Know Your Molecular Oncology

A Cancer Cell

Biological changes that should happen so a cell becomes cancerous:

  1. proliferate independently of growth signals
  2. circumvent programmed cell death
  3. replicate indefenitely
  4. induce vascular formation
  5. 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! )
  • 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
  • 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
  • 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