Know Your Molecular Oncology
A Cancer Cell
Biological changes that should happen so a cell becomes cancerous:
- proliferate independently of growth signals
- circumvent programmed cell death
- replicate indefenitely
- induce vascular formation
- invade tissues
Cancer Related Genes!
There are three types of such gene.
- Tumor suppressor genes
- Function = restrain cell proliferation
- Oncogenes
- Oncogene is a gene whose protein produt contributes to the development and or progression of CANCER.
- If activated by mutation or amputation ==> They have transforming properties
- DNA mismatch repair genes
- Encode for proteins that correct errors that normally occur during DNA replication
Tumour suppressor genes
- Prevent the uncontrolled growth of cells that may result in cancerous tumors.
PTCH
- On chromosome 9q
- Protein patched homolog 1
- A member of the patched gene family
- A tumor suppressor gene
- Receptor for sonic hedgehog
- Molecule responsible in the formation of embryonic structures and in tumorigenesis
- Nevoid basal cell carcinoma
- Esophageal SCC
- Bladder TCC
- Gorlin syndrome (with a midline cleft lip)
- Medulloblastoma
p53
- Where the name come from?!
- On some form of electrophoresis it is weighted 53 kilo-daltone
- Chromosome 17p
- codone 72
- Protein 53 or tumor protein 53
- Regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer
- "the guardian of the genome" because of its role in conserving stability by preventing genome mutation
- Anticancer function
- Role genomic stability, and inhibition of angiogenesis
- After DNA damage
- Activate DNA repair proteins
- Induce growth arrest by holding the cell cycle at the G1/S regulation point
- If it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle
- Initiation of apoptosis
- p53 negative regulator is MDM2
- Common in Lung Ca
- NSCLC : 50%
- SCLC : 90%
- Common in Pancreas Ca
RB1
- Retinoblastoma protein
- On chromosome 13
- Active when not phosphorylated; means when phosphorylated is not active
- The active form attachs to a transcription factor name: E2F1
- So active Rb makes E2F inactive ==> no cell division!
- Imagine Rb and E2F like parent and child.
- and imagine phosphorylation like making the parent drunk ( no control on child! )
- The active form attachs to a transcription factor name: E2F1
- Inactive when phosphorylated
- Phosphorylation of Rb is by Cdk (Cyclin dependent kinase)
- Cyclin D and Cdk4
- Cyclin E and Cdk2
- Know one more thing and that's p21
- p21 inhibits the formation of Cyclin D
- ==> Inhibits the phosphorylation of Rb
- ==> Inhibits the release of E2F
- ==> inhibits the cell cycle division
- So all in all p21 is good good for cell cycle control
- p21 become active when there is DNA damage
- So you can imagine this is a great cell cycle protection mechanism
- If there is a DNA damage who wants the cell progress from G1 to S? nobody sure!
- So we want E2F protein not active and not free
- So we need Rb tumor suppressor gene active
- so it can bind to E2F and inactivates E2F
- To keep Rb activated one should inhibit the phosphorylation (you remember phosphorylation inactivates Rb)
- What p21 does is that in detection of DNA damage inhibits Cdk ==> inhibits Rb phosphorylation
- So you can imagine this is a great cell cycle protection mechanism
- p21 inhibits the formation of Cyclin D
- Phosphorylation of Rb is by Cdk (Cyclin dependent kinase)
- Tumor suppressor protein
- So if Rb gene is mutated ==> It does not bind to E2F ==> E2F is constantly released ==> cell pass the restriction G1-S point
- Prevent excessive cell growth <== inhibiting cell cycle progression until a cell is ready to divide
- Dysfunction ( loss of heterogeneity ) ==> Cancer
- Mutated gene is recessive
- pRb prevents the cell from replicating damaged DNA <== preventing its progression along the cell cycle through G1 into S
- Binds and inhibits transcription factors of the E2F family
