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66 Cards in this Set
- Front
- Back
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tumor |
abnormal mass of tissue that results from excessive cell division or reduced cell death. |
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benign |
no invasion to nearby tissue or spreading to other parts of body |
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malignant |
tendency to invade and destroy nearby tissue and/or spread to other parts of the body to form metastases |
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in mammals what is cancer/tumors largely caused by _____ and sometimes by _______ |
somatic mutations, epigenetic changes |
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what do tumor cells lack normal restraints on? |
increased: cell growth, cell division decreased: cell death |
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which part of cell cycle is there only one copy of the genome present? |
G1 |
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what occurs in S phase? |
chromosomes duplicated |
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What occurs in G2 phase? |
rapid cell growth, ready to undergo mitosis |
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What are the cell cycle checkpoints? What is being checked? |
1. G1/S: is the environment favourable? 2.G2/M: is all DNA replicated? is the environment favourable? 3. Metaphase/ Anaphase: are all chromosomes attached to the spindle? |
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what kind of "environment" is the cell looking for to replicate? |
-determine if there is enough resources to undergo DNA replication -enough space in multicellular organism -signals like mitogens/hormones that indicate now is a good time to replicate |
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Why is there a lag phase between exposure to carcinogen and tumor development? |
accumulation of many mutations across many cell divisions is necessary for a tumor to form |
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tumor progresssion |
1.normal tissue 2.mild disorder 3.benign tumor 4. malignant cancer |
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List the types of genetic alterations that can lead to cancer |
1. Genetic gene inactivation 2. Epigenetic gene inactivation -Histone modifications -methylation |
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genetic gene inactivation |
coding region acquires mutation that renders gene functionless and all daughter cells after division will have the same gene inactivated |
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epigenetic gene inactivation: histone modifications |
doesn't change the sequence itself but instead how it is packaged
histones form backbone of chromatin and can cause it to form heterochromatin which is tightly packed and not accessible |
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epigenetic gene inactivation: methylation |
doesn't change the sequence itself but instead how it is packaged
Methylation of DNA makes it into tightly packed and inaccessible heterochromatin |
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How does genetic instability begin and how is it continued? |
Caused by mutations in genes involved in DNA repair, damage response, and epigenetic control
Increases the mutation rates of cells because of not functioning properly due to initial mutation (ex. mutation in DNA repair, can't be fixed properly, so more mutations) |
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What do subsequent mutations cause the cell to do (list) |
-become insensitive to external signals -keep activating cell division in absence of growth factors -induce help from normal tissues -become invasive |
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what external signals do cells become insensitive to? |
-anti-proliferating factors -apoptosis inducing factors -factors inducing differentiation -factors that prevent proliferation without adhesion |
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how do cancerous cells induce help from normal tissues? |
- support stroma cells that give structure and form matrix of tumor by producing growth factors and remodel extracellular matrix
- induction of angiogenesis to bring nutrients and sugars to rest of tumor |
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gain-of-function mutations in cancer critical genes create |
oncogenes
(dominant, overexpressed) |
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loss-of-functions in cancer critical genes create |
tumor suppressor genes
(recessive, underactive/missing) |
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what can lead to loss of regulation on protein level? |
post-translational modifications from mutations in coding regions |
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what can lead to mis-regulated expression (overexpression)? |
-mutation in promoter/enhancer -gene amplification -chromosomal rearrangement |
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Oncogenes vectored by retroviruses: Rous Sarcoma Virus (RSV) |
-RSV carries a tyrosine kinase v-Src in addition to Gag (capsids) Pol (RT, integration), and Env (envelope) that is responsible for cancer -similar gene c-Src occurs in host and is involved in cellular signalling -virus by chance integrates at beginning of c-Src, and mutates it so it becomes unregulated and hyperactive |
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what kind of mutation renders the protein non-functional? |
loss-of-function mutation in coding region (nonsense, indels) |
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What can lead to no expression of the gene altogether? |
Loss-of function mutation - in promoter - in enhancer - epigenetic silencing |
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What can make the gene no longer be present? |
loss of function deletion mutation |
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how can the second allele now be eliminated once the first one has? |
- epigenetic silencing - nondisjunction - chromosome loss then duplication of remaining one - mitotic recombination - gene conversion - deletion -point mutation |
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how do rare cases of hereditary forms of cancer occur? Example of one? |
mutation in the germ line
Retinoblastoma (Rb) |
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General inactivation mechanism in HEREDITARY Rb -how common? how many tumors? |
1. start off with only one good copy, inherited random inactivation of one from parent 2. random inactivation again, this time on only good Rb copy 3. excessive cell proliferation-->retinoblastoma
most people have many tumors in both eyes
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General inactivation mechanism in NON-HEREDITARY Rb -how common? how many tumors? |
1. occasional cell inactivates one of the good Rb genes 2. second copy randomly inactivated 3.excessive cell proliferation-->retinoblastoma
very rare, only one tumor in one eye |
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What is E2F? |
family of transcription factors involved in activation of transcription of S-phase related genes like -DNA polymerase -Replication origin binding proteins -nucleotide biosynthetic genes -cell cycle regulators |
