nuclei of hypoxic cells and turns on many things including?
VEGF, PDGF, GLUT1.
| so LOF VHL = inc. HIF1A even under normal O2 causes these things
160
Germline loss of Ecadherin = CDH1 can cause what? and a variable proportion of sporadic gastric carcinomas are also associated?
familial gastric carcinomas
161
What gene/protein is a tumor repressor gene that repairs double stranded breaks in DNA and causes familial breast and ovarian carcinoma?
BRCA1 - breast cancer 1
162
What gene/protein is a tumor suppressor that functions in DNA mismatch repair, which when mutated causes hereditary nonpolyposis colon carcinoma?
MSH2 / MSH1/6
163
What gene/protein is a tumor repressor gene that repairs double stranded breaks in DNA and when mutated causes chornic lymphocytic leukemia?
BRCA2
164
What phenomenon occurs even in the presence of ample oxygen, cancer cells demonstrate a distinctive form a cellular metabolism chracterized by high levels of glucose uptake and increased conversion of glucose to lactose (FERMENTATION) via the glycolytic pathway?
Warburg effect or aerobic glycolysis
165
Programmed death ligand 1 (PDL1) or CD274 or B7H1 is a protein in humans encoded by CD274gene. PD1 is a checkpoint protein on T cells. It normally acts as on off switch that prevents T cells from attacking othe cells in the body. What happens when PDL1 binds PD1?
It tells the T cell to leave the cell alone... cancer cells have large amounts of PD-L1, allowing them to evade immune attack
166
What can be used that target PD-1/PDL1 to block the binding and boost the immune response against cancer cells?
Monoclonal Antibodies
167
There are also many PD1 and PDL1 inhibitors such as keytruda/opdivo/libtayo and tecentriq/bavencio/imfinz respectively. however, what is bad about this?
these drugs allow the immune system to attack normal cells and organs in the body = side affects like fatigue, cough, nausea, skin rash, itching
168
Ipilimumab (Vervoy) is a monoclonal antibodie that attaches to what, blocking its expression? It has been used in treating melanoma but has much more severe side affects than other drugs.
Attaches to CTLA4 (cancer cells use it to downregulate T cell response)
169
What is a key enzyme involved in modulating production of inflammatory mediators by immune cells?
Phosphodiesterase 4 PDE4
170
The glucose hunger of tumor cells using the warburg effect are useful clincally to visualize tumors via?
positron emission tomography PET scan
171
Why do cancer cells use warburg effect/aerobic glycolysis - which only produces 2atp per cycle, instead of oxidative phosphorylation which produces much more energy?
aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components where as mT oxidative phosphorylation does not
172
Growing/tumor cells rely more on aerobic metabolism because it provides carbon moeities that can be used to build cellular components - so the parent cell can make 2 daughter cells. What is the balance acheived by these cells?
The shunt small amounts of glucose to oxidative phosphorylation for energy and then use aerobic metabolism to make cell components
173
The warburg effect (reprogramming of metabolism) is produced by signaling cascades downstream of GF receptors, they are the very same pathways that are deregulated in oncogenes and tumor suppressor genes in cancers. What does this mean?
cancer cell reprogramming persists due to the action of oncogenes and the loss of tumor supressor genes
174
What are the three most important things involved in the warburg effect in growing cancer cells?
PI3K/AKT signaling
RTK activity
MYC
175
Intrinsic Apoptotic pathway?
bax/bak to APAF to apoptosome to caspase 9 to caspase 3 (executioner) cleaves DNA- held in check via inhibitors of apoptosis proteins IAPs
176
Extrinsic apoptotic pathway?
FasL to Fas(CD95) to trimerization of FADD to caspase 8 to caspase 3
177
85% of B cell lymphomas of the follicular type carry a characteristic 14;18 (q32;q21) translocation. This translocation causes what to occur in the intrinsic apoptosis pathway?
Translocation causes overexpression of BCL2 protecting lymphocytes from apoptosis
(MCL1 overexpression is said to have large role in resistance of tumors to therapy via radiation/chemotherapy)
178
Extrinsic apoptotic pathway can be mutated and cause lymphomas either due to reduced levels of CD95/Fas or sometimes cancers have high levels of?
