Radiation Oncology/Cancer genetics

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List of Chromosomes and their related cancer genes

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, involved in bcr-abl fusion gene
9q34: TSC1, involved in tuberous sclerosis

Chromosome 10

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

Chromosome 13

13q15: Rb, retinoblastoma, other tumors

Chromosome 14

Chromosome 15

Chromosome 16

16p13: TSC2, involved 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

Chromosomal translocations involved in oncology

See also List of chromosomal translocations at Wikipedia

See also Lymphoma Triangle

t(1;12)(q21;p13)
- Acute myelogenous leukemia
t(1;13)
- PAX7-FKHR: Rhabdomyosarcoma
t(2;5)(p23;q35)
- Anaplastic large cell lymphoma
t(2;13)
- PAX3-FKHR: Rhabdomyosarcoma
t(8;14)
- c-myc
- Burkitt's lymphoma
t(9;12)(p24;p13) CML, ALL
t(9;22)(q34;q11)
- BCR-ABL (Philadelphia chromosome). Role of BCR is not completely clear, but appears to be involved with superoxide production. Abl has 2 isoforms: nuclear abl is involved with regulation of cell death after DNA damage. Cytoplasmic abl appears to function in cell adhesion
- Results in CML, ALL
t(11;14)
- Mantle cell lymphoma
t(11;18)
- MALT lymphoma - associated with antibiotic resistance in gastric MALT
t(11;22)(q24;q11.2-12)
- EWS-FLI1: Ewing's sarcoma
t(12;16)
- TLS-CHOP: Myxoid liposarcoma
t(14;18) (q32;q21)
- Bcl-2 (18) is translocated next to the immunoglobulin heavy chain locus. See Apoptosis for further discussion of Bcl-2
- Follicular lymphoma 80-90%
- DLBCL ~30%
t(15;17)
- Acute promyelocytic leukemia
t(17;22):
- PDFGB-COL1A1: Dermatofibrosarcoma protuberans
t(21;22)
- EWS-ERF: Ewing's sarcoma
t(X;18)(p11.2;q11.2)
- SYT-SSX: Synovial sarcoma

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! )
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

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 18

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

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