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Rb blocks the cells from _______ by suppressing ______ through _____ |
entering S phase
E2F
binding |
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how does Rb inactivation affect E2F activity? (whole mechanism) |
1. external signal (mitogen) binds and activates a signalling cascade 2. S-Cdks activated and phosphorylate Rb 3. Rb can't bind E2F 4. E2F activates transcription of S-phase genes 5. cell enters S phase |
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which oncogene when overactive can cause cancer by itself? What does it control? |
Ras, a GTP binding protein
controls entry into S phase |
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what does Ras encode? |
a small protein with GTP-ase activity |
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how is Ras activated? Deactivated? |
activation stimulated by GEF (becomes GTP-bound)
deactivation stimulated by GAP (GDP-bound) |
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once activated, what does Ras do? |
acts on MAP kinases which act on each other (phosphorylate to activate) to induce a kinase cascade
MAP kinase-->MAP kinase kinase--> MAP kinase kinase kinase |
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what mutation would cause Ras to stay on always, contributing to cancer development? what usually l does this? |
lack of ability to hyrdrolyze GTP
generally done by protein phosphatases |
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the S-phase activating pathway |
1. mitogen binds to cell surface receptor to activate a GEF 2. activated Ras initiates a MAPK cascade 3. activated MAPK phosphorylates transcription factor 4. TF myc expressed and activates transcription of delayed response genes like G1 and S cyclins 5. cyclin binds to CdK 6. S1-CdK phosphorylates Rb |
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what happens when MYC is mutated in its promoter? |
constitutively expressed and downstream cascade is activated |
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why must both copies of Rb be mutated/not present for it to lose function? |
Rb is a negative regulator |
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What transcription factor is not essential for development and seems to be dedicated to only being a tumor suppressant? |
p53 |
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what are homozygous null mutants of p53 like? Exceptions? |
null mutants appear normal except those who develop cancer early in life (before 10 months of age) |
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p53 amounts ____________ in response to stress |
increase |
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what are some consequences to p53 activation? |
-induction of apoptosis if cells are very strong -enhance cell aging (senescence) -cell cycle arrest when signals aren't too strong and there is still a chance for repair |
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what do mutations in p53's DNA binding domain result in? |
prevents p53 from binding to its target cis-reg elements even though p53 itself is still there |
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What activates p53? |
1. DNA double strand break triggers signal transduction cascade of kinase phosphorylation
2.p53 eventually phosphorylated and activated itself |
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what is the role of Mdm2? |
binds non-phosphorylated p53 and targets it for breakdown |
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how much p53 is present in a normal cell usually? |
Very little, because even though it's made a lot it is also broken down a lot |
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What prevents interaction between p53 and Mdm2? What is the result of this? |
phosphorylation of p53
accumulates to a higher level than is stable in the cell and activates/represses all its target genes |
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what is one of the target genes of p53? what does it target itself? |
activates p21
which targets and binds G1/S-Cdk
prevents the Cdk from phosphorylating and inactivating Rb
so S phase gene expression isn't activated |
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Cancer whole genome sequencing: why do we compare tumor cell samples to both normal cells and reference genome? |
Reads are very short on normal sample so hard to assemble completely
mapping a read to high quality reference genome makes it easy to read and map to detect a one base difference |
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what is a SNV? |
a single nucleotide variant, namely between a tumor and normal sample |
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what kind of copy number alterations are possible between a tumor cell and a reference genome? |
- homozygous deletion: region of reference genome with no reads mapped (usually at least 20-30) - hemizygous deletion: half has been deleted - duplication: double the number of usual reads from an amplification or duplication |
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what kind of differences between reference genomes and tumor genomes are focused on when determining causes of cancer?why? Why not the others? |
point mutations and indels because they are the easiest to detect
the others require a statistical approach to determine expected amounts which is more complicated |
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why choose a cytogenetically normal cells for cancer cell sequencing? What constitutes as one? |
chosen because it makes it much easier to compare to reference genome
no large scale translocations based on karyogram or obvious duplications/deletions |
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How was it determined if a change in nucleotide was a real SNP? What does this mean? |
high quality reads, differences both in tumor and normal skin cell
probably does not contribute to the cancer if present in both |
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why did they not analyze non-genic regions of the genome? |
could still contribute to cancer but a smaller chance, easier to figure out contributions in genic region |
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why were introns and UTR sites not analyzed? |
don't affect coded regions and are not on splice sites |
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why were synonymous changes discarded? |
wouldn't change the function of the gene and thus wouldn't contribute to cancer development |
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how were candidate SNVs validated? What were discarded after this? |
PCR and sanger sequencing
germline and false positive wild type genes that were missed by illumina sequencing |
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What genes were determined to contribute, not previously known as cancer-critical genes? |
8 new mutated proteins with functions in signalling and transport |
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what were the functions in signalling in the 8 new cancer genes |
G-protein coupled receptor
protein phosphatase
nucleotide exchange factor
(signal transduction components based on their sequence) |
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what were the functions in transport in the 8 new cancer genes |
peptide/drug transporter
cadherin family protein (signalling, vesicle transport) |