FLIP a protein that prevents activation of caspase 8
179
All cancers contain cells that are immortal and have limitless replicative potential (stem cell like properties of cancer cells) What are the three factors that allow cancer to do this?
evasion of senescence
evasion of mitotic crisis
capacity for self renewal
180
senescent state is associated with upregulation of tumor suppressors like p53 and ink4/p16, they help with this state via?
maintaining RB in a hypophos state which favors cell cycle arrest - so mutations here leads to evasion
181
Mitotic crisis occurs when there is no telomere left to divide, if there is no p53, nonhomologous ends may join ends of 2 chrs. resulting in dicentric chromosomes that are pulled apart at anaphase resulting in new double stranded DNA breaks, this is calld?
bridge fusion breakage - can be fixed because cancer cells can reactivate telomerase
182
In a symetric division, both daughter cells remain stem cells, in assymetric disivion what occurs?
only one daughter cell remains a stem cell and the nonstem cell proceeds along some differentiation pathway loosing its stemness
183
Do cancer stem cells arise from transformation of tissue stem cells or from the conversion of conventional somatic cells to transformed cells with acquired stemness?
both
*note cancer cells undergo assymetric division, keeping one stem cell and the other to commited progenitor which proliferate more rapidly than stem cells
184
Even if a solid tumor possesses all the genetic aberrations that are required for malignant transformation, it cannot enlarge beyond 1-2mm in diameter unless it has the capacity to?
induce angiogenesis
185
Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients and oxygen and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting GFs such as?
IGFs and PDGF
***vessels are leaky and dilated leading to metastasis
186
Most tumors remain small for months to years until an angiogenic switch termiantes this stage of vascular quiesence. The basis of this switch is?
increased production of angiogenic factors and or loss of angiogenic inhibitors
187
Lack of O2 due to hypoxia activates HIF1A, which activates VEGF and bFGF (Angiogenic factors). Loss of p53 in tumor cells not only removes cell cycle checkpoints and alters tumor cell metablosim but also provides?
a more permissive environment for angiogenesis (doesnt express antiangiogenic factors like thrombospondin 1 anymore)
188
VEGF is also influenced by RAS/MAPK pathway so GOF in RAS or MYX upregulates?
VEGF
189
What are the results of complex interactions between cancer cells and normal stroma and are the major cause of cancer related morbidity and mortality?
Invasion and metastasis
190
What are the two main phases of metastatic cascade?
1. invasion of ECM
| 2. vascular dissemination, homing of tumor cells and colonization
191
Tumor cells must interact with ECM.. Carcinoma must first breach the underlying basement membrane, traverse the interstitial connective tissue and ultimately?
gain access to the circulation by penetrating the vascular basement membrane
192
What is the first step in the process of invasion?
separation of cancer cells from one another via alterations in intercellular adhesion molecules (E-cadherins)
193
In epithelial tumors such as adenocarcinomas of the colon, stomach and breast, E cadherin is lost and allows the cancer cells to 'loosen up' allowing?
detachtment from primary tumor and advance into the surrounding tissues
194
The second step of invasion is degredation of BM and interstitial CT, which is accomplished by secreting proteolytic enzymes or by inducing stromal cells to do so. Cathepsin D, urokinase plasminogen activator and what else has been implacted in tumor cell invasion?
matri metalloproteinasese MMPs (regulate tumor invasion)
195
What is the third step of invasion after degredation of BM and interstitial CT?
changes in attachment of tumor cells to ECM proteins (Cleavage of BM proteins collagen IV and laminin by MMP2 or MMP9 act as receptors and stimulate tumor migration)
196
The fourth and final step of invasion is locomotion, propelling tumor cells through the degraded BMs and zones of matrix proteolysis. How do the actin cytoskeleton work to accomplish this?
cells attach to matrix at leading edge, detach from matrix at trailing edge and then contract to ratchet forward
NOte: cleavage products (collagen/laminin) have chemotactic activity for tumor cells
197
The concentration of what is elevated at the advancing edge of the highly invasive brain tumor glioblastoma, which supports its role in motility?
hepatocyte GF/scatter factor (from stromal cells)
198
Once in the circulation, tumor cells are vulnerable to destruction by many ways. Tumor cells clump in circulation which is favored by homotypic adhesions among tumor cells. Sometimes they bind?
coagulation factors resulting in emboli - note Platelet tumor aggreagates may form, enhancing tumor survival
199
What adhesion molecule which is used by T cells, is used by tumor cells to migrate to selective sites in lymphoid tissues / LNs?
