Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

• Published in: Modern pathology Vol. 27; no. 7; pp. 958 - 971
• Main Authors: Tzankov, Alexandar, Xu-Monette, Zijun Y, Gerhard, Marc, Visco, Carlo, Dirnhofer, Stephan, Gisin, Nora, Dybkaer, Karen, Orazi, Attilio, Bhagat, Govind, Richards, Kristy L, Hsi, Eric D, Choi, William WL, van Krieken, J Han, Ponzoni, Maurilio, Ferreri, Andrés JM, Ye, Qing, Winter, Jane N, Farnen, John P, Piris, Miguel A, Møller, Michael B, You, M James, McDonnell, Timothy, Medeiros, L Jeffrey, Young, Ken H
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.07.2014; Nature Publishing Group US; Elsevier Limited
• Subjects: 692/699/67/1990/291/1621/1915; 692/699/67/68; 692/700/139/422; 692/700/1750; Adult; Aged; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cyclophosphamide - therapeutic use; diffuse large B-cell lymphoma; Doxorubicin - therapeutic use; Female; FISH; Gene expression; Gene Rearrangement; germinal center B-cell; Hematology; Hospitals; Humans; Laboratory Medicine; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; MYC; original-article; Pathology; Prednisone - therapeutic use; Prognosis; Proto-Oncogene Proteins c-myc - genetics; rearrangement; Risk Assessment; Rituximab; translocation; Treatment Outcome; Vincristine - therapeutic use; New York; United States > US; Basel Switzerland; China; Denmark; Italy; Switzerland; translocation; MYC; FISH; germinal center B-cell; diffuse large B-cell lymphoma; prognosis; rearrangement
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2013.214

In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.