Cancer I & II: Lect 17 and 18 Flashcards
(55 cards)
1
Q
Cancers are of what origin?
A
- manifestation of mutation, usually of somatic origin.
- inherited in a mendelian fashion but may exhibit non-mendelian family clustering (multifactorial causation).
- accumulation of genetic alterations.
2
Q
Tumor progression;
A
- normal > hyperplastic > dysplastic > neoplastic > metastatic.
- result of clonal expansion
3
Q
Malignant transformation:
A
Survival and growth
- self sufficiency
- insensitive to growth inhib signals
- evades apoptosis
- escape immune attack
- limitless replicative potential
Metastasis
- loss of contact inhib
- loss of cell-cell adhesion
- invades other tissues
Incr. mutation rate
-breakdown in DNA repair and genomic stability
Energy supply
-sustained angiogenesis
4
Q
Are cancers derived from a single cell?
A
- yes; monoclonal tumors.
ex: 1. all cells from cancers have same copy of the X inactivated
2. all cells in the tumor contain the abberration.
3. multiple myelomas produce monoclonal Ig.
5
Q
Multiple myeloma
A
- malignancy of B-cell.
- all myeloma cells in a pt produce the same Ab mx. “evidence of monoclonality”
6
Q
Cancer causing genes;
3 types
A
-imbalance of cell birth and cell death.
Oncogenes - stimulate growth.
Supressor genes - inhibit growth
Repair genes - limit mutations
7
Q
Proto-oncogenes
A
- produce proteins which promote cell growth or prevent apoptosis.
- mutation/mis-expression = cell growth
- gain of function mutation
8
Q
Tumor suppressor genes
A
- produce proteins that inhibit the cell cycle preventing proliferation
- loss of function mutation
9
Q
Mutations in DNA repair genes
A
-increase the frequency of mutations in cells.
10
Q
Cellular growth control
A
- GF bind to GF rcp trk = autophosphrylation in cytoplasmic side.
- activation of GTPase proteins which activate TF in the nucleus.
- activate gene exp to drive DNA replication.
11
Q
Oncogenes
A
-mutant or misregulated form of proto-oncogenes.
12
Q
Transmembrane proteins:
Cytoplasmic:
Nuclear:
A
- erbB, neu, fms, ras
- abl
- myc, fos, jun.
13
Q
GF receptors:
G protein/signal transduction:
Intracellular tyrosine kinase:
Transcription factors:
A
- c-erbB
- c-ras
- c-abl
- c-myc, c-fos, c-jun
14
Q
MAP Kinase pathway
A
- cell prolif pathway
- initiated by GF interacting w/ rcp
- triggers activation of kinases = phos. of ser/thr residues.
- activates gene driving cell division.
15
Q
Tyrosine kinase rcp activation
A
- receptor trk binds to ligand sites
- dimerization and phosph. of activation lip tyrosines.
- phos. of additional tyr. residues downstream.
16
Q
What renders a receptor constitutively active?
A
- Point mutations or truncation.
- rcp dimerizes w/o the signal and starts to activate downstream signals.
17
Q
Oncogenically activate a receptor by?
A
- Point mutation: single AA change w/o the presence of a GF. ex: Her2 rcp
- Truncation/deletion: ErbB oncoprotein.
18
Q
Oncogenic activation by translocations;
A
- exchange of genetic material btwn non-homologous chrom “illegitimate recombination”
- Burkitt lymphoma -> activation of myc
- Chronic Myeloid Leukemia -> activation of abl.
19
Q
Burkitt lymphoma
A
- myc oncogene(chrom 8) is fused to Ig locus(chrom 14). (t8:14)
- oncogene expression increases as myc is under regulation of IgH promoter = incr. myc production.
- lymphocyte fail to differentiate
20
Q
Bcr-Abl translocation and Chronic Myeloid Leukemia:
A
- Philadelphia chrom t(9;22)
- abl on chrom9 fuses to bcr region of chrom22 = unregulated cytosolic trk so abl.
21
Q
Gleevec/Imatinib mesylate
A
- powerful trk inhibitor specific for a few TKs including Abl.
- very effective against the BCR/ABL by binding to active site.