CD44 which binds to hyaluronate on high endothelial venules
200
The site at which circulating tumor cells leave the capilaries to form secondary deposits is related to the anatomic location and?
vascular drainage of theprimary tumor as well as the tropisms of particular tumors for specific tissues
201
Organ tropism is related to a few things, including tumor cells having adhesion molecules who ligands are expressed on the target organ, 2) chemokines have role in determining target tissue 3) target tissue may be unfavorable soil, ei: well vascularized skeletal m and spleen. What are some exmaples of preffered tropism for tumors?3
Prostatic carcinoma spreads to bone
Bronchogenic carcinoms spread to adrenals and brain
Neuroblastomas spread to liver and bones
202
What is referring to the prolonged survival of micrometastases without progression as seen in melanoma, breast cancer and prostate cancer?
Dormancy
203
Stromal cells interact with tumor cells in invasion and metastasis... For example, mø in the stroma secrete matrix-degrading proteases and cleavage of ECM proteins can release latent angiogenic factors and GFs such as ?
TGFB
204
Successful tumor cells must co-opt these and other interactions and use them to promote their growth and invasion, thats why stromal cells are potential?
targets for in cancer treatments
*Note most tumors arrest in the first capillary bed they encounter (most commonly liver and lung)
205
What is used to describe the ability of the immune system to shape and mold the immunogenic properties of tumor cells in a fashion that ultimately leads to the darwinian selection of subclones that are best able to avoid immune elimination?
Cancer immunoediting
206
Antigens found in tumors that elicit an immune response have been demonstrated in many experimentally induced tumors and in some human cancers. product of oncogene or mutated tumor suppressor gene is present to T cell what is an example of some things presented?
oncogene products: mutated RAS, BCR/ABL fusion protein
| suppressor: mutated p53 protein
207
What are proteins that are expressed at high levels on cancer cells and in normal developing fetal tissues?
oncofetal antigens
208
Amounts of oncofetal proteins are increased in tissues and in the circulation in various inflammatory conditions. Oncofetal antigens are sufficiently specific that they can serve as?
markers that aid in tumor diagnosis and clinical management
**carcinoembryonic antigen CEA a-fetoprotein AFP
209
Cell mediated immunity is the dominant anti tumor mechanism, there is limited evidence that abs play a protective role under normal conditions. What are three antitumor effector mechanisms?
CTLs
NK
Macrophages
210
CD8CTLs have a clear protective role against virus assocaited neoplasms (EBV and HPV) and studies have shown the # of tumor CTLs is associated with?
better prognosis in many cancers
211
NK cells are capable of destroying tumor cells without prior sensitization, providing first line defense. NK cells can lyse tumors cells that cannot be lysed by T cells.. What is being used to activate NK in immmunotherapy?
IL2 and IL15 to induce NK cells
212
Activated mø exhibit cytotoxicity against tumor cells - activated by IFN-y. They kill tumors via?
mechanisms similar to those used to kill microbes (ROS)
213
Tumor cells must develop mechanisms to escape immune system in hosts. This is done via 1) selective outgrowth of antigen negative variants 2) loss or reduced expression of MHC molecules what other way?
may downregulate costimulatory factors on APCs and instead activate CTLA4 (inhibitory)
They may also upregulate PDL1 which activate cell death and inhibit activation in the T cell
214
Tumors may also secrete TGFB , an immunosuppressant and lastly, they may induct what type of cells to escape immune system?
T reg cells = immunoevasion
215
Genetic abberations (deviations) that increase mutation rates are very common in cancers and expidite the acquisition of driver mutations that are required for?
transformation and subsequent tumor progression
216
What syndrome is an autosomal dominant disorder characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon... due to a DNA MISMATCH REPAIR MUTATION?
