gen/neonat Wk 2
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- abnormal mass of tissue whose gorwth exceeds and is uncoordinated with that of the normal tissues
- persists in the same excessive manner after cessation of stimuli
- Autonomous growth
- Escapes normal restraints on cell proliferation
- Genetic disease; we know very few of the details
Variation in the size and shape of a tumor; in poorly differentiated, cells look very different from each other
Cells of tumor look similar to each other but completely different from the original
What are the differences between benign and metaplastic neoplasms?
- Benign: localized; incapable of invasion or metastasis; generally good prognosis; expansile, slow growth with good differentiation; smooth margins; circumscribed; uniform; low mitotic activity; lack of hemorrhage and necrosis
- Malignant: invasion and metastasis; infiltrative with fast growth and poor differentiation; poor prognosis; may induce fibrotic host response called desmoplasia; hemorrhage and necrosis; pleomorphic and atypical nuclei
Adenoma (epithelial cells and glands), chondroma (mesenchymal), lipoma (fat), papilloma, and leiomyoma (smooth muscle) are all examples of what?
Benign tumors; "-oma"
How are malignant neoplasms named?
- Based on tissue of origin
- Epithelial carcinoma (adenocarcinoma, squamous cell carcinoma, renal cell carcinoma)
- Mesenchymal sarcoma (Chondrosarcom, liposarcoma, leiomyosarcoma)
- Hematopoietic (lymphoma and leukemia)
- Melanocytic (melanoma)
- Neoplasm of germ cells with derivatives of different germ layers (skin, teeth, hair, intestines)
- Hamartoma is a disordered mass of tissue components native to an organ
- Choristoma is an ectopic island of normal tissue (normal, wrong location)
- Disordered growth of neoplastic epithelial cells, confined by the basement membrane
- Loss of uniformity of individual cells, loss in polarity
- Intraepithelial neoplasia
- Carcinoma in situ: highest grade of dysplasia with all the cellular features of carcinoma but still confiened by the basement membrane
What is the difference between grading and staging in reference to malignant neoplasms?
- Grading: histologic determination of degree of differentiation (well, moderate, or poorly differentiated)
- Staging: multimodal determination of extent of spread; clincial, radiological, pathological, biochemical
- For staging, T is the primary tumor size, N is the involvement of regional lymph nodes, and M is distant metastasis
What are paraneoplastic syndromes?
Patterns of symptoms or symptoms complexes associated with cancer that cannot be directly explained by local or distant spread of the cancer, or by the elaboration of hormones indigenous to the tissue from which the tumor arose
What are the systematic effects of cancer (in general)?
local invasion or impingement, functional activity change, bleeding and secondary infections, rupture and infarction, orcachexia (change in catabolic state)
Which paraneoplastic symptom is most closely related to Cushings (small cell lung carcinoma)?
von Hippel Lindau Syndrome
- deletion of VHL gene (3p25); gene products of this bind and send HIF (hypoxia inducible factor) to the proteasome for degredation; accumulation of HIF activates transcription of HI gene
- Clinical features: hemangioblastomas (CNS and Retina, both benign); Renal cell carcinoma; pheochromocytoma (neuroendocrine tumor of the medulla of the adrenal glands); neuroendocrine tumors of the pancreas; endolymphatic sac tumors; papillary cystadenomas of epididymus
- Subtypes: I (H and RCC); IIA (Pheo, H, and low RCC); IIB (Pheo, H, and high RCC); III (Pheo only)
Defintion: Gene penetrance
Percent of population with affected allele that show clinical symptoms
What factors put a patient at greater risk for VHL?
- Clinical diagnostic criteria: person has classic symptoms or family history or
- Presymptomatic testing: person from a family in which a germline mutation has been identified
- Testing: Checking for the absence of the 3 critical exons of the VHL gene
genes whose protein products are responsible for promoting proliferation; need a gain of function mutation here; typically only need one hit (one affected allele to increase risk of neoplasia)
Definition: Tumor suppressor genes
Inhibitors and regulators of the cell cycle; typically loss of function mutations associated; need two hits to increase risk of neoplasia
What are the 3 types of cancer causing genes?
Oncogenes, tumor suppressor genes, and DNA repair genes
How often should a patient with VHL be screened?
