Radiation Oncology/Cancer genetics

List of Chromosomes and their related cancer genes thumb|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 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: 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 BRCA2 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 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)