HNPCC syndrome
| hereditary nonpolyposis colon cancer
217
HNPCC syndrome people inherit one abnormal copy of mismatch repair gene and trouble occurs when they lose the other. WHy are DNA repair genes said to affect cell grorwth indirectly?
because they allow mutations in other genes during the process of normal cell division- by not repairing the mismatched DNA
218
What is a hallmark of patients with mismatch repair defects which are tandem repeats of one to six nucleotides throughout the genome?
microsatellite instability - unstable and increase and decrease in size in tumor cells
219
What gemline mutations (2) cause HNPCC?
MSH2 and MLH1
220
What dz is due to a defect in the nucleotide excision repair pathway, with increased risk to get skin cancer from UV light/radiation due to inability to repair pyrimidine dimers?
Xeroderma Pigmentosum
221
Syndromes involving defects in ___________ constitute a group of disorders- Bloom syndrome, ataxia-telangiectasia, fanconi anemia- that are characterized by hypersensitivity to DNA damaging agents such as ionizing radiation.
homologous recombination DNA repair system
222
What two genes, which are associated with breast cancer when mutated, are involved in DNA repair?
BRCA1/2
223
mutations in lymphoid cell gene products that create genomic change, such as RAG 1 RAG2 and AID lead to what types of cancer?
Lymphoid Neoplasms
224
Proposed cancer-enabling effects of inflammatory cells and resident stromal cells include; release of factors that promote growth suppressors, removal of growth suppressors and?
enhanced resisitance to cell death
inducing angiogenesis
activating invasion and metastasis
evading immune destruction
225
Inflammation from cancer can cause what three things?
anemia, fatigue and cachexia
| *anemia comes from inflammation induced sequestration of Fe and the downregulation of EPO
226
What has been shown to decrease the incidence of colonic adenomas and are now approved fro the treatment of patients with familial adenomatous polyposis?
COX-2 inhibitors
227
Translocations activate proto-oncogenes in two ways 1) by promoter or enhancer substitution and 2) formation of a fusion gene. Overexpression of proto-oncogene caused by translocation is exemplified by?
Burkitt Lymphoma
228
All burkitt lymphomas are translocations where MYC and IGH sit, during translocation it moves MYC sequence on chr8q24 to chr14q32. What does this translocation do to MYC?
removes regulatory sequences and replaces them with IGH gene = MYC overexpression and tumor
229
What chromosome characteristic of CML and a subset of Bcell acut lymphoblastic leukemias, provides the prototypic example of a translocation creating a fusion gene?
philadelphia chr
| -2 breaks in ABL gene on chr 9 and in BCR on chr22 - join forming BCR-ABL fusion protein on chr 22
230
ACute promyelocytic leukemia APML is always associated with reciprocal translation between chr15 and 17 that produces what fusion?
PML-RARA fusion gene
231
```
Match the follow translocation/gene with their malignancy:
Burkitt Lymphoma
Chronic Myelogenous Leukemia CML
Acute myeloid Leukemia AML
ABL9q34/BCR22q11 (9;22)(q34;q11)
PML15q22/RARA 17q21 (15;17)(q22q21)
MYC8q24/IGH14q32 (8;14)(q24;q32)
```
Burkitt Lymphoma =MYC8q24/IGH14q32 (8;14)(q24;q32)
Chronic Myelogenous Leukemia CML =ABL9q34/BCR22q11 (9;22)(q34;q11)
Acute myeloid Leukemia AML =PML15q22/RARA 17q21 (15;17)(q22q21)
232
Chromosomal deletions are commonly associated with deletiong of tumor suppressor genes such as?
RB (rb)
| VHL (renal cell carcinoma)
233
In gene amplification, 2 patterns are seen. 1) multiple small extrachromosomal structures called double minutes and 2)?
homogenous staining regions d/t insertion of amplified gene into a place it shouldnt be
234
Some examples of gene amplification are NMYC in neuroblastomas and ERBB2 in breast cancers. NMYC is amplified in 25-30% and?
