Radiation Oncology/Cancer genetics

=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 Chromosome 6
 * 5q deletion: Familial Adenomatous Polyposis (FAP) Syndrome and Hereditary Colorectal Syndromes

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

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</li> </ul> </li> <li> Oncogenes <ul> <li>Oncogene is a gene whose protein produt contributes to the development and or progression of CANCER.</li> <li>If activated by mutation or amputation ==&gt; They have transforming properties </li> </ul> </li> <li> DNA mismatch repair genes <ul> <li>Encode for proteins that correct errors that normally occur during DNA replication</li> </ul> </li> </ul> Tumour suppressor genes <ul> <li>Prevent the uncontrolled growth of cells that may result in cancerous tumors.</li> </ul> PTCH <ul> <li>On chromosome 9q</li> <li>Protein patched homolog 1</li> <li>A member of the patched gene family</li> <li>A tumor suppressor gene</li> <li>Receptor for sonic hedgehog <ul> <li>Molecule responsible in the formation of embryonic structures and in tumorigenesis</li> </ul> </li> </ul> <ul> <li>Nevoid basal cell carcinoma</li> <li>Esophageal SCC</li> <li>Bladder TCC</li> <li>Gorlin syndrome (with a midline cleft lip)</li> <li>Medulloblastoma</li> </ul> p53 <ul> <li>Where the name come from?! <ul> <li>On some form of electrophoresis it is weighted 53 kilo-daltone</li> </ul> </li> <li>Chromosome 17p <ul> <li>codone 72</li> </ul> </li> <li>Protein 53 or tumor protein 53</li> <li>Regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer</li> <li>&quot;the guardian of the genome&quot; because of its role in conserving stability by preventing genome mutation</li> <li>Anticancer function <ul> <li>Role genomic stability, and inhibition of angiogenesis</li> <li>After DNA damage <ul> <li>Activate DNA repair proteins</li> <li>Induce growth arrest by holding the cell cycle at the G1/S regulation point <ul> <li>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</li> </ul> </li> <li>Initiation of apoptosis</li> </ul> </li> </ul> </li> </ul> <ul> <li>p53 negative regulator is MDM2</li> <li>Common in Lung Ca <ul> <li>NSCLC : 50%</li> <li>SCLC : 90%</li> </ul> </li> <li>Common in Pancreas Ca</li> </ul> RB1 <ul> <li>Retinoblastoma protein</li> <li>On chromosome 13 </li> <li>Active when not phosphorylated; means when phosphorylated is not active <ul> <li>The active form attachs to a transcription factor name: E2F 1 <ul> <li>So active Rb makes E2F inactive ==&gt; no cell division!</li> <li>Imagine Rb and E2F like parent and child. <ul> <li>and imagine phosphorylation like making the parent drunk ( no control on child! )</li> </ul> </li> </ul> </li> </ul> </li> <li>Inactive when phosphorylated <ul> <li>Phosphorylation of Rb is by Cdk (Cyclin dependent kinase) <ul> <li>Cyclin D and Cdk4</li> <li>Cyclin E and Cdk2</li> </ul> </li> <li>Know one more thing and that's p21 <ul> <li>p21 inhibits the formation of Cyclin D <ul> <li>==> Inhibits the phosphorylation of Rb</li> <li>==> Inhibits the release of E2F</li> <li>==> inhibits the cell cycle division</li> <li>So all in all p21 is good good for cell cycle control</li> </ul> </li> <li>p21 become active when there is DNA damage <ul> <li>So you can imagine this is a great cell cycle protection mechanism <ul> <li>If there is a DNA damage who wants the cell progress from G1 to S? nobody sure!</li> <li>So we want E2F protein not active and not free</li> <li>So we need Rb tumor suppressor gene active <ul> <li>so it can bind to E2F and inactivates E2F</li> </ul> </li> <li>To keep Rb activated one should inhibit the phosphorylation (you remember phosphorylation inactivates Rb)</li> <li>What p21 does is that in detection of DNA damage inhibits Cdk ==&gt; inhibits Rb phosphorylation</li> </ul> </li> </ul> </li> </ul> </li> </ul> </li> <li>Tumor suppressor protein <ul> <li>So if Rb gene is mutated ==> It does not bind to E2F ==> E2F is constantly released ==> cell pass the restriction G1-S point</li> </ul> </li> <li>Prevent excessive cell growth <== inhibiting cell cycle progression until a cell is ready to divide</li> <li>Dysfunction ( loss of heterogeneity ) ==&gt; Cancer</li> <li>Mutated gene is recessive</li> <li>pRb prevents the cell from replicating damaged DNA <== preventing its progression along the cell cycle through G1 into S </li> <li>Binds and inhibits transcription factors of the E2F family</li> </ul> CDKN2A (p16) <ul> <li>Cyclin-dependent kinase inhibitor 2A</li> <li>Multiple tumor suppressor 1 (MTS-1)</li> <li>Tumor suppressor protein</li> <li>Encoded by the CDKN2A gene</li> <li>Regulating the cell cycle</li> <li>Mutations ==> Cancer <ul> <li>Melanoma</li> <li>Common in NSCLC</li> <li>Rare in SCLC</li> <li>Common in Pancreas Ca</li> <li>Mucoepidermoid Ca (Salivary Gland) <ul> <li>increased invasiveness</li> </ul> </li> </ul> </li> <li>Chromosome 9</li> </ul> SMAD4 <ul> <li>in pancreas ca</li> </ul> BRCA2 MAP2K4 <ul> <li>in pancreas ca</li> </ul> APC <ul> <li>Adenomatous Polyposis Coli</li> <li>Has been found in all mammals ( so far )</li> <li>Long arm(q) of chromosome 5 </li> <li>Involved in several cellular processes that determine whether a cell may develop into a tumor</li> <li>Control how often a cell divides</li> <li>Cells attachment to each other</li> <li>Cell movement within or away from a tissue</li> <li>Ensures that the chromosome number in cells produced through cell division is correct</li> <li> —> increase in colon Ca</li> <li>in FAP </li> </ul> Oncogenes c-KIT/CD117 <ul> <li>Membrane tyrosine kinase receptor</li> <li>Binding to the ligands stem cell factor or mast cell growth factor ==> Become ACTIVATED <ul> <li>==> signals for: <ul> <li>Cell Survival</li> <li>Proliferation</li> <li>Differentiation</li> </ul> </li> </ul> </li> <li>Overexpression <ul> <li>Adenoid Cystic Ca(Salivary Gland)</li> </ul> </li> <li> Imatinib <ul> <li>Small molecule tyrosine kinase inhibitor</li> <li>Inhibits the activation of c-KIT receptor and other TK receptor</li> </ul> </li> </ul> bcl-2 <ul> <li> B C ell L ymphoma gene 2 </li> <li>produce anti-apoptotic protein</li> <li>found in follicular lymphoma ( NHL ) <ul> <li>t(14:18)</li> </ul> </li> <li>Located on chromosome 18</li> </ul> MYC <ul> <li>Produce transcription factors <ul> <li>Activity in the nucleus</li> </ul> </li> <li>Regulator gene</li> <li>If persistently expressed ==> unregulated expression of many genes</li> </ul> * Some of these genes are involved in cell proliferation ==> cancer <ul> <li>A common translocation involving MYC</li> </ul> * t(8;14)
 * 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