22
Q
Point Mutations
A
- activation of the Ras proto-oncogene
- Ras activated by binding GTP; initiates cell proliferation. It is inactivated by GTPase activity (GTP->GDP)
23
Q
Oncogenic activation
A
- depends on Ras hyper-activity.
- Ras-GTP activates growth pathway
- Ras-GDP inactive (no growth)
- mutations inhibiting GTPase activity = Ras becomes constitutively active.
24
Q
Oncogenesis by gene amplification:
A
- Double minutes
- Homogenously staining regions
25
Double minutes
- extrachromosomal fragments of DNA; not assoc. w/ the chrom
- contain an amplified region of chrom
- seen in tumors
- EGFR; often amplified as double minute chrom
- visualized w/ FISH probes
26
HSR
- withing the chrom in cancers often contain amplified oncogenes.
- ex: N-MYC amplification in neuroblastomas
- visualized w/ FISH
27
Mutations in tumor suppressor genes:
- Inherited AD cancer syndromes: recessive at cellular level but w/ loss of second copy.
- Inherited AR cancer syndrome of defective DNA repair: XP, Ataxia telangiectasia, Bloom syndrome, Fanconi anemia.
- Familial cancers: multifactorial cause breast/ovarian/pancreatic cancer.
- role of predisposition not clear for each indiv.
28
Tumor suppressor genes:
APC -
TP53 -
BRCA1/2 -
RB -
WT1 -
MSH1/2, PMS1/2 -
-Familial adenomatous polyposis; bowel carinoma.
- Li-Fraumeni syndrome; soft tissue sarcoma, glioma, leukemia
- Familial breast/ovarian cancer.
- Retinoblastoma; schwannoma, menigioma, ependymoma.
- WAGR (Wilms tumor, aniridia, GU anomalities, growth retardation)
- Hereditary nonpolyposis colon cancer; colorectal carcinoma, endometrial carcinoma
29
Wilms tumor:
- AD inheritance
- loss of function in the WT1 gene on chrom 11; which encodes TF important in the control of cell growth and differentiation.
30
Tumor suppressor genes:
- genes that cause cancer when they are lost "loss of function mutation"
- nl function is to stop cancer
- cell cycle control genes, apoptosis promoting genes, DNA repair genes.
- must loss function of both gene to get cancer = two hits
31
Two-hit hypothesis:
Familial form:
Non-familial (sporadic):
- 1st mutation from inherited from mom/dad and present in every cell.
- 2nd occurs in somatic cell = cancer; loss of tumor sup
- earlier and more severe than sporadic.
- multiple/bilateral tumors.
- not born w/ the mutation
- 1st hit during cell division = no cancer.
- 2nd hit later in life = cancer
- two somatic mutations that result in cancer = loss of all tumor suppressor activity.
32
Loss of Heterozygosity:
- seen in tumor suppressor mutations
- homozygous parent at locus (1 or 2)
- child is heterozygous (1 and 2)
- tumor tissue has a single allele type (2) so loss of allele 1 = LOH
33
Mechanisms producing 2nd hit:
- loss through non-disjunction
- mitotic recombination
- gene deletion
- point mutation
34
Loss of Tumor suppressor gene function:
- result of aberrant methylation = gene still present but silenced.
- mutations in DNA silencing mechanisms can result in tumors.
ex: methylation of Rb (90% penetrance)
35
Rb protein:
w/ cyclin/Cdk and without??
- regulator of G1/S phase transition.
- --cyclin/Cdk present = Rb hyperphos. = Rb no longer represses E2Fs = E2Fs activate S-phase genes = cell divides.
---no cyclin/Cdk = hypophos of Rb = Rb/E2F complex bound to DNA = recruit histone MT and HDAC = no transcription.
36
What happens when Rb is mutated?
- mutant Rb = hyperphos Rb = cell division and no G1 arrest.
- inactivation of Rb is critical in driving G1/S transition.
37
Mutations of one of four genes that regulate the phos. of Rb?
- Rb: inhibitor of E2F
- CDK4: inactivates Rb by phos.
- Cyclin D: inactivates Rb by phos.
- CDKN2A(p16): CDK inhib
38
Retinoblastoma:
Inherited;
Sporadic;
- childhood cancer; AD inheritance but recessive at cellular level
- mutation of Rb gene on chrom 13.