20% in ERBB2 (HER2 treatment)
235
Genomic sequencing has revealed not only many simple rearrangments that were not appreciated by prior methods, but also much more dramatic chr catastrophes called?
chromothrypsis (dozens to hundrend of chr breaks)
236
Epigenetics can play an important role in malignant phenotype as well, such a silencing of tumor suppressor genes by local hypermethylation which result in?
transcriptional silencing as seen in the silencing of CDKN2A which enhances p53/RB = bad
237
Global changes in DNA methylation are seen i some cancers throughout the entire genome - hypo and hypermethylation can cause what?
altered expression of genes, which may be overexpressed or underexpressed compared to normal
238
Changes in histones are also seen in cancers, were what occurs?
alterations in protein complexes that write read and erase histone marks or that position nucleosomes on DNA
239
MicroRNAs (miRs) are small noncoding single stranded RNAs that mediate sequence specific inhibition of messenger RNA translation through action of the?
RNA induced silencing complex RISC
miRs control cell growth, survival and differentiation
240
Decreased expression of miRNAs increases translation of oncogenic mRNAs. miR-200 has been shown to promote epithelial-mesenchymal transitions belived to be important in invasivness and metastasis, what about miR155?
overexpressed in human B cell lymphomas and indirectly upregulates a large number of gene proliferation including MYC
*oncomiRs
241
Deletions affecting tumor suppressive miRs such as miR15/16 are among the most frequent genetic lesions seen in ?
chronic lymphocytic leukemia (miR15/16 loss leads to upregulation of BCL2)
242
Rare ovarian and testicular tumors have been linked back to germline defects in DICER a genethat encodes endonuclease that is required for processing and production of miRsm making DICER what?
a tumor suppressor
243
Long intervening noncoding RNAS lincRNA regulate the activity of chromatin writers, the factors that modify what?
histones and control gene expression
244
Cancers result from the accumulation of multiple mutations that act in complementary ways to produce fully malignant tumors. What presents a great example of incremental aquisitiion of malignant phenotype?
colon carcinoma
245
In the colon inactivation of APC tumor suppressor is the first hit causing AT RISK mucoas, second hit occurs due to methylation abnormalities & inactivation of second APC, followed by KRAS activation (protooncogene mutations) causing the formation of an adenoma, lastly what occurs?
mutation of TP53 (homozygous loss) leading to carcinoma
246
There is a step process involved in chemical carcinogenesis. INitiation results from exposure of cells to a sufficient dose of a carinogenic agent- an initiated cell is alterd making it?
potentially capable of giving rise to a tumor, initiation alone is NOT sufficient for tumor formation
247
Initiation due to chemical carcinogenesis causes permanent DNA damage/mutations, it is therefore rapid and irreversible and has memory. Thus meaning?
application of promoting agent is able to produce a tumor months AFTER initiation occurs
248
Promoters can induce tumors to arise from intiated cells but they are nontumorigenic by themselves. what does this mean?
tumors do not develop with the promoter agent by itself, it needs the initiation agent to cause the OG damage and THEN the promoter agent to cause tumorigenesis
249
All intiating chemical carcinogens are what?
highly reactive electrophiles (electron-deficient atoms) that can react with nucelophiles (electron rich) such as DNA RNA and proteins
250
Direct acting carcinogens require no metabolic conversion to become carcinogenic. What is an example?
*note: most chemical carcinogens require metabolic activation for conversion into carcinogens*
chemotherapy which can cure one type of cancer while evoking another- usually acute myeloid leukemia
251
Indirect acting carcinogens refer to chemicals that require metabolic activation to become carcinogens. The most potent chemical carcingoens in fossil fuels are?
polycyclic hydrocarbons - form epoxides
| benzoapyrene from soot
252
Most known carcinogens are metabolized by CYP450 dependent mono oxygenases (CYP1A1). It may be possible to asses cancer risk based on?
genetic analysis of enzyme polymorphisms associatd with CYP450
253
An example of molecular targets of chemical carcinogens are displayed as aflatoxin B1 which occurs in aspergillus mold, which grows in grains/nuts. What correlation does this mold have with cancer?
aflatoxin B1 and hepatocellular carcinoma
| d/t TP53 mutation a G:C to T:A transversion
254
Promoters are chemical agents that are not mutagenic, but which instead stimualte cellular proliferation (hormones, phenols, drugs). How do these nontumorigenic things cause tumors?
