MYC Translocations In Mature B-Cell Neoplasms: Single, Double, Triple and Quadruple Hit Lymphoma

According to the WHO classification from 2008 the subclassification of mature B-cell neoplasms is based mainly on cytomorphological features. So far entities are not defined by genetics, although some close associations between morphology and genetic abnormalities exist like MYC translocation and Burkitt lymphoma/leukemia, CCND1-translocation and mantle cell lymphoma, BCL6 translocation and diffuse large B-cell lymphoma and BCL2 translocation and follicular lymphoma. However, most of the mentioned genetic abnormalities are characteristic but not specific for the respective morphological subtype. Further, these genetic lesions can occur concomitantly. For lymphomas harboring MYC translocations as well as one, two or three additional translocations, respectively, involving BCL2, BCL6 and/or CCND1 the terms “double hit”, “triple hit” and “quadruple hit” lymphoma have been introduced.

To characterize a large cohort of patients with mature B-cell neoplasms and MYC translocation with respect to phenotypic presentation and additional cytogenetic abnormalities with a special focus on concomitantly occurring BCL2, BCL6 and CCND1 rearrangements.

214 patients with mature B-cell neoplasms harboring a MYC translocation were included in this study. For all cases chromosome banding analysis and FISH data verifying the MYC rearrangements were available.

141 (65.9%) were male, 73 (34.1%) female, median age was 66.4 years (range: 5.5-88.2 years). Patients were diagnosed as ALL (n=38, 17.8%), Burkitt lymphoma (n=37, 17.3%), CLL (n=43, 20.1%), and other mature B-cell neoplasms including follicular lymphoma, mantle cell lymphoma and PLL (n=96, 44.9%). 134/214 (62.6%) patients showed a MYC translocation but no translocation involving BCL2, BCL6 or CCND1 (single hit), while 59 (27.6%), 19 (8.9%) and 2 (0.9%) patients had so-called double, triple and quadruple hits. Multiple hit lymphomas displayed more frequently a complex karyotype (defined as ≥5 abnormalities in addition to MYC, BCL2, BCL6 and/or CCND1 translocation) in comparison to single hit lymphomas (61.3% vs 28.4%, p<0.001). In mean 3.8 chromosome abnormalities in addition to the MYC translocation (ACA) were observed in single hit cases as compared to 9.2 in multiple hit cases (p<0.001). The most frequently translocated gene in addition to MYC in double hit lymphomas was BCL2 (n=41/59; 69.5%) and in triple hit lymphomas BCL2 together with BCL6 (n=18/19; 94.7%). While in ALL, Burkitt lymphoma and other mature B-cell neoplasms MYC was involved in a translocation with one of the immunoglobulin loci (IGH, IGK, IGL) in the majority of cases (86.8%, 94.6%, 83.3%, respectively), in CLL MYC was translocated to other loci/genes in 62.8% of cases. Additionally, patients presenting as CLL showed most frequently single hit lymphoma (93%) and only 4.1 ACA in mean compared to all others (6.2, p=0.035). Also the pattern of ACA differed between CLL and other entities. The most frequently observed ACA in CLL resemble the spectrum of abnormalities typically found in CLL such as del(13q) (n=16/43, 37.2%), del(11q) (n=11/43, 25.6%), del(17p) (n=12/43, 27.9%) and +12 (n=2/43, 4.7%). In contrast in ALL, Burkitt lymphoma and other mature B-cell neoplasms the most frequently observed ACA were gains of 1q (n=83/171, 48.5%), del(6q) (n=41/171, 24.0%), gains of chromosome 7 (n=49/171, 28.7%), del(17p) (n=31/171, 18.1%), gains of 18q (55/171, 32.2%) and +12 (n=29/171, 17.0%). MYC translocations occurred in Burkitt lymphoma and ALL always within the primary clone, while in mature B-cell neoplasms and in CLL it was also present within subclones exclusively.

1. MYC translocations occured either as single hit or multiple hit lymphoma and presented as ALL or different mature B-cell neoplasms. 2. Multiple hit lymphomas more often harbored a complex karyotype in comparison to single hit lymphomas. 3. In double, triple and quadruple hit cases MYC translocations were most frequently accompanied by BCL2 rearrangements. 4. While in Burkitt lymphoma and ALL MYC translocations were always present in the primary clone, MYC translocations could also occur as secondary events in CLL and other mature B-cell neoplasms. 5. MYC translocations in CLL differed from those found in other lymphatic malignancies with respect to their translocation partners and their additional chromosome aberrations.

Denzel:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.