- Eye exam, MRI-CNS, Abdominal ultrasound (yearly; start before early teens)
- Ct/MRI and audiology prn (when symptoms present)
- Catecholamines (start at 2 years and do it every year)
Explain the multistep process of transformation and tumor progression
- DNA damage to normal cell which fails to be repaired (or inherited); mutations must affect TS, oncogenes, or apoptosis genes
- Results in increased cell proliferation and decreased cell death (clonal expansion)
- With additional mutations and angiogenesis (and lack of immune system targeting), these cells progress to tumor, and eventually malignant neoplams
- Malignancy leads to invasion and eventually metastasis
What are the main mechanisms of transformation?
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis (usually p53 mutation)
- Defects in DNA repair
- Limitless replicative potential (regain of telomerase function)
- Invasion and metastasis
How can oncogenes be mutated?
- growth factors/receptors
- signal transducing protein
- non-receptor tyrosine kinases
- trascription factors
- cyclin and cyclin-dependent kinases (cdks)
What is the mechanism of action for the oncogene RAS?
- single point mutations
- Signal transducing protein; RAS normally has GTPase activity and stops activation
- Constitutive activation of growth factor pathways
What is the mechaism of action for the oncogene BCR/ABL and what disease is it involved in?
- t(9;22); chronic myelogenous leukemia (CML)
- translocation forms a chimeric protein that structurally alters the gene for nonreceptor tyrosine kinase; activates ABL
- Non-receptor tyrosine kinase
What is the mechanism of action for the oncogene c-myc?
- t(8;14) causes c-myc to be overexpressed leading to Burkitt's lymphoma
- Transcription factor
What is the mechanism of action for the oncogene n-myc?
- Gene amplification leads to n-myc overexpression and consequently, to neuroblastoma
- Transcription factor
- poor clinical outcome
What is the mechanism of action for the oncogene HER2?
- HER2 is a growth factor receptor with tyrosine kinase activity that responds to estrogen
- Gene amplification leads to overexpression of HER2 (ERBB2) and breast cancer
What is the mechanism of action for RET?
point mutations in this growth factor receptor with tyrosine kinase activity leads to multiple endocrine neoplasia
What is the mechanism of inactivation for tumor suppressor genes?
loss of function mutations; unless there is an inherited mutation, there has be 2 mutations (hits) for inactivation and formation of neoplasms
What is the mechanism of action for the oncogene cyclin D1?
- Final protein responsible for taking cell from G1 to G0
- over-expression in mantle cell lymphoma
Which disorder led to Knudson's development of the 2 hit hypothesis?
- Retinoblastoma; the inactivation of RB1 tumor suppressor gene at both alleles is required for development of tumor (intra-ocular)
- Copy can be deleted; loss and reduplication of bad chromosome; mitotic recombination and methylation of promoter; Normal Rb can be phosphorylated by activated cyclin/CDK complexes
- Normally, the protein product sequesters E2F factor, thereby inhibiting the cell cycle; free E2F causes G1-S phase transition
What is the mechanism of action of the tumor suppressor p53?
- Accumulation of p53 leads to cell cycle arrest at the G1/S phase checkpoint and the activation of genes involved in DNA repair
- Inactivatio ncan be caused by mutations on the p53 gene and abnormal regulation of the protein's activity
- Most common genetic defect in human neoplasms (important factor in decided whether cell is salvageable or not)
What is the mechanism of action of the tumor suppressor beta-catenin/APC?
- Normal APC binds and inhibits beta catenin and thus prevents the activation of transcription factors by beta catenin
- Abnormalitites result in FAP (familial adenomatous polylposis) and sporadic colon cancer
- Constitutive activation of beta catenin and transcription factors
What are some molecular causes of LOH (loss of heterozygosity)?
- REfers tot eh disruption of the last normally functioning gene in a cell
- Multiple causes from genetic to environmental; causes don't have to be the same, just have to both cause a loss of function
At the molecular level, what is the difference between sporadic and heritable cancers?
Sporadic cancers come from spontaneous mutations, while heritable cancers come from having at least one preexisting mutation (makes it much more likely that you will get disease and earlier age of onset)
What are some common characteristics fo inherited cancer syndromes?
- Multiple affected relatives
- Early age of cancer onset
- Bilaterally affected organs
- Multiple primary cancers in the same individual
- Autosomal dominant inheritance pattern
Why are many familial cancer syndromes inherited in a dominant fashion, though they involve recessive tumor suppressor genes?
- If you already have an abnormal copy of the gene in every cell in your body, it only takes one genetic mistake in any cell to develop cancer (with sporadic you would need to mess up 2 alleles in the same cell, less likely)
- This leads to dominant inheritance of symptoms in a recessive gene (though gene is recessive, you will most probably develop symptoms)
How can external exposures (carcinogen) cause cancer?