Promotors cause cell proliferation and clonal expansion of intiated mutated cells. (cause hyperplasia)
255
Radiant energy in the form of UV rays of sunlight on ionizing electromagnetic and particulate radiation is carcinogenic. UV rays from the sun is associated with?
increased risk of SCC, BCC and melanoma
256
People of european decent with fair skin or people with lots a sunshine (AZ/austrailia) have the highest incidence of skin cancer. What UV is the worst?
UV B is responsible for induction of cutaneous cancers
| UVC is a potent mutagen but is filtered out by the ozone layer
257
The carcinogenicity of UVB light is due to formation of pyrimidine dimers in DNA. How does this occur?
UV light damage causes covalent crosslinking of thymidines in DNA = pyrimidine dimers
258
The pyrimidine dimers are fixed via neucleotide excision repair, which with excessive sunexposure, it is overwhelmed and error prone = cancer. What dz is d/t lack of NER?
xeroderma pigmentosum
| BCC/SCC considers cumulative exposure, melanoma is d/t intesense intermediate exposure - that one time u got burnt bad
259
Ionizing radiation (xrays,yrays) and particulate radiation are carcinogenic. Numerous examples including The follow up of survivors of atomic bomb in hiroshima, after this there were?
many many types of cancers with long latent periods including breast colon thyroid and lung cancers
260
Most frequent radiation induced cancer is myeloid leukemias, and cancer of thyroid. Incontrast what is resistant to radiation induced cancer?
skin bone and GI tract
| intermediate vulerablility is breast lungs salivary glands
261
What causes chromosome breakage, translocations, and point mutations leading to genetic damage and carcinogenesis?
ionizing radiation
262
Many RNA and DNA viruses have proved to be oncogenic. What causes adult T cell leukemia/lymphoma (ATLL) a tumor that is endemic in certain parts of japan, caribbean, south america, and africa and found randomly in the US?
HTLV-1 (human T cell leukemia virus type 1)
oncogenic RNA virus
263
Transmission of HTLV1 occurs via intercourse, blood or breastfeeding. It is hypothesized that the neoplastic expansion of TRegs in ATLL may underlie the ?
susceptibility of affected patients to opportunistic infections
264
The site of HTLV1 integration in host chormosomes is random, the site of integration is identical in all cells of that given cancer. HTLV1 has gag,pol,env, but in contrast to other viruses it has Tax, which is important why?
HTLV1's transformation activity are attributable to Tax- it is essential for viral replication as it stimulates transcription of viral rna for 5'long terminal repeat
265
Tax contributes to the acquisition of several cancer hallmarks including: increased progrowth signaling and cell survival and it also?
increases genomic instability by interfering with DNA repair functions and inshibiting cell cycle checkpoint
266
The oncogenic potential of HPV can largely be explained by the activities of the two viral genes encoding?
E6
| E7
267
HPV E6 binds and degrades p53 and stimualtes TERT which acitvates telomerase. E7 protein, like E6 speed cells thru the cell cycle it binds RB and displaces EF2 allowing?
progression through the cell cycle
268
High risk HPC types express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis and?
combat cellular sensence
(Note: HPV along doesnt cause cervical cancer, needs more mutations/ environmental factors
269
What oncogenic DNA virus is a member of the herpesvirus, that forms burkitt lymphoma, *B cell lymphomas, a subset of hodgkin lymphom, *nasopharyngeal and some gastric carcinomas and rare forms of T cell lymphoma and NK cell lymphoma?
Epstein Barr Virus EBV
| * MC
270
EBV infects B lymphocytes using CD21 receptor to infect B cells-hijacking them. Latent membrane protein -1 LMP1 is an oncogene that induces B cell lymphomas. LMP1 acts as what?
CD40 receptor that is stimulated by T cells - stimulating B cell growth
lmp1 also prevents apoptosis via BCL2
271
EBNA-2 (EBV gene) mimics a consituitively active notch receptor, activating Cyclin D and SRC family of protooncogenes. it also releases what viral cytokine which prevents macrophages and monocytes from activating T cells and is needed for EBV dependent transformation of B cells?
vIL-10
272
More than 90% african tumors carry EBV genome, 100% have elevated antibody titers against capsid ags, serum abs titers again viral capsid ags are correlated w risk of developing tumor, also it does no express LMP1 or EBNA2.... what cancer?
Burkitt Lymphoma ***activates MYC oncogene
273
In burkitt lymphoma, EBV is not directly oncogenic, but by acting as a polyclonal B cell mitogen, it sets the stage for the acquisition of what translocation?
MYC activation translocation 8;14
274
Nasopharyngeal carcinoma is associated with EBV infection, endemic in southern china and africa. 100% of carcinomas are from EBV (unlike burkitt). LMP1 is expressed which?
activates NFkB pathway, upregulating VEGF, FGF2, MMP9, COX2 = oncogenesis
275
HepB and C virus cause between 70-85% of hepatocellular carcinomas worldwide. Oncogenic effects are mutlfactorial, dominant effect of HBV/HCV seems to be immunologically mediated?
chronic inflammation and hepatocyte death leading to regeneration and eventual genomic damage
276
What protein of HBV and the HCV core protein can acitvate signal transduction pathways that also may contribute to carcinogenesis?
HBx
277
Helicobacter pylori (H pylori) is the first bacteria classified as a carcinogen. H pylori infection is impicated in the genesis of what two things?
gastric adenocarcinomas and gastric lymphomas
278
Hpylori involves increased epithelial cell proliferation in a background of chronic inflammation (like hepb). The sequence from gastritis to cancer takes decades and only effects 3% patients. What pathogenicity gene may contribute by stimulating growth factors?
CagA
279
Chronic H pylori infection leads to polyclonal B cell proliferations that may give rise to a monoclonal B cell tumor known as ?
MALT lymphoma of the stomach d/t accumulations of mutations
280
A small benign pituitary adenoma may compress and destroy surrounding normal gland and lead to hypopituitarism. A neoplasm in the gut may do what?
obstruct
281
What is progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia in cancer?
Cachexia
| TNF
282
Some cancer bearing individuals develop signs and symptoms that cannot readily be explained by the anatomic distribution of the tumor or by the eleboration of hormones indigenous to the tissue from which the tumor aroses, known as?
paraneoplstic syndromes
283
Endocrinopathies such as cushing syndrome, is the most common with cancer. Caused by excessive production of corticotropin, due to elevated pro-opiomelanocortin as seen in what cancer?
Small cell carcinoma of lung
284
Hypercalcemia is the most common paraneoplastic syndrome due to osteolysis d/t cancer or d/t production of calcemic humoral substances*. What is the most important humoral factor?
parathyroid hormone related protein (PTHRP) molecule related to parathyroid hormone
285
PTHRP regulats calcium transport in the lactating breasts and across the placenta. Tumors most associated with paraneoplastic hypercalcemia are? 3
squamous cell carcinoma of lung
breast carcinoma
renal carcinoma
286
Neuromyopathic paraneoplastic syndromes take diverse forms such as peripheral neuropathies and myasthenic syndrome similar to myasthenia gravis. What is the major cancer and cause?
bronchogenic carcinoma / thymic neoplasia d/t immunogenic cause
287
Acanthosis nigricans is a gray black patches of thickened hyperkeratotic skin with a velvety appearance. What cancer is this associated with? 3
gastric, lung, and uterine carcinoma
288
Hypertrophic osteoarthropathy is seen in 1-10% of lung cancers. This DO is characterized by periosteal new bone formation, arthritis of adjacent joints and?
clubbing of the digits
| bronchogenic carcinoma
289
Migratory thrombophlebitis (trousseau syndrome) may be encountered in association with deep seated cancers, most often? 2
pancreatic and bronchogenic carcinoma
290
Disseminated intravascular coagulation DIC may complicate a diversity of clincal DOs, can be seen w what two cancers?
acute promyelocytic leukemia
| prostatic carcinoma
291
Grading of cancer is done by pathologist and based on the degree of differentiation, number of mitoses or architectural features. Based on the idea that behavior and differentiation are related, such that?
poorly-differentiated = poorly behaved or more agressive
292
Staging of solid cancers is based on size of the primary lesion, its extent of spread to regional LNs and the presence or absence of?
blood borne metastases
293
TNM system (T primary tumor, N regional LN involvement, M metastasis) T0 = in situ lesion, T1-4 caracterized primary lesion, N0 no node involved, M2 = 2 sites metastasis... What is more important for prognosis grading or staging?
STAGING
294
What procedure involves aspirating cells and attendant fluid with a small bore needle followed by cytologic examination of the satined smear?
fine needle aspiration - used for breast, thyroid and LNs
295
Immunohistochemistry uses antibodies to facilitate the identificiation of cell product or surface markers. Antibodies specific to intermediate filaments are used why?
they are characterisitc of cell origin
Ex: cytokeratins = epithelial origin(carcinoma)
desmin= neoplasma of muscle cell origin
296
What can rapidly and quantitivly measure several individual cell characteristics, but is mainly used to identify cellular antigens expressed by liquid tumors, those that arise from the blood forming tissues?
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Flow cytometry
(B/Tcell lymphomas/leukemias)
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297
What is a marker for lung cancers and lymphomas expressing fusion proteins?
ALK
298
What evaluation of T cell receptor or immunoglobulin genes allows distinction between monoclonal (neoplastic) and polyclonal (reactive) proliferations?
PCR
299
Detection of translocations and deletion locations can use what?
FISH
300
What are good for looking finding deletions or amplifications genome wide?
DNA microarrays
301
What is common of the following? 1) amplification of the NMYC gene and deletions of 1p bode poorly for patients with neuroblastomas
2) oligodendrogliomas in which the only genomic abnormality is the loss of chromosomes 1p and 19q respond well to therapy and are associated with long-term survival when compared to tumors with intact 1p and 19q but with RGF receptor amplification
genetic alterations with poor prognosis
302
PCR-based amplification for nucleic acid sequences can be useful for looking for early relapse of a cancer or ?
minimal residual disease (detection of BCR-ABL transcripts by PCR gives measeure of residual cells in treated patients)
303
Mapping the genome of a patient allows for the ability to look for known mutations that can increase the risk, such as?
hereditary predispositions to cancer
304
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Molecular methods are good for finding specific oncoproteins that very specialized chemotherapy can target - oncoprotein directed drugs. Match the following 'targets' with their cancer
PMLRARA fusion
BCR-ABL fusion
ERBB1 and ALK rearrangements
BRAF mut
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PMLRARA fusion - acute promyelocytic leukemia APL
BCR-ABL fusion - CML/ALL
ERBB1 and ALK rearrangements - Lung cancer
BRAF mut- melanoma
305
Melanoma, papillary thyroid carcinoma, colon adenocarcinoma, langerhands cell histiocytosis, and hairy cell leukemia all have what common mutation?
BRAF (V600E) mutation - treated with BRAF inhibitor
306
Blood tests for prostate specific antigen (PSA) a marker prostatic adenocarcinoma, are measured in serum. However it is seen in benign prostatic hyperplasia and many other cancers.... so?
PSA test lacks specificity and sensitivity required for early detection of cancers- but may be useful for detection of recurrences after excision
307
Other tumor markers like carcinoembryonic antigen (CEA- in colon pancreas stomach and breast) and alpha-fetoprotein (AFP in hepatocellular carcinomas, yolk sac remnants in the gonads and teratocarcinomas), can have high serum levels by a variety of?
NON neoplastic conditions as well -- lack specificity and sensitivity- useful to measure post excision
308
human chorionic gonadotropin HCP for testicular tumor and CA-125 for ovarian tumors and immunoglobulin/light chains in?
multiple myeloma
309
What are some free cells being evaluated as tumor markers, in stools, sputum and saliva?
APC, TP53, RAS
