Radiation Oncology/Cancer genetics – Wikibooks, open books for an open world

• An oncovirus is a virus that may trigger most cancers
• This time period originated from research of acutely reworking retroviruses within the 1950–60s, when the time period “oncornaviruses” was used to indicate their RNA virus origin
• With the letters “RNA” eliminated, it now refers to any virus with a DNA or RNA genome inflicting most cancers and is synonymous with “tumor virus” or “most cancers virus”
• The overwhelming majority of human and animal viruses don’t trigger most cancers, in all probability due to longstanding co-evolution between the virus and its host
• Oncoviruses have been necessary not solely in epidemiology, but additionally in investigations of cell cycle management mechanisms such because the retinoblastoma protein

Chromosome 1

Chromosome 2

Chromosome 3

• 3p26: Von-Hippel Lindau, VHL gene (3p26)

Chromosome 4

Chromosome 5

• 5q deletion: Familial Adenomatous Polyposis (FAP) Syndrome and Hereditary Colorectal Syndromes

Chromosome 6

Chromosome 7

Chromosome 8

Chromosome 9

• 9q34.1: Abl, concerned in bcr-abl fusion gene
• 9q34: TSC1, concerned in tuberous sclerosis

Chromosome 10

Chromosome 11
ATM is positioned on human chromosome 11 (11q22.3)
Chromosome 12

Chromosome 13

• 13q15: Rb, retinoblastoma, different tumors

Chromosome 14

Chromosome 15

Chromosome 16

• 16p13: TSC2, concerned in tuberous sclerosis

Chromosome 17

• 17p13.1: p53 (TP53) tumor suppressor

Chromosome 18

• 18q21.3: Bcl-2 gene, follicular lymphoma, t(14;18)(q32;q21)

Chromosome 19

Chromosome 20

Chromosome 21

Chromosome 22

• 22q11.2: Bcr gene, bcr-abl translocation (Philadelphia chromosome), CML
• 22: EWS gene, Ewing’s sarcoma

Chromosome X

Chromosome Y

See additionally Record of chromosomal translocations at Wikipedia

See additionally Lymphoma Triangle

• t(1;12)(q21;p13)
  • Acute myelogenous leukemia
• t(1;13)
• t(2;5)(p23;q35)
  • Anaplastic giant cell lymphoma
• t(2;13)
• t(8;14)
• t(9;12)(p24;p13) CML, ALL
• t(9;22)(q34;q11)
  • BCR-ABL (Philadelphia chromosome). Position of BCR shouldn’t be fully clear, however seems to be concerned with superoxide manufacturing. Abl has 2 isoforms: nuclear abl is concerned with regulation of cell demise after DNA injury. Cytoplasmic abl seems to operate in cell adhesion
  • Ends in CML, ALL
• t(11;14)
• t(11;18)
  • MALT lymphoma – related to antibiotic resistance in gastric MALT
• t(11;22)(q24;q11.2-12)
• t(12;16)
• t(14;18) (q32;q21)
  • Bcl-2 (18) is translocated subsequent to the immunoglobulin heavy chain locus. See Apoptosis for additional dialogue of Bcl-2
  • Follicular lymphoma 80-90%
  • DLBCL ~30%
• t(15;17)
  • Acute promyelocytic leukemia
• t(17;22):
• t(21;22)
• t(X;18)(p11.2;q11.2)

Organic modifications that ought to occur so a cell turns into cancerous:

1. proliferate independently of progress alerts
2. circumvent programmed cell demise
3. replicate indefinitely
4. induce vascular formation
5. invade tissues

There are three varieties of such gene.

• Tumor suppressor genes
  • Perform = restrain cell proliferation
• Oncogenes
  • Oncogene is a gene whose protein produt contributes to the event and or development of CANCER.
  • If activated by mutation or amputation ==> They’ve reworking properties
• DNA mismatch restore genes
  • Encode for proteins that right errors that usually happen throughout DNA replication

Tumour suppressor genes

• Forestall the uncontrolled progress of cells that will end in cancerous tumors.

PTCH

• On chromosome 9q
• Protein patched homolog 1
• A member of the patched gene household
• A tumor suppressor gene
• Receptor for sonic hedgehog
  • Molecule accountable within the formation of embryonic constructions and in tumorigenesis

• Nevoid basal cell carcinoma
• Esophageal SCC
• Bladder TCC
• Gorlin syndrome (with a midline cleft lip)
• Medulloblastoma

p53

• The place the title come from?!
  • On some type of electrophoresis it’s weighted 53 kilo-daltone
• Chromosome 17p
• Protein 53 or tumor protein 53
• Regulates the cell cycle and, thus, features as a tumor suppressor that’s concerned in stopping most cancers
• “the guardian of the genome” due to its position in conserving stability by stopping genome mutation
• Anticancer operate
  • Position genomic stability, and inhibition of angiogenesis
  • After DNA injury
    • Activate DNA restore proteins
    • Induce progress arrest by holding the cell cycle on the G1/S regulation level
      • If it holds the cell right here for lengthy sufficient, the DNA restore proteins could have time to repair the injury and the cell shall be allowed to proceed the cell cycle
    • Initiation of apoptosis

• p53 unfavorable regulator is MDM2
• Frequent in Lung Ca
• Frequent in Pancreas Ca