* Common in Burkitt's Lymphoma <ul> <li>Chromosome 8</li> <li>regulate global chromatin structure by regulating histone acetylation</li> <li>Overexpression and amplification seen in SCLC</li> </ul> * Chemoresistant

* Rare in NSCLC ErbB (EGFR) <ul> <li>Epidermal Growth Factor Receptor</li> <li>Family of 4 structurally related receptor tyrosine kinases </li> <li>When activated ==> mitogenic signals <ul> <li>ErbB-1, also named epidermal growth factor receptor (EGFR)</li> <li>ErbB-2, also named HER2 in humans and neu in rodents <ul> <li>Breast Ca</li> <li>Lung Ca <ul> <li>Particularly in adenoca</li> <li>poor prognostic factor</li> <li>less responsive to Herceptin than breast Ca</li> <li>Erlotinib (Tarceva)</li> <li>Gefitinib (Iressa) —> EGFR inhibitor</li> </ul> </li> <li>Reported for Salivary Gland <ul> <li>Strong overexpression in mucoepidermoid &amp; salivary duct ca</li> <li>Rare in adenoid Cystic</li> </ul> </li> <li>ErbB-3, also named HER3</li> </ul> </li> <li>ErbB-4, also named HER4</li> </ul> </li> <li>Excessive ErbB signaling ==> solid tumor</li> <li>Involved in cell growth and cell survival.</li> </ul> RAS family of gene <ul> <li>A family of related proteins found inside cells</li> <li>Also a family of genes that encode these proteins</li> <li>A class of protein called small GTPase2 <ul> <li>Involved in transmitting signals within cells ( cellular signal transduction ).</li> </ul> </li> <li>Name &#8212;&gt; 'Rat sarcoma' <ul> <li>The way they were were discovered</li> </ul> </li> <li>These proteins when are switched on by a signal ==&gt; <ul> <li>Cell growth</li> <li>Differentiation</li> </ul> </li> </ul> <ul> <li> Mutations in ras genes ==&gt; Permanently activated RAS proteins</li> <li>Overactive RAS signaling ==&gt; cancer</li> <li>Subfamilies: <ul> <li>HRAS</li> <li>NRAS</li> <li>KRAS <ul> <li>Adenocarcinoma and NSCLC</li> <li>Only in Smokers <ul> <li>Very rarely in non-smokers</li> </ul> </li> <li>Tumours with mutated KRAS almost never respond to EGFR tyrosine kinase inhibition (EGFR-TKI)</li> <li>Adverse prognostic factor</li> <li>Rare in SCLC</li> <li>Common in pancreas ca</li> </ul> </li> </ul> </li> </ul> DNA mismatch repair genes Microsatellite instability=Simple Sequence Repeats(SSRs) <ul> <li>Condition manifested by damaged DNA</li> <li>It is due to defects in the normal DNA repair process</li> <li>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.</li> <li>Identified in the HNPCC syndrome of colon cancer</li> <li>4% of pancreatic cancers <ul> <li>Unique morphologic appearance, the presence of wild-type (normal) KRAS, diploidy, and improved prognosis</li> </ul> </li> <li>Risk factor for gastric ca</li> </ul>

Footnotes 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)