Cancer I & II: Lect 17 and 18 Flashcards
Cancers are of what origin?
- 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.
Tumor progression;
- normal > hyperplastic > dysplastic > neoplastic > metastatic.
- result of clonal expansion
Malignant transformation:
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
Are cancers derived from a single cell?
- 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.
Multiple myeloma
- malignancy of B-cell.
- all myeloma cells in a pt produce the same Ab mx. “evidence of monoclonality”
Cancer causing genes;
3 types
-imbalance of cell birth and cell death.
Oncogenes - stimulate growth.
Supressor genes - inhibit growth
Repair genes - limit mutations
Proto-oncogenes
- produce proteins which promote cell growth or prevent apoptosis.
- mutation/mis-expression = cell growth
- gain of function mutation
Tumor suppressor genes
- produce proteins that inhibit the cell cycle preventing proliferation
- loss of function mutation
Mutations in DNA repair genes
-increase the frequency of mutations in cells.
Cellular growth control
- 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.
Oncogenes
-mutant or misregulated form of proto-oncogenes.
Transmembrane proteins:
Cytoplasmic:
Nuclear:
- erbB, neu, fms, ras
- abl
- myc, fos, jun.
GF receptors:
G protein/signal transduction:
Intracellular tyrosine kinase:
Transcription factors:
- c-erbB
- c-ras
- c-abl
- c-myc, c-fos, c-jun
MAP Kinase pathway
- cell prolif pathway
- initiated by GF interacting w/ rcp
- triggers activation of kinases = phos. of ser/thr residues.
- activates gene driving cell division.
Tyrosine kinase rcp activation
- receptor trk binds to ligand sites
- dimerization and phosph. of activation lip tyrosines.
- phos. of additional tyr. residues downstream.
What renders a receptor constitutively active?
- Point mutations or truncation.
- rcp dimerizes w/o the signal and starts to activate downstream signals.
Oncogenically activate a receptor by?
- Point mutation: single AA change w/o the presence of a GF. ex: Her2 rcp
- Truncation/deletion: ErbB oncoprotein.
Oncogenic activation by translocations;
- exchange of genetic material btwn non-homologous chrom “illegitimate recombination”
- Burkitt lymphoma -> activation of myc
- Chronic Myeloid Leukemia -> activation of abl.
Burkitt lymphoma
- 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
Bcr-Abl translocation and Chronic Myeloid Leukemia:
- Philadelphia chrom t(9;22)
- abl on chrom9 fuses to bcr region of chrom22 = unregulated cytosolic trk so abl.
Gleevec/Imatinib mesylate
- powerful trk inhibitor specific for a few TKs including Abl.
- very effective against the BCR/ABL by binding to active site.
Point Mutations
- activation of the Ras proto-oncogene
- Ras activated by binding GTP; initiates cell proliferation. It is inactivated by GTPase activity (GTP->GDP)
Oncogenic activation
- depends on Ras hyper-activity.
- Ras-GTP activates growth pathway
- Ras-GDP inactive (no growth)
- mutations inhibiting GTPase activity = Ras becomes constitutively active.
Oncogenesis by gene amplification:
- Double minutes
- Homogenously staining regions
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
HSR
- withing the chrom in cancers often contain amplified oncogenes.
- ex: N-MYC amplification in neuroblastomas
- visualized w/ FISH
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.
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
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.
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
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.
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
Mechanisms producing 2nd hit:
- loss through non-disjunction
- mitotic recombination
- gene deletion
- point mutation
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)
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.
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.
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
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.
Loss of Rb/mutant Rb:
- destroys the G1/S chkpt.
- does NOT bind to E2F -> increased transcription of S phase genes.
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.
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.
p53 duties?
- slows cell cycle and allows time to do repairs.
- increase DNA repair capabilities.
- too much damage; initiates apoptosis via Bcl-2 fam members.
- has anti-angiogenic proteins.
p53 influences apoptosis by increasing expression of:
- pro-apoptotic Bcl-2 family members
- Fas receptor (CD95)
- IGFBP-3
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)
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
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.
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.
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.
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
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.
HER2 overexpression in sporadic breast cancer;
- Human epidermal growth factor rcp 2
- 30% of breast cancers have HER2 amplified
- form double minutes chrom
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.
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
MicroRNAs in tumors
-miRNAs act to reduce the expression of genes by targeting specific mRNAs.
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)
