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

Alexandar Tzankov, Zijun Y. Xu-Monette, Marc Gerhard, Carlo Visco, Stephan Dirnhofer, Nora Gisin, Karen Dybkaer, Attilio Orazi, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han Van Krieken, Maurilