Molecular Basis of Carcinogens Flashcards
What are 5 properties of malignant cancer cells?
- Unresponsive to proliferation control signals
- DE-Differentiated: do not have specialized structures /function of tissue where they are growing
- Invasive: can grow into neighboring healthy tissue, extending the boundaries of the tumor
4; Malignant: can shed cells that travel through circulatory system and proliferate at other sites - Clonal in origin: all cells from same single cell origin
- Resistance to apoptosis
- limitless replication potential
What is the multistep process for carcinogenesis?
cancer is the result of the accumulation of somatic mutations produced by environmental factors
Important steps are: Tumor initiation promotion conversion progression
What is the relative importance of heredity in carcinogenesis? The environment?
Heredity:
- susceptibility to cancer is heritable
- cancer is caused by changes in cellular heredity
- Cancer is not inherited as a single gene (mendelian inheritance)
Environment:
- mutagenic events early in life can be associated with cancer later
What types of early mutations are associated with later cancer?
UV light exposure
mutations to DNA repair genes
How do mutations in DNA repair genes cause later cancers?
increases rate of future mutations
Ex: p53, BRCA1, BRCA2
What 2 types of genes are usually mutated in tumor initiation?
- Oncogenes: encourage cell proliferation -> activated
2. Anti-oncogenes: inhibit cell proliferation -> inactivated
What are at least 2 cytogenetic abnormalities associated with malignancy?
- translocations/ deletions
ex: CML- Philadelphia chromosome - Loss of heterozygocity (LOH)
ex: retinoblastoma - Aneuploidy
What events can lead to a loss of heterozygocity?
Classic 2 Hit hypothesis of tumorgenesis (Kundson)
1st hit: pont mutation in activating tumor supressor gene
2nd hit: deletion resulting in loss of WT copy
Both are necessary because 1 good copy is enough for normal function
What are some dominantly inherited susceptibilities to cancer?
familial Adenomatous Poluposis Familial retinoblastoma Familial breast and ovarian cancer Wilms tumor syndromw von hippel lindau
What are some recessively inherited susceptibilities to cancer?
xeroderma pigmentosa
ataxia-telegiectasia
bloom’s syndrome
fanconi’s congenital aplastic anemia
How was the retinoblastoma gene identified?
many tumors had abnormal structure on chromosome 13 near q14 -> some completely deleted, some partial deletions, some rearrangements
-> in most patients, heterozygosity for Rb gene
=> tumor descends from single cell that has become homozygous for susceptibility gene
What are 3 functions of the normal Rb protein?
- Prevent excessive cell growth by inhibiting cell cycle
- recruits chromatin remodeling enzymes
- Has a “pocket” for function binding of other proteins -> can be targeted by pathologies like HPV and become inactivated
How doe Rb function during the cell cycle
inhibits cell proliferation -> anti oncogene
- hypophosphorylation of Rb protein prevents cells from entering S phase
- if Rb protein hyperphosphorylated -> cell proceeds to S
What happens during the cell cycle if Rb is lost/ nonfunctional?
Cells cannot down regulate their division and growth is out of control
What is a hallmark of tumor suppressor genes?
protects a cell from one step on the path to cancer
ex) Rb prevents cell from entering s phase
their loss may be more important than oncoactivation in many cancers
What is the normal function of the APC gene?
tumor suppressor of FAP - familial Adenomatous Polyposis
on chromosome 5q
Encodes cytoplasmic protein that regulates location of beta-catenin (keeps it at the plasma membrane)
APC protein also degrades free beta catenin in cytoplasm
What happen if APC gene is lost?
Beta catenin enters nucleus and produces transcription of oncogenes like c-myc
What types of genes are BRCA1 and BRCA2?
tumor suppressor genes - “checkpoints”
What type of gene is p53?
tumor suppressor gene - “guardian of the genome”
Why was p53 originally thought to be an oncogene?
certian p53 mutations are dominant to the WT allele
- they bind the WT and inactivate it
- dominant negative “spoiler”
Why is p53 considered the “guardian of the genome”
- prevents cell from replicating damaged DNA
- required for apoptosis
What is the name for specific mutations that are frequently found in human cancers?
hotspots
Give 1 example of a virus that is oncogenic
HPV: inactivates p53
How were oncogenes discovered?
through their identification in retroviruses which have the ability to insert new genetic info into host genome (and produce malignancy if they contain v-onc)
What are some of the functions of viral oncogenes?
- affect gene expression (kinase that phosphorylates tyrosine)
- Growth stimulation (miic EGFR)
- de-regulate growth signals to allow unregulaed prolifeation
What are at least 4 examples of oncogenes with known function?
v-src: rous sarcoma- fibrosarcoma in birds
v-erb: avian erythroblasosis- in chickens
v-abl: abelson leukemia from mice
v-myc: neoplastic transformation of cells
- c-ras - transforms normal cells when introduced via DNA transfomation - bladder cancer
- N-myc (c-myc family) - amplified in neuroblastoma
How does amplification correlate with prognosis?
Higher levels of amplification correlate with poor prognosis
=> quantitative model- too much of a protein leads to malignancy
What is the qualitative model of cancer transformation?
overactive or unregulated protein can lead to malignancy
What combination of activation and suppression can lead to malignancy?
activation of oncogenes
suppression of tumor suppressor genes
How does herceptin work?
specific antibody to protein product of HER2 oncogene -> reverses transformed phenotype of cancer cell
How does gleevac work?
inhibits typrosine kinase in BCR-ABL translocation (philadelphia chromosome)
How is a heat map used in cancer treatment?
changes in gene copy number/ gene expression are correlated with tumor grade
How is a heat map used in breast cancer?
Xpress chip-
123 genes know to be altered in breast cancer
- tx determined based on Rxs known to creat response in specific mutations
