Reference SummaryWright SM, Cancer Res 2009 May 15;69(10):4454-60

Title

Complex oncogenic translocations with gene amplification are initiated by specific DNA breaks in lymphocytes.

Authors

Wright SM; Woo YH; Alley TL; Shirley BJ; Akeson EC; Snow KJ; Maas SA; Elwell RL; Foreman O; Mills KD

Journal

Cancer Res

Volume

69

Issue

10

Year

2009

Pages

4454-60

Abstract

Chromosomal instability is a hallmark of many tumor types. Complex chromosomal rearrangements with associated gene amplification, known as complicons, characterize many hematologic and solid cancers. Whereas chromosomal aberrations, including complicons, are useful diagnostic and prognostic cancer markers, their molecular origins are not known. Although accumulating evidence has implicated DNA double-strand break repair in suppression of oncogenic genome instability, the genomic elements required for chromosome rearrangements, especially complex lesions, have not been elucidated. Using a mouse model of B-lineage lymphoma, characterized by complicon formation involving the immunoglobulin heavy chain (Igh) locus and the c-myc oncogene, we have now investigated the requirement for specific genomic segments as donors for complex rearrangements. We now show that specific DNA double-strand breaks, occurring within a narrow segment of Igh, are necessary to initiate complicon formation. By contrast, neither specific DNA breaks nor the powerful intronic enhancer Emu are required for complicon-independent oncogenesis. This study is the first to delineate mechanisms of complex versus simple instability and the first to identify specific chromosomal elements required for complex chromosomal aberrations. These findings will illuminate genomic cancer susceptibility and risk factors.

Links

J:148474 – Mouse Genome Informatics
19435904 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Dclre1ctm1Fwa Trp53tm1Brd Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

very high

C57BL/6J-Dclre1ctm1Fwa Igh-Jtm1Cgn Trp53tm1Brd Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

44

C57BL/6J-Dclre1ctm1Fwa Igh-Jtm1Cgn Trp53tm1Brd Leukocyte - Lymphocyte - Thymocyte lymphoma Thymus

12.5

B6.129S7-Trp53tm1Brd Leukocyte - Lymphocyte - Thymocyte lymphoma Thymus

observed

C57BL/6J-Dclre1ctm1Fwa Igh-Jtm1Cgn Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

37.5

B6.129S7-Trp53tm1Brd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed