© F e r r a t a S t o r t i F o u n d a t i o nphomas. In BL the MYC translocation always involves one of the immunoglobulin loci (most commonly IGH, alternatively IGL or IGK) and is considered a disease-initiating event which occurs in the context of a rather simple karyotype. Indeed, the genomic complexity in BL is, overall, low. [6][7][8] In contrast, MYC translocations in other mature Bcell lymphomas frequently involve non-IG partners and are mostly found in complex karyotypes, often in addition to well-known primary aberrations including the IGH-BCL2 translocation.6,9-11 Consequently, they likely occur during disease progression rather than disease initiation. Indeed, in 20-80% of cases of DLBCL and BCLU with a MYC breakpoint, there is an accompanying BCL2 and/or BCL6 breakpoint. [12][13][14][15][16] According to the World Health Organization (WHO) classification, lymphomas in which such a combination of a MYC break with a BCL2 break and/or a BCL6 break (fur- (DHL). 4 All other lymphomas with a MYC breakpoint, irrespective of the presence of other aberrations, are called "single-hit" lymphomas (SHL). MYC breaks are seen in approximately 10% (3-17%) of all DLBCL and 15-20% of FL grade 3B, 17,18 representing on average a DHL in 50-60%. 14,[16][17][18][19][20] This also implies that the remaining 40-50% of MYC + lymphomas are "single-hit" and that their importance, despite this high percentage, might have been underappreciated. These lymphomas with MYC translocations, including DHL, have received increased attention because several studies showed them to run an aggressive clinical course. 9,11,21 However, gene expression and other molecular genetic data are scarce 3,22 and, consequently, the molecular make up of DHL and SHL other than BL remains largely unknown. Moreover, it is unclear in which pathological and molecular aspects DHL differs from SHL other than molecular Burkitt lymphoma (mBL).therIn that respect it should be noted that, in the presence or absence of a MYC break, oncogenes other than BCL2 and BCL6, including BCL3, chromosomal locus 9p13 (potentially affecting PAX5), CCNE1, as well as unknown partners involved in IGH breaks, can be deregulated through juxtaposition to one of the IG-loci. 16,[23][24][25][26] Breakpoints affecting both MYC and these genes might, therefore, also point to a DHL, although according to the WHO classification they are defined as SHL. 4 To investigate differences and similarities between SHL and DHL as well as between BCL2 + /MYC + and
BCL6+ /MYC + DHL we explored the morphological, immunohistochemical, genetic and gene expression features of 80 adult MYC + mature aggressive B-cell lymphomas other than mBL.
Methods
Sample selection and pathology reviewAll lymphomas were investigated as part of the Molecular Mechanisms in Malignant Lymphomas (MMML) network project. The MMML protocols have been approved centrally by the institutional review board of the coordination center in Göttingen, Germany. All cases with an mBL gene expression signature (see Bioinformatica...