CDKN2A (p16)
- Cyclin-dependent kinase inhibitor 2A
- Multiple tumor suppressor 1 (MTS-1)
- Tumor suppressor protein
- Encoded by the CDKN2A gene
- Regulating the cell cycle
- Mutations ==> Cancer
- Melanoma
- Common in NSCLC
- Rare in SCLC
- Common in Pancreas Ca
- Mucoepidermoid Ca (Salivary Gland)
- increased invasiveness
- Chromosome 9
SMAD4
- in pancreas ca
BRCA2
MAP2K4
- in pancreas ca
APC
- Adenomatous Polyposis Coli
- Has been found in all mammals ( so far )
- Long arm(q) of chromosome 5
- Involved in several cellular processes that determine whether a cell may develop into a tumor
- Control how often a cell divides
- Cells attachment to each other
- Cell movement within or away from a tissue
- Ensures that the chromosome number in cells produced through cell division is correct
- —> increase in colon Ca
- in FAP
Oncogenes
c-KIT/CD117
- Membrane tyrosine kinase receptor
- Binding to the ligands stem cell factor or mast cell growth factor ==> Become ACTIVATED
- ==> signals for:
- Cell Survival
- Proliferation
- Differentiation
- ==> signals for:
- Overexpression
- Adenoid Cystic Ca(Salivary Gland)
- Imatinib
- Small molecule tyrosine kinase inhibitor
- Inhibits the activation of c-KIT receptor and other TK receptor
bcl-2
- B Cell Lymphoma gene 2
- produce anti-apoptotic protein
- found in follicular lymphoma ( NHL )
- t(14:18)
- Located on chromosome 14
MYC
- Produce transcription factors
- Activity in the nucleus
- Regulator gene
- If persistently expressed ==> unregulated expression of many genes
* Some of these genes are involved in cell proliferation ==> cancer
- A common translocation involving MYC
* t(8;14)
* Common in Burkitt's Lymphoma
- Chromosome 8
- regulate global chromatin structure by regulating histone acetylation
- Overexpression and amplification seen in SCLC
* Chemoresistant
* Rare in NSCLC
ErbB (EGFR)
- Epidermal Growth Factor Receptor
- Family of 4 structurally related receptor tyrosine kinases
- When activated ==> mitogenic signals
- ErbB-1, also named epidermal growth factor receptor (EGFR)
- ErbB-2, also named HER2 in humans and neu in rodents
- Breast Ca
- Lung Ca
- Particularly in adenoca
- poor prognostic factor
- less responsive to Herceptin than breast Ca
- Erlotinib (Tarceva)
- Gefitinib (Iressa) —> EGFR inhibitor
- Reported for Salivary Gland
- Strong overexpression in mucoepidermoid & salivary duct ca
- Rare in adenoid Cystic
- ErbB-3, also named HER3
- ErbB-4, also named HER4
- Excessive ErbB signaling ==> solid tumor
- Involved in cell growth and cell survival.
RAS family of gene
- A family of related proteins found inside cells
- Also a family of genes that encode these proteins
- A class of protein called small GTPase2
- Involved in transmitting signals within cells (cellular signal transduction).
- Name —> 'Rat sarcoma'
- The way they were were discovered
- These proteins when are switched on by a signal ==>
- Cell growth
- Differentiation
- Mutations in ras genes ==> Permanently activated RAS proteins
- Overactive RAS signaling ==> cancer
- Subfamilies:
- HRAS
- NRAS
- KRAS
- Adenocarcinoma and NSCLC
- Only in Smokers
- Very rarely in non-smokers
- Tumours with mutated KRAS almost never respond to EGFR tyrosine kinase inhibition (EGFR-TKI)
- Adverse prognostic factor
- Rare in SCLC
- Common in pancreas ca
DNA mismatch repair genes
Microsatellite instability=Simple Sequence Repeats(SSRs)
- Condition manifested by damaged DNA
- It is due to defects in the normal DNA repair process
- Sections of DNA called microsatellites, which consist of a sequence of repeating units of 1-6 base pairs in length, become unstable and can shorten or lengthen.
- Identified in the HNPCC syndrome of colon cancer
- 4% of pancreatic cancers
- Unique morphologic appearance, the presence of wild-type (normal) KRAS, diploidy, and improved prognosis
- Risk factor for gastric ca
page revision: 76, last edited: 22 Mar 2013 18:59