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 cheatsheet for oncology

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


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