- A carcinogen is anything that increases the incidence of cancer
- Exposure to these external stimuli can either directly cause DNA damage, or can be modified by the body to create compounds that cause DNA damage; can also interact with epigenetic control factors that cause faulty DNA expression and eventually lead to neoplasm
What ar the three stages of carcinogenesis?
- Initiation (irreversible genetic change in phenotypically normal cells)
- Promotion (reversible phenotypic change with clear threshold to clonal expansion); if carcinogen is removed here, tumor will not progress
- Progression (genotypic and phenotypic changes that are irreversible; huge genetic changes; genomic instability; selection for malignant phenotype)
What is the mechanism for genotypic carcinogenesis?
directly affects the sequence of DNA and changes the composition of a gene; this mutation affects cell cycle processes that lead to uncontrollable proliferation
What role do hormones play in carcinogenesis?
- cause increased tumor growth and proliferation of cells; at higher levels they can be detrimental to DNA machinery such that mutations are more likely to occur
- abnormal hormonal stimulation-->excessive proliferation-->accumulation of DNA errors-->more proliferation-->cancer!
What role do infectious agents play in carcinogenesis?
- H pylori: (bacteria) causes constant proliferation of the gastric lining; leads to accumulation of DNA errors and increased risk for carcinogenesis
- Chronic inflammation from bacterial infection can lead to cancer through reactive oxygen and nitrogen species
- Viruses: (Hep B/c and HPV) viral promoters can be reverse transcripted into the human genome and activate c-onc genes, leading to inappropriate expression of growth factors; the viral genome may also contain v-onc which can be reverse transcripted into the human genome to introduce altered growth control
- Parasites: plasmodium (malaria) and lymphoma
Do individuals vary in susceptibility to carcinogens?
- depends on sex, biochemisry of individual, exposure levels, environment, etc
- Environmental, physiological, and genetic factors work together to determine risk of cancer
How can you know if something is a carcinogen?
- Methods for detecting include clinical observation, epidemiologic studies, experimental animal studies, mutagenesis assays, and assays for DNA binding and damage
- IARC classification scheme for carcinogenic risk ranges from 1 (carcinogen) to 4 (probably not carcinogenic)
study of heritable changes in genome function that occur without alterations to the DNA sequence
process by which one of the X chromosomes is inactivated in females by way of the Xist gene on the X inactivation center (XIC)
- Certain genes are expressed in a parent-of-origin specific manner
- Epigenetic process that involves methylation and histone modifications in order to achieve monoallelic gene expression without altering the DNA sequence
- Epigenetic markers are established in the germline and maintained in every somatic cell of the body
Beckwith-Wiedman syndrome is caused by what?
- paternal UPD; the loss of the maternal chromosome leads to loss of imprinting and regulation at specific sites on chromosome 11
- Not activated until after passing through the female line (50% chance passing on incorrectly imprinted gene to kids)
Definition: Epigenetic therapy
- Stem cells: developmental reprogramming of somatic nucleus
- Cancer therapies
How do epigenetic modifications relate to gene expression and genetic diseases?
Modifications to the gene are important in terms of timing of replication and expression of DNA; if this is out of order, vast changes in gene expression can be made; these may lead to cancer or other disease (overexpression or lack of expression)
What are the mechanisms of normal epigenetic changes?
- DNA methylation on cytosine residues
- Histone modification (acetylation, replacement/substitution)
- Non-coding RNAs (miRNAs are produced from introns and affect transcription and translation)
- Chromatin remodeling (hetero and euchromatin, ATP dependent, huge complex changes)
How does DNA methylation on cytosine residues occur?
- 1% of all bases in genome are methylated; happens on the 5' carbon of cytosine; most frequently at 5'-CpG-3' sites (underrepresented in genome, found primarily in promoters of DNA, inherited)
- Parental strands are demethylated prior to replication
- DNMT1 is maintenance methylase; methylates daughter strand opposite site in parent strand; faithful methylation
- DNMT3A/B are responsible for de novo methylation
Distinguish heterochromatin from euchromatin
- Hetero: tightly packed; repetitive; gene poor; H3-K9 methylation; high CpG methylation
- Euchromatin: dispersed; gene-rich; H3-K4 methylation; low CpG methylation; irregular nucleosomes
How does acetylation (histone modification) affect gene expression?
- Modification of lysine residues in histones (reduces the positive charge and weakens nucleosome interactions with DNA; thereby making DNA more accessible to RNAPII)
- Enzymes that acetylate are recruited to genes that need to be activated
- Enzymes that deacetylate are recruited to methylated DNA
- In short, acetylation allows gene expression
How does methylation affect gene expression?
