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MCB2 Block 1 (Chromosomal instability syndromes (Xeroderma pigmentosum…
MCB2 Block 1
Chromosomal instability syndromes
These are autosomal recessive and both hits inherited
Not hereditary cancers
Xeroderma pigmentosum
Defect in NER (nucleotide excision repair)
Bloom syndrome
BLM = DNA helices
Ataxia telangiectasia
Mutation in ATM
Werner syndrome
Mutation in WRN = DNA helices and exonuclease
Fanconi anemia
DNA repair defect
Transformation by viruses
EBV --> Burkitts lymphoma (found in the jaw)
2 ways of transformation
Induction of expression
Activation / Disruption
HPV --> Cervical Cancer
Viral oncogene E6 --> inactivates P53
Viral Oncogene E7 --> inactivates Rb
Hepatitis B & C
Chronic inflammation --> extensive cell division in liver -->
Liver cancer
Oncogenes
Gain of function mutation in
RET
Multiple endocrine neoplasia type 2 (MEN2)
Autosomal Dominant Familial Cancer Syndrome
Constituitive activation of
R
eceptor
T
yrosine
K
inase
Gain of function mutation in
MET (HGFR)
MET constituitively activated
Hereditary papillary renal carcinoma
ABL
This guy involved in CML is a
non receptor tyrosine kinase
so he is
cytoplasmic
WNT
Binds frizzled
Dishevelled activated
Dishevelled binds to GSK3-beta/axin/APC complex inhibiting it
Beta catenin translocates to the nucleus
Myc activated
Cyclin D transcribed
CDK4 recruited
1 more item...
Sporadic cancers
Sporadic Breast Cancer
BRCA1 & BRCA 2
NOT
frequently mutated in this
Sporadic Colorectal cancer
APC mutation seen in FAP
Loss of mismatch repair genes MLH1 and MSH2 in HNPCC
Loss of TGF-beta receptor in HNPCC
SMAD4 loss in pancreatic cancer
Pediatric kidney cancer
loss of WT-1
Chromosomal Rearrangements
Translocation events leading to creation of fusion chimeric gene
t(9:22)
Philadelphia chromosome =
ABL:BCR
fusion protein produced
CML is disorder produced
Imatinib
(Gleevec) blocks fusion protein
t(15:17)
PML - RAR
alpha fusion protein produced
AML M3 (Acute Promyelocytic Leukaemia) is disorder
INTERESTING DISORDER WHY
t(11:22)
EWS-FLI1
(TF) fusion protein produced
Ewing Sarcoma is disorder produced
Translocations leading to overexpression of protooncogenes
t(8:14)
Myc
(TF) translocated next to Ig heavy chain promoter
Burkitt lymphoma is disorder
t(14:18)
Bcl-2
(anti apoptotic) placed under control of strong Ig promoter
Follicular lymphoma is disorder produced
Chemical Carcinogenesis
3 stage model
Initiation
Promotion
Progression
Can act directly or indirectly
Direct --> electrophilic compounds react with DNA
Indirect --> compound metabolized before reacting with DNA (CYP450 oxidase)
Aflatoxin --> epoxide
Benzo-a-pyrene --> BPDE
Mechanisms of Oncogenesis
Protooncogene activation --> Oncogene
1 gain of function mutation
Gene amplification
Over expression of the wildtype
Neuroblastoma due to overexpression of oncogene
N-myc
Double minutes - Prognostic factor
Chromosome Rearrangement
Over expression of the wildtype as seen in burkitts lymphoma
Fusion protein created as seen in CML
Regulatory mutation
Over expression of the wildtype
Deletion / Point Mutation
Mutated protein in normal amounts
Loss of tumor suppressor
2 loss of function mutations needed
Gatekeepers
Control cell cycle
Nf1
(Ras-GAP)
p53
Rb
Caretakers
DNA Repair
BRCA2
Mismatch repair genes
BRCA1
Inherited Cancers
Loss of Heterozygosity
Deletion
Recombination
Non-disjunction
Hypermethylation
Bilateral
Autosomal Dominant
Syndromes
Neurofibromatosis type 1
Mutation in
Nf1
Cafe au lait spots and lisch nodules seen
Hereditary breast cancer
Mutation seen in
BRCA1 & BRCA2
Also linked to ovarian and prostate cancer
Li-fraumenti
Inherited
p53
mutation
Damaged cells survive and proliferate
Many different cancers in relatives
Familial polyposis coli (FAP)
Mutation in
APC
Uninhibited transcription of myc by beta catenin --> massive cell proliferation
Retinoblastoma
Inherited
RB1
mutation
Cell proliferation uninhibited
Hereditary nonpolyposis colon carcinoma (HNPCC)
Repeat instability mutation seen in
DNA mismatch repair enzymes (MLH1
, 3, MSH2, 6, PMS1, 2)
Mutation can also occur in TGF-beta 2 receptor
Sporadic Cancers
Unilateral
MiRNA
Over expresson or under expression of genes due to miRNA function
miR21
overexpressed
Glioblastoma
Apoptosis
Stopping apoptosis
Growth factor binds to growth factor receptor
Receptors dimerize and cross autophosphorylate
PI3-kinase activated
PIP2 converted to PIP3
PIP3 activates Akt
Act activates Bcl-2 (oncogene)
Bcl-2 inhibits the release of cytochrome c from the mitochondria
Killing the cell
PTEN converts PIP3 back to PIP2
Act turns off and Bcl -2 turned off
Cytochrome c released from the mitochondria
Caspases activated
Cell dies
TGF-Beta 2 inhibitory pathway
TGF binds TGF - beta receptor
Receptors dimerize
Receptors cross autophosphorylate
Smad 2/3 activated through phosphorylation
Smad 4 recruited
Smad complex translocates to the nucleus
p15 and p16 transcribed
Cell cycle arrests
Loss of SMAD 4 seen in
pancreatic cancer
Loss of TGF-beta receptor
seen in HNPCC