neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4 þ CD56 þ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16 ink4a , p14 arf ) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.

Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-celllike (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (Po0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM þ tumor (P ¼ 0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM þ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur.

[(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is essential to optimize the initial staging and to predict the prognosis of diffuse large B-cell lymphoma (DLBCL). To assess the relationship between the germinal center B cell-like/activated B cell-like (GCB/ABC) classification and PET scan features in DLBCL, 57 cases treated with rituximab and a cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)/CHOP-like regimen were analyzed. The expression profile of 18 GCB/ABC related genes and five genes coding for glucose transporters (GLUTs) was determined from frozen tissues using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology. According to the gene expression profile (GEP), 30 cases of DLBCL were classified as GCB subtype (2-year progression-free survival [PFS] 76%) and 27 cases as ABC subtype (2-year PFS 51%, p = 0.03). Using a semiquantitative assessment of the decrease in standard uptake value (SUV) at interim PET performed after 3-4 cycles of chemotherapy, we defined fast (n = 36) and slow (n = 9) metabolic responders. In multivariate analysis, GCB/ABC subtype, age-adjusted international prognostic index (aaIPI) and slow/fast metabolic response were independent variables that predicted outcome. A score incorporating aaIPI, fast/slow metabolic response and GCB/ABC classification was used to define two groups with highly significantly distinct outcomes. Our study suggests that the combination of GEP, aaIPI and interim PET more accurately predicts DLBCL prognosis and is therefore suitable for tailoring therapeutic strategies.

Expression of BIRC5 (survivin), a member of the inhibitor of apoptosis protein (IAP) family, is elevated in fetal tissues and in various human cancers. Mechanisms up-regulating BIRC5 in cancer are poorly understood. Here, we show that overexpression of BIRC5 induces a high proliferation level in MCF-7 breast tumor cells. In a population of 191 breast carcinomas, BIRC5 expression is not affected by BIRC5 promoter polymorphism at -31, or BIRC5 gene copy number. However, a significant correlation was found between expression of demethylase (dMTase) and expression of BIRC5. In addition, among 13 chromosomal regions tested for allelic loss [loss of heterozygosity (LOH)], two regions close to D3S1478 and D6S264 were related to BIRC5 expression. In tumors with LOH at D3S1478 and/or D6S264, BIRC5 expression was significantly increased. These regions have been suggested to harbor tumor suppressor genes and/or common fragile sites that may play a role in increasing genetic instability. These results suggest that genes located near D3S1478 and D6S264 might work by inhibiting, directly or indirectly, BIRC5 expression and thus their loss leads to its up-regulation. In addition, BIRC5 expression may induce breast tumor proliferation by promoting genetic instability. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

IntroductionFollicular lymphoma (FL) is the most frequent indolent nonHodgkin B-cell lymphoma. This disease is usually sensitive to therapeutic agents but, paradoxically, most often remains incurable. Its clinical course is marked by recurrent relapses, suggesting that a few FL cells invariably escape treatment. If clinical remission can often be reached, t(14;18)-positive cells persist in the peripheral blood (PB) and bone marrow (BM) during remissions, accounting for the so-called residual disease. 1 A better understanding of the clonal history of these cells may help us to understand how they survive therapies.Clonal evolution in FL was addressed mainly through analysis of the mutations that accumulate in the variable regions of the immunoglobulin heavy chain genes (IgV) in germinal centers (GCs). [2][3][4][5][6][7][8][9][10] Frequent intraclonal variations (ICVs) were initially reported in lymph node (LN) biopsies, suggesting that an antigendriven selection process may remain active in transformed cells and participate in diversification and progression. [2][3][4] However, this hypothesis was challenged when IgV mutations were compared between diagnosis and relapse. These studies showed that the mutation pattern was not always compatible with linear evolution, and that relapse could arise through the evolution of pre-existing minor subclones. [10][11][12] Unfortunately, as the IgV regions of the rare t(14;18) cells that circulate in PB and BM are difficult to characterize, only LN and a few BM samples with massive involvement were analyzed, giving a limited view of the clonal history of the tumor.The class-switch recombination process (CSR) is the second physiologic mechanism that somatically modifies the IGH loci in GCs. By reorganizing the constant genes (Cg's), CSR enables B cells to express a different isotype. In FL, the Cg's often show extensive and aberrant rearrangements, suggesting major episodes of CSR activity during lymphomagenesis. 13,14 As for somatic hypermutation (SHM), the initial analysis of relatively few tumors suggested that CSR may remain ongoing in fully transformed cells and participate in progression. 5,14 However, this hypothesis was challenged when only one case showing convincing evidence for secondary Cg reorganization was identified in a large series of patients. 11 Furthermore, even if, in this case, CSR had remained active after the acquisition of the fully transformed phenotype, several features suggested that it was no longer ongoing in the studied sample. 15 Due to this stability, CSR does not appear to make a suitable marker for following clonal evolution in this pathology. However, reorganization of the Cg is only the final step in a complex cascade of molecular events. As in SHM, an early step of CSR is controlled by activation-induced cytidine deaminase (AID). 16 AID introduces mutations at the 5Ј end of the switch region (S) that precede but do not necessarily lead to a reorganization of the Cg. Although mutations in the S share several features with SHM mutations, suc...