Translocations - Paralog

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.