Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Blood (Impact Factor: 10.45). 04/2006; 107(6):2477-85. DOI: 10.1182/blood-2005-07-2950
Source: PubMed


To identify, in high-resolution regions of DNA, the copy number changes associated with outcome in patients with diffuse large B-cell lymphoma (DLBCL), a disease with an approximately 50% mortality rate, we performed array comparative genomic hybridization (array-CGH) on specimens from 64 patients with newly diagnosed DLBCL treated with anthracycline-based chemotherapy. For the entire cohort, 55 commonly gained/lost regions, ranging in size from less than 1 Mbp to entire chromosomes, were identified using 1- to 2-Mbp and 2- to 4-Mbp resolution BAC arrays. Copy number changes of 9 minimal regions significantly correlated with overall survival, of which 6 were 10 Mbp or smaller. On multivariate analysis, loss of chromosomes 2 (2.4-4.1 Mbp) and 16 (33.8-35.6 Mbp) were found to be prognostic indicators of poor survival, independent of clinical features routinely used to predict outcome. Loss of chromosome 1 (78.2-79.1 Mbp) was predictive of good outcome. For a subset of 55 specimens classified according to cell-of-origin expression signature subtype, gain of chromosome 12 (45.4-53.8 Mbp) was found to be significantly associated with the germinal center B-cell-like DLBCL subtype. Overall, array-CGH identified relatively small genomic regions associated with outcome, which, along with follow-up expression studies, may reveal target genes important in DLBCL clinical behavior.

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    • "* Regions also reported to show gain or loss in diffuse large B-cell lymphoma by CHEN et al[19]. "
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    ABSTRACT: Plasmablastic lymphoma (PL) is a subtype of diffuse large B-cell lymphoma (DLBCL). Studies have suggested that tumors with PL morphology represent a group of neoplasms with clinopathologic characteristics corresponding to different entities including extramedullary plasmablastic tumors associated with plasma cell myeloma (PCM). The goal of the current study was to evaluate the genetic similarities and differences among PL, DLBCL (AIDS-related and non AIDS-related) and PCM using array-based comparative genomic hybridization. Examination of genomic data in PL revealed that the most frequent segmental gain (> 40%) include: 1p36.11-1p36.33, 1p34.1-1p36.13, 1q21.1-1q23.1, 7q11.2-7q11.23, 11q12-11q13.2 and 22q12.2-22q13.3. This correlated with segmental gains occurring in high frequency in DLBCL (AIDS-related and non AIDS-related) cases. There were some segmental gains and some segmental loss that occurred in PL but not in the other types of lymphoma suggesting that these foci may contain genes responsible for the differentiation of this lymphoma. Additionally, some segmental gains and some segmental loss occurred only in PL and AIDS associated DLBCL suggesting that these foci may be associated with HIV infection. Furthermore, some segmental gains and some segmental loss occurred only in PL and PCM suggesting that these lesions may be related to plasmacytic differentiation. To the best of our knowledge, the current study represents the first genomic exploration of PL. The genomic aberration pattern of PL appears to be more similar to that of DLBCL (AIDS-related or non AIDS-related) than to PCM. Our findings suggest that PL may remain best classified as a subtype of DLBCL at least at the genome level.
    Journal of Hematology & Oncology 11/2009; 2(1):47. DOI:10.1186/1756-8722-2-47 · 4.81 Impact Factor
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    • "In immunocompetent hosts, de novo post GC-cases are characterized by deletions of 6q (PRDM1 and TNFAIP3), 9p (CDKN2A), trisomy of chromosome 3, gain/amplifications of 3p (FOXP1, NFKBIZ), 3q, 18q (BCL2) and 19q (SPIB) (Tagawa et al, 2004; Bea et al, 2005; Chen et al, 2006; Lenz et al, 2008a; Compagno et al, 2009). On the contrary, GCB- DLBCL display more commonly gains of 1q, 2p (REL), 7q, 9q, 12q (MDM2), 13q (MIR17HG), and deletions of 1p (TP73), 10q (PTEN) and 13q (ING1) (Tagawa et al, 2004; Bea et al, 2005; Chen et al, 2006; Lenz et al, 2008a). Analogous to GCB-DLBCL, HIV-DLBCL clearly showed recurrent gains of 2p (REL), 7q and 12q, as well as losses of 1p. "
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    ABSTRACT: Non-Hodgkin lymphomas (NHL) represent a frequent complication of human immunodeficiency virus (HIV) infection. To elucidate HIV-NHL pathogenesis, we performed a genome-wide DNA profiling based on a single nucleotide polymorphism-based microarray comparative genomic hybridization in 57 HIV-lymphomas and, for comparison, in 105 immunocompetent diffuse large B-cell lymphomas (IC-DLBCL). Genomic complexity varied across HIV-NHL subtypes. HIV-Burkitt lymphoma showed a significantly lower number of lesions than HIV-DLBCL (P = 0.032), whereas the median number of copy number changes was significantly higher in Epstein-Barr virus negative (EBV-) HIV-DLBCL (42.5, range 8-153) compared to EBV+ cases (22; range 3-41; P = 0.029). Compared to IC-DLBCL, HIV-DLBCL displayed a distinct genomic profile with no gains of 18q and specific genetic lesions. Fragile sites-associated genes, including FHIT (FRA3B), WWOX (FRA16D), DCC (FRA18B) and PARK2 (FRA6E) were frequently inactivated in HIV-NHL by interstitial deletions, and a significantly higher prevalence of FHIT alterations was observed in HIV-DLBCL compared to IC-DLBCL. The same genes involved by fragile site deletions were also frequently affected by aberrant methylation of regulative regions.
    British Journal of Haematology 10/2009; 148(2):245-55. DOI:10.1111/j.1365-2141.2009.07943.x · 4.71 Impact Factor
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    • "Some approaches have been suggested to transform the segment means to copy numbers or aberration classes based on thresholds (e.g. Willenbrock and Fridlyand, 2005) or by constraining the means in the segmentation process (Chen et al., 2006). The latter approach seems more robust, though the method is not yet available. "
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    ABSTRACT: MOTIVATION: Copy number profiling methods aim at assigning DNA copy numbers to chromosomal regions using measurements from microarray-based comparative genomic hybridizations. Among the proposed methods to this end, Hidden Markov Model (HMM)-based approaches seem promising since DNA copy number transitions are naturally captured in the model. Current discrete-index HMM-based approaches do not, however, take into account heterogeneous information regarding the genomic overlap between clones. Moreover, the majority of existing methods are restricted to chromosome-wise analysis. RESULTS: We introduce a novel Segmental Maximum A Posteriori approach, SMAP, for DNA copy number profiling. Our method is based on discrete-index Hidden Markov Modeling and incorporates genomic distance and overlap between clones. We exploit a priori information through user-controllable parameterization that enables the identification of copy number deviations of various lengths and amplitudes. The model parameters may be inferred at a genome-wide scale to avoid overfitting of model parameters often resulting from chromosome-wise model inference. We report superior performances of SMAP on synthetic data when compared with two recent methods. When applied on our new experimental data, SMAP readily recognizes already known genetic aberrations including both large-scale regions with aberrant DNA copy number and changes affecting only single features on the array. We highlight the differences between the prediction of SMAP and the compared methods and show that SMAP accurately determines copy number changes and benefits from overlap consideration.
    Bioinformatics 04/2008; 24(6):751-8. DOI:10.1093/bioinformatics/btn003 · 4.98 Impact Factor
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