RB1

• Retinoblastoma protein
• On chromosome 13
• Energetic when not phosphorylated; means when phosphorylated shouldn’t be lively
  • The lively kind attachs to a transcription issue title: E2F¹
    • So lively Rb makes E2F inactive ==> no cell division!
    • Think about Rb and E2F like dad or mum and youngster.
      • and picture phosphorylation like making the dad or mum drunk ( no management on youngster! )
• Inactive when phosphorylated
  • Phosphorylation of Rb is by Cdk (Cyclin dependent kinase)
    • Cyclin D and Cdk4
    • Cyclin E and Cdk2
  • Know another factor and that is p21
    • p21 inhibits the formation of Cyclin D
      • ==> Inhibits the phosphorylation of Rb
      • ==> Inhibits the discharge of E2F
      • ==> inhibits the cell cycle division
      • So all in all p21 is sweet good for cell cycle management
    • p21 develop into lively when there’s DNA injury
      • So you’ll be able to think about it is a nice cell cycle safety mechanism
        • If there’s a DNA injury who desires the cell progress from G1 to S? no person positive!
        • So we would like E2F protein not lively and never free
        • So we want Rb tumor suppressor gene lively
          • so it may possibly bind to E2F and inactivates E2F
        • To maintain Rb activated one ought to inhibit the phosphorylation (you keep in mind phosphorylation inactivates Rb)
        • What p21 does is that in detection of DNA injury inhibits Cdk ==> inhibits Rb phosphorylation
• Tumor suppressor protein
  • So if Rb gene is mutated ==> It doesn’t bind to E2F ==> E2F is consistently launched ==> cell move the restriction G1-S level
• Forestall extreme cell progress <== inhibiting cell cycle development till a cell is able to divide
• Dysfunction ( lack of heterogeneity ) ==> Most cancers
• Mutated gene is recessive
• pRb prevents the cell from replicating broken DNA <== stopping its development alongside the cell cycle by G1 into S 
• Binds and inhibits transcription components of the E2F household

CDKN2A (p16)

• Cyclin-dependent kinase inhibitor 2A
• A number of tumor suppressor 1 (MTS-1)
• Tumor suppressor protein
• Encoded by the CDKN2A gene
• Regulating the cell cycle
• Mutations ==> Most cancers
  • Melanoma
  • Frequent in NSCLC
  • Uncommon in SCLC
  • Frequent in Pancreas Ca
  • Mucoepidermoid Ca (Salivary Gland)
• Chromosome 9

SMAD4

BRCA2

MAP2K4

APC

• Adenomatous Polyposis Coli
• Has been present in all mammals ( to this point )
• Lengthy arm(q) of chromosome 5
• Concerned in a number of mobile processes that decide whether or not a cell could develop right into a tumor
• Management how typically a cell divides
• Cells attachment to one another
• Cell motion inside or away from a tissue
• Ensures that the chromosome quantity in cells produced by cell division is right
• —> improve in colon Ca
• in FAP

Oncogenes

c-KIT/CD117

• Membrane tyrosine kinase receptor
• Binding to the ligands stem cell issue or mast cell progress issue ==> Turn into ACTIVATED
  • ==> alerts 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 different TK receptor

bcl-2

• B Cell Lymphoma gene 2
• produce anti-apoptotic protein
• present in follicular lymphoma ( NHL )
• Situated on chromosome 18

MYC 

• Produce transcription components
• Regulator gene
• If persistently expressed ==> unregulated expression of many genes

 * A few of these genes are concerned in cell proliferation ==> most cancers

• A standard translocation involving MYC

 * t(8;14) 
  * Frequent in Burkitt’s Lymphoma

• Chromosome 8
• regulate world chromatin construction by regulating histone acetylation
• Overexpression and amplification seen in SCLC

 * Chemoresistant
 * Uncommon in NSCLC

ErbB (EGFR)

• Epidermal Development Issue Receptor
• Household of Four structurally associated receptor tyrosine kinases
• When activated ==> mitogenic alerts
  • ErbB-1, additionally named epidermal progress issue receptor (EGFR)
  • ErbB-2, additionally named HER2 in people and neu in rodents
    • Breast Ca
    • Lung Ca
      • Significantly in adenoca
      • poor prognostic issue
      • much less attentive to Herceptin than breast Ca
      • Erlotinib (Tarceva)
      • Gefitinib (Iressa) —> EGFR inhibitor
    • Reported for Salivary Gland
      • Sturdy overexpression in mucoepidermoid & salivary duct ca
      • Uncommon in adenoid Cystic
    • ErbB-3, additionally named HER3
  • ErbB-4, additionally named HER4
• Extreme ErbB signaling ==> stable tumor
• Concerned in cell progress and cell survival.

RAS household of gene

• A household of associated proteins discovered inside cells
• Additionally a household of genes that encode these proteins
• A category of protein known as small GTPase²
  • Concerned in transmitting alerts inside cells (mobile sign transduction).
• Title —> ‘Rat sarcoma’
  • The way in which they have been have been found
• These proteins when are switched on by a sign ==>
  • Cell progress
  • Differentiation

• Mutations in ras genes ==> Completely activated RAS proteins
• Overactive RAS signaling ==> most cancers
• Subfamilies:
  • HRAS
  • NRAS
  • KRAS
    • Adenocarcinoma and NSCLC
    • Solely in People who smoke
      • Very hardly ever in non-smokers
    • Tumours with mutated KRAS virtually by no means reply to EGFR tyrosine kinase inhibition (EGFR-TKI)
    • Adversarial prognostic issue
    • Uncommon in SCLC
    • Frequent in pancreas ca

DNA mismatch restore genes

Microsatellite instability=Easy Sequence Repeats(SSRs)

• Situation manifested by broken DNA
• It is because of defects within the regular DNA restore course of
• Sections of DNA known as microsatellites, which include a sequence of repeating models of 1-6 base pairs in size, develop into unstable and may shorten or lengthen.
• Recognized within the HNPCC syndrome of colon most cancers
• 4% of pancreatic cancers
  • Distinctive morphologic look, the presence of wild-type (regular) KRAS, diploidy, and improved prognosis
• Danger issue for gastric ca