translocations - paralog
TRANSCRIPT
Translocations in Cancer
MI616Spring 2007
Andrew J. Pierce
Microbiology, Immunology and Molecular GeneticsGraduate Center for Toxicology
Markey Cancer CenterUniversity of Kentucky
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http://www.pathology.washington.edu/galleries/Cytogallery/
Traditional G-banding Karyotyping
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Spectral Karyotyping
http://www.infobiogen.fr/services/chromcancer/Deep/ComparCancerCytogenet.html
Patel, A. S., Hawkins, A. L. & Griffin, C. A. Cytogenetics and cancer. Curr Opin Oncol 12, 62-7 (2000).
Spectral Karyotyping
Philadelphia Chromosome - CGL
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Diagnostic for CGL (Chronic Granulocytic Leukemia)aka CML (Chronic Myeloid Leukemia)
Also seen in: 25-30% of adult ALL (Acute Lymphocytic Leukemia) 5% of childhood ALL
9q34 : ABL (tyrosine kinase)22q11.2 : BCR results in disregulation of the ABL tyrosine kinase
treat with imatinib mesylate (Gleevec) to inhibit ABL kinase activity
Non-Hodgkin’s Lymphoma
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14q32: IGH18q21: BCL2Over-expression of BCL2 : anti-apoptotic
http://www.slh.wisc.edu/cytogenetics/cancer/
Translocation Histologic Type Oncogene Involved
t(11;14)(q13;q32) Mantle Cell bcl-1
t(4;18)(q32;q21) All follicular lymphomas and some diffuse large B-cell lymphomas
bcl-2
t(4;19)(q32;q13) Small lymphocytic bcl-3
t(3;14)(q27;q32) Diffuse large B-cell bcl-6
t(2;5)(p23;q35) Anaplastic large cell ALK
t(8;14)(q24;q32) Burkitt’s c-myc
The Chemotherapy Source Book, 3rd edition
Burkitt’s Lymphoma
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t(2;8)(p12;q24.1)
2p12: IG
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t(8;14)(q24.1;q32)80% of patients
14q32: IGH
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t(8;22)(q24.1;q11.2)
22q11.2: IG
8q24.1 : MYC
Over-expression of Myc - pro-growth
http://www.slh.wisc.edu/cytogenetics/cancer/
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t(11;22)(q24;q12) 90% of all Ewing’s Sarcomas
22q12 : EWS
11q24 : FLI1
http://www.slh.wisc.edu/cytogenetics/cancer/
Ewing Tumors
EWS 22q12 can also translocate with:
Ewing Tumors21q22 : ERG7p22 : ETV12q33 : FEV
17q12 : EIAF
Desmoplastic Small Cell,Round Cell Tumor
11p13 : WT1
Clear Cell Sarcoma12q13 : ATF1
Elliott, B. & Jasin, M. Double-strand breaks and translocations in cancer. Cell Mol Life Sci 59, 373-85 (2002).
Desmoplastic Small Round Cell Tumor (DSRCT)
transcriptionalactivator
DNA binding
Elliott, B. & Jasin, M. Double-strand breaks and translocations in cancer. Cell Mol Life Sci 59, 373-85 (2002).
Burkitt’s lymphoma:c-myc coding exons fused to IgH promoter and strong enhancer deregulates myc expression
mouse model: Ku-/- p53-/- very aggressive pro-B-cell lymphomas
CML (CGL):fusion of BCR promoter and initial coding sequences to ABL non-receptor tyrosine kinase to constitutively activate ABL kinase function:misregulation of downstream genes eg. RAS, adhesion molecules, apoptotic factors, MYC, cyclin D1
DSRCT:fusion of EWS coding sequence to WT1 coding sequencereplaces RNA-binding domain of EWS with the DNA-binding domain of WT1 creating a novel transcription factoractivates: PDGF-A, EGR-1 and IGF-1R all of which would normally be repressed by WT1
Elliott, B. & Jasin, M. Double-strand breaks and translocations in cancer. Cell Mol Life Sci 59, 373-85 (2002).
Immune System Involvement in Translocation Formation
ProteinRag1/Rag2ArtemisKu70/Ku80/DNA-PKcs???XRCC4/DNL-IV
FunctionMake hairpin-end DSBsOpen hairpin endsHold ends together & signallingProcessing of endsCovalently close ends
only 1 RAG break
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Ring Chromosomes
Di-centrics
Ongoing Genomic Instability
Gisselsson D, Pettersson L, Hoglund M, Heidenblad M, Gorunova L, Wiegant J, Mertens F, Dal Cin P, Mitelman F, Mandahl N.Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5357-62.
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Chromosome 12Chromosome 15
Amplification of c-myc / IGH fusion
Cell. 2002 Jun 28;109(7):811-21. Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW.Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.