- transcriptional activation of repression, constitutive heterochromatin, chromosome segregation during mitosis, DNA repair
- One type is associated with cancer
- In short, methylation inhibits gene expression
How does phosphorylation affect gene expression?
- Transcription, chromosome condensation, and DNA repair
- Phosphorylating the p53 tumor suppressor gene allows it to be activated and thus, cell cycle arrest
How do ubiquitin and sumoylation affect gene expression?
- Both ubiquitylation and deubiquitylation are required for gene activation
- Sumoylation addes a ubiquitin-like component and alters gene expression in the same way
How does ADP ribosylation affect gene expression?
It's a quick and transient way to decondense chromatin
How does glycosylation affect gene expression?
How is DNA methylation at CpG islands related to gene transcription and cancer?
- It represses gene transcription in 2 ways: interference with binding of TFs to DNA or recruitments of methyl-CpG binding proteins
- Gene is effectively silenced
- If tumor suppressor or DNA repair genes are silenced, you can develop cancer
What is the mechanism of x-inactivation in females?
- Initiated at a single site (XIC); on this site there is a gene for XIST non-coding RNA; XIST acts in cis to recruit factors to silence inactive X chromosome; chromosome alterations; histones under-acetylated, DNA heavily methylated on cytosines of CpG islands
- ICE is the chromatin boundary element that binds CTCF in unmethylated state
How is the x chromosome that will be inactivated chosen, and why is the other chromosome not inactivated?
- In sperm and oocytes, XIST is not expressed and X is active
- During the 2-4 cell stage, paternal X is inactivated, then XIST is downregulated and X is reactivated
- As the epiblast cells differentiate, either of the 2 is inactivated (random)
- Expresion of XIST on active X is bolocked by antisense RNA (TSIX); if the chromosome expresses TSIX, it will be activated
Definition: Genomic imprinting
- Mechanism of gene regulation through which the activity of a gene is reversibly modified depending on the sex of the parent that transmits it
- 131 genes currently identified; heritable; occur in clusters and usually have non-coding RNAs and antisense transcripts
- Challenges the idea that 2 working copies are associated with normal functioning
What is the mechanism of genomic imprinting?
- During meiosis, imprinting (methylation) is removed from both parents DNA
- For a specific gene, only the maternal chromosomes will be imprinted and the paternal will not; for another gene, only the paternal may be imprinted and the maternal will not
- Result is that the offspring have identical genes, but the expression from those genes is different
- Can also result in tissue specific variations
What is the function of ICE?
- ICE is a chromatin boundary element
- Silences down-stream enhancers (inhibits them) when unmethylated. When CTCF binds ICE, it shuts off this ability to inhibit and the downstream genes are NOT imprinted. If CTCF does not bing ICE, then downstream genes are inhibited
How does Beckwith-Wiedman Syndrome relate to imprinting?
- On chromosome 11, the Igf2 is upstream of the ICE, while H19 is downstream.
- In the maternal allele, ICE is bound by CTCF, so H19 is expressed while Igf2 is repressed.
- In the paternal allele, ICE is not bound by CTCF, so downstream genes are inhibited. Consequently, H19 is repressed while Igf2 is expressed.
- Deletion of the maternal allele and pUPD resulting in excess Igf2
- Igf2 promotes embryonic growth (overgrowth) while H19 is a tumor suppressor (high risk for tumor development)
What is fundamentally wrong with the clonal genetic model of cancer?
It doesn't allow for epigenetic effects
How do pathogens differ from the host and how can this help achieve selectivity?
- Unique target present in pathogen (absent in host)
- Target structurally different in pathogen and host
- Target more essential in pathogen than host
- The selectivity of the agent is a consequence of the uniqueness of the target, the specificty of the drug for that target, and the dose of active drug delivered
- Possible to target purine, pyrimidine, ribonucleotides, deoxynucleotides, DNA, RNA, or proteins and enzymes
What is the role of the cell cycle in susceptibility to cancer chemotherapy?
Cancerous cells go through the cell cycle more often than do host cells. Metaphase is the time when the DNA is most vulnerable (because it is open and less time to fix mutations); cancer cells are in this phase more often
What is the mechanism of action of alkylating agents?
- Cross bind biological molecules (DNA) thereby blocking access
- CCNS with DNA target
- Methchloamine, cyclophosphamide, and cis-platin
What is the mechanism of action of antibmetabolites?
