Deletion or methylation of CDKN2A/2B and PVT1 rearrangement occur frequently in highly aggressive B-cell lymphomas harboring 8q24 abnormality
2013
Among various cytogenetic abnormalities involved in lymphomagenesis and disease progression of highly aggressive and treatment-resistant B-cell lymphomas (HABCLs), classified as the so-called aggressive B-cell lymphomas (BCLs) such as diffuse large B-cell lymphoma (DLBCL) and Burkitt-like lymphoma or Burkitt lymphoma (BL), 8q24 chromosomal abnormality is one of the major genetic/cytogenetic abnormalities, with a frequency of 5–15% [1,2]. Moreover, MYC rearrangements at 8q24 have been occasionally found in combination with a t(14;18)(q32;q21) involving BCL2 in 4% of highly aggressive “double-hit” DLBCLs (DHLs), with an extremely poor prognosis [3–5]. Indeed, MYC and BCL2 synergistically induce tumor formation, as observed in experimental models [6,7]. Therefore, better genetic/molecular diagnostic criteria are needed for the more accurate prediction of outcomes and the development of novel treatments for HABCLs. Because the complex karyotypes often found in HABCLs may cause the gene alterations associated with their biological functions, aberrations of other molecules besides MYC and BCL2 may also further affect the pathogenesis of HABCLs [4,8,9]. In this study, we subjected eight patients with aggressive BCLs with 8q24 abnormality treated at the Kyoto Prefectural University of Medicine (KPUM) between April 2006 and September 2012 (Table I) to a comprehensive molecular analysis using G-banding, spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) for IGH, MYC, PVT-1 [Figure 1(A)], BCL-2, BCL-6, BACH2 and CDKN2A/2B, oligonucleotide array and methylation-specific polymerase chain reaction (PCR) (MSP) (Supplementary Materials and Methods available online at http://www.informahealthcare. com/lal/doi/10.3109/10428194.2013.790543) [8–10]. Patients 1, 2, 3, 7 and 8 were included in our previous publication on survival analysis for DLBCL [5]. We established two cell lines, KPUM-MS3 and KPUM-UH1, from patients 2 and 3, respectively [11]. This study was approved by the ethics committee of KPUM. Three patients had Burkitt-like lymphoma and five had DLBCL. As shown in Table I, all patients presented with advanced disease stage and with unfavorable International Prognostic Index scores. All patients were characterized by systemically disseminated involvements including bone marrow involvement, fluid retention, central nervous system involvement and/or multiple extranodal disease sites. As for response to immunochemotherapy incorporating rituximab and/or irradiation therapy, five patients showed disease progression, while three achieved a complete response. Patient 7 had three disease recurrences prior to a complete response to various salvage chemotherapies. The median survival of eight patients was 6.7 months. In these series, 8q24 abnormalities were detected by G-banding and SKY analysis in five patients, and by FISH in the remaining three. All patients thus showed 8q24 abnormalities, including MYC/PVT1 amplification in patient 4 [Figure 1(B)]. Based on the results obtained by FISH using both PVT1-A and PVT1-S probes, breakpoints were assigned to the PVT1 gene in two patients (2 and 5) and to the region covered by the bacterial artificial chromosome (BAC) CTD-3066D1 containing MYC in four (3, 6, 7 and 8) [Figures 1(A) and 1(C) and Supplementary Table I to be found online at http://www.informahealthcare.com/lal/doi/10.3109/1042 8194.2013.790543]. The MYC-Cg fusion gene was detected in patient 1 by long-distance PCR. Oligonucleotide array analysis demonstrated that the 8q24 rearrangement demarcated copy number changes within PVT1 in intron 1 in patient 2 (Supplementary Figure 1 to be found online at http://www. informahealthcare.com/lal/doi/10.3109/10428194.2013. L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y K yo to F ur its u Id ai L ib ra ry o n 09 /2 8/ 14
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