- 30-40% of Rb w/ 90% penetrance. Multiple/bilat tumors and early onset. 1 germline and 1 somatic mutation.
-60-70% of Rb. Single/unilat tumors and later onset. 2 somatic mutations = 2 hits.
39
Loss of Rb/mutant Rb:
- destroys the G1/S chkpt.
| - does NOT bind to E2F -> increased transcription of S phase genes.
40
p53
- tumor sup. that controls both cell birth and cell death
- TF activated by cell stress/DNA damage which impinges on G1/S chkpt.
- mutated in 50% of all cancers.
41
Roles of ATM and ATR in signaling through the G1 chkpt?
-DNA double strand breaks induces ATR and ATM to act on p53 causing G1 arrest or apoptosis.
42
p53 duties?
1. slows cell cycle and allows time to do repairs.
2. increase DNA repair capabilities.
3. too much damage; initiates apoptosis via Bcl-2 fam members.
4. has anti-angiogenic proteins.
43
p53 influences apoptosis by increasing expression of:
1. pro-apoptotic Bcl-2 family members
2. Fas receptor (CD95)
3. IGFBP-3
44
Li-Fraumeni syndrome:
- inherited mutation in p53.
- increases risk of cancer at young age/high penetrance
- results in several kinds of cancer; breast, bone, brain, adrenocortical and soft-tissue carcinomas "affects multiple organs"
- 1st hit from parent
- 2nd hit is somatic (Loss of H)
45
Colorectal cancers:
Familial Adenomatous Polyposis.
- gatekeeper/tumsup protein involved
- AD inheritance
- mutation in the APC gene on chrom5 & allelic heterogeneity
- multiple >100 adenomatous polyps develop in distal colon.
- slow progression
- high penetrance
46
APC pathway: WNT present
-encodes a tumor sup whose role is to down-regulate growth promoting signals.
- When WNT is present, no APC/B-catenin complex; so B-catenin is not degraded.
- B-catenin moves to the nucleus and forms complex w/ TCF-4 = growth promoting genes.
47
APC pathway: WNT absent
- no signal for growth
- APC interacts w/ B-catenin; phos and ubiquinates B-cat
- B-cat is degraded = no complex w/ TCF-4 = no growth.
48
APC mutation?
- mutant APC does not interact w/ B-cat in the absence of WNT signal
- B-cat not phos and degraded
- B-cat interacts w/ TCF-4 = growth in abs of WNT.
49
Hereditary Non-Polyposis Colon Cancer: Lynch syndrome
- caretakers/DNA repair proteins involved.
- mutation of DNA mismatch repair (MMR) genes.
- MSH2 chrom 2; 60% of known mutations
- MLH1 chrom 3, 30-35% of known mutations.
- locus heterogeneity
- tumor exhibits microsatellite instability (short repetitive seq)
- few polyps and progress rapidly
50
Breast/Ovarian Cancer:
- 20% familial hx
- penetrance 85% for breast and 55% (BRCA1) or 25% (BRCA2) for ovarian cancer.
- BRCA1/2 = Locus heterog.
- involved in DNA repair or apoptosis
- loss of BRCA1, cell duplicate w/ DNA damage = cancer
- 100s of mutations in BRCA1 gene = Allelic het.
51
HER2 overexpression in sporadic breast cancer;
- Human epidermal growth factor rcp 2
- 30% of breast cancers have HER2 amplified
- form double minutes chrom
52
Herceptin:
- Ab to HER2
- binds to HER2 and prevents bind of EGF to HER2
- decreases tumor proliferation
- very effective for Her2+; not as effective for Her2- tumors.
53
Epigenetics in tumors and roles?
- tumor sup. loci are frequently hypermethylated in cancer "silenced"
1. silencing of tumor sup = overgrowth
2. loss of imprinting = activation of growth assoc. genes (IGF2)
3. MicroRNAs
54
MicroRNAs in tumors
-miRNAs act to reduce the expression of genes by targeting specific mRNAs.
55
Expression array analysis and cancer
- cancer classification
- in order to determine; rate of prolif, invasion capacity, metastases potential.
- determine changes in expression of large number of genes btwn two groups (tumor vs. non tumor, benign vs. malignant)