- Analog (purine, pyrimidine, folate) of normal component of target cell; enters metabolic pathway and shuts it down
- MTX, 5-FU, the 6s
What is the mechanism of action of plant alkaloids?
- Inhibit microtubule polymerization
- Vinca Alkaloids, Taxanes, and Podophylloctoxins/Camptothecins (topoisomerase inhibitors)
What is the mechanism of action of antitumor antibiotics?
- Intercalate into DNA (non-covalent) and block access to DNA (also cause DS breaks)
- Anthracyclins (rubies) and bleomycin
What is the mechanism of action of Hormone Inhibitors?
- Shut down cancerous cells that depend on hormones to grow
- Corticosteroids, Aromatase inhibitors, SERMS, and Flutamide
What is the mechanism of action for biologic antineoplastics?
- Interferon jacks up immune function (cytokine produced by WBCs) and Trastuzumab is an antibody gainst HER2 and EGF receptors
What is the mechanism of action of signal transduction inhibitors?
- tyrosine kinase inhibitors
- Imatinib, Gefitinib, Sunitinib, Temsirolimus, Erlotinib, Cetuximab, Bevatuzumab, and Sorafenib
How do cells become resistant to alkylating agents and antimetabolites?
- Alkylating agents: impermeable to drug, drug pumped out, alternate targets for drug, increased DNA repair, no apoptosis (mutant p53)
- Antimetabolites: Decreased drug accumultation, increased clearance (upregulation of CYP2D6)
At what levels can you intervene when treating a patient with a genetic condition?
- Mutant gene
- Mutant mRNA
- Mutant Protein
- Clinical phenotype (symptoms)
- Family (genetic counseling)
What 2 ways can you treat a mutant protein?
- Administer cofactor to increase function of protein
- Protein replacement
- This is treatin without getting to the root of the cause
How do compensatory and salvage therapy differ from one another?
- Compensatory: drug either removes substrate so it won't be improperly converted or actively inhibits conversion
- Salavge: drug fixes misfolded protein to increase catalytic activity
What are 2 ways of modifying the somatic genotype?
- By transplant
- By DNA transfer (i.e. p53 in non-small cell lung cancer or BRCA1 in ovary cancer)
What is the goal of gene therapy?
- To manage and correct disease by replacing abnormal genes with normal ones
- Really trying to fix the problem
What is the mechanism of gene therapy?
- Take a regulator region (enhancer or promoter) and cDNA (protein coding sequence) and insert them into a plasmid or vector
- You can either transfer these directly into patient's cells or put it in culture first; important to have the right amount of expression of protein in the cell
What are the 3 categories of somatic cell gene therapy?
- Ex vivo: cells removed from body, incubated with vector and gene, returned to body; best with blood cells; i.e. sickle cell anemia
- In situ: vector placed directly into affected tissues; i.e. injection of tumor mass with vector carrying gene for cytokine or toxin and injection of dystrophin gene into muscle of MD patients and injection of adenoviral into trachea and bronchi of CF patients
- In vivo: vector injected directly into blood stream (just a theory, no clinical examples)
What are the ideal vector characteristics?
target limited to single cell type, no immune response, stable and not mutated, easy to produce high concentration
What are the different types of vectors utilized and their respective (dis)advantages?
- RNA viruses (retroviruses): randomly integrate into genome, wide host range, long-term expression; but, small capacity to carry therapeutic genes, limited to infecting dividing cells, not very safe
- DNA viruses: high efficieny of transduction, high gene expression, increased capacity for exogenous DNA; but expression may be transient, no cell-specific targeting, not very safe
- Non-viral vectors: (i.e. liposomes, naked DNA, and liposome-polycation complexes) may overcome limitations of viral; higher capacity for therapeutic DNA, cell specific targeting, safe; but, not proven to work yet
Describe the antisense approach to gene therapy
- turning off genes and modifying gene products; a manipulation of the genome, but not of the DNA; can prevent expression of RNA complement or result in RNA splicing
- Used to turn Duchenne's into less severe Becker's
What is the mechanism of action for oncolytic virus gene therapy?
- Virus targets cancer cells but not normal ones; increased ability to replicate; cancerous cell swells and lyses
- Currently in clinical trials
What does the term mixed chimerism mean in reference to gene therapy?
- Means the ablasion wasn't high enough; the patient's marrow comes back and mixes with the donor's
- With hemoglobopathies, you only need 20% of donor's marrow to prevent this problem because the turnover rate of sickle cells is so much higher
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