# Radiation Oncology/Cancer genetics

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

# List of Chromosomes and their related cancer genes

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 indefinitely
* 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 product 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: E2F$^1$
*** 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 GTPase$^2$
** 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
1. E2F: A protein which when is free initiate further cell division and move the cell pass the G1-S restriction point and move from G1 to S phase. 2. a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP)