We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.

SUMMARY During an immune response, B cells undergo rapid proliferation and AID-dependent remodeling of immunoglobulin (IG) genes within germinal centers (GCs) to generate memory B and plasma cells. Unfortunately, the genotoxic stress associated with the GC reaction also promotes most B cell malignancies. Here we report that exogenous- and intrinsic AID-induced DNA strand breaks activate ATM, which signals through an LKB1 intermediate to inactivate CRTC2, a transcriptional coactivator of CREB. Using genome-wide location analysis, we determined that CRTC2 inactivation unexpectedly represses a genetic program that controls GC B cell proliferation, self-renewal, and differentiation while opposing lymphomagenesis. Inhibition of this pathway results in increased GC B cell proliferation, reduced antibody secretion, and impaired terminal differentiation. Multiple distinct pathway disruptions were also identified in human GC B cell lymphoma patient samples. Combined, our data show that CRTC2 inactivation, via physiologic DNA damage response signaling, promotes B cell differentiation in response to genotoxic stress.

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AIDS-related non-Hodgkin's lymphoma (AIDS NHL) comprises a diverse and heterogeneous group of high-grade B cell tumors. Certain classes of AIDS NHL are associated with alterations in oncogenes or tumor-suppressor genes or infections by oncogenic herpesviruses. However, the clinically significant class of AIDS NHL designated immunoblastic lymphoma plasmacytoid (AIDS IBLP) lacks any consistent genetic alterations. We identified the TCL1 oncogene from a set of AIDS IBLP-associated cDNA fragments generated by subtractive hybridization with non-AIDS IBLP. Aberrant TCL1 expression has been implicated in T cell leukemia/lymphoma development, and its expression also has been seen in many established B cell tumor lines. However, TCL1 expression has not been reported in AIDS NHL. We find that TCL1 is expressed in the majority of AIDS IBLP tumors examined. AIDS-related non-Hodgkin's lymphoma (AIDS NHL) occurs in up to 10% of HIV-infected individuals who have moderate to severe immunodeficiency (1-3). These lymphomas are biologically and genetically heterogeneous, are derived from germinal center or postgerminal center B cells, and are classified according to body location and histologic criteria (reviewed in refs. 4-7). Certain AIDS NHL classes are associated with specific oncogenic lesions or viral involvement. For example, AIDS-related Burkitt's lymphoma usually contain activating c-MYC translocations, whereas AIDS-related primary-effusion lymphoma consistently contain human herpesvirus-8 (8-24). AIDS diffuse large B cell lymphoma accounts for 70% of systemic lymphomas and is the second most common type of cancer after Kaposi's sarcoma in AIDS patients (25,26). Systemic AIDS diffuse large B cell lymphoma are further classified into two subclasses (6,7,(27)(28)(29). AIDS large noncleaved-cell lymphoma is postulated to originate from germinal center B cells and often exhibits dysregulated expression of the BCL-6 protooncogene because of chromosomal translocations or promoter mutations. AIDS immunoblastic lymphoma plasmacytoid (AIDS IBLP) is thought to derive from postgerminal center B cells and is not associated with any predominant genetic alteration (30, 31). AIDS IBLP are monoclonal tumors that usually contain Epstein-Barr virus, indicating that they are not simply Epstein-Barr virusdriven polyclonal proliferations. The lack of any consistently associated oncogene involvement in AIDS IBLP strongly suggests that these tumors arise through novel patterns of dysregulated gene expression (7,15,32).We sought to identify differentially expressed genes in AIDS IBLP patient samples versus non-AIDS lymphoma samples by using suppression subtractive hybridizations (SSH) (33,34). Large cell lymphomas with immunoblastic/plasmacytoid features consistent with postgerminal center derivations (IBLP) were selected for these subtractions from HIV-infected or uninfected patient samples. The TCL1 oncogene was identified among multiple differentially expressed genes isolated from AIDS IBLP in these studies.TCL1 is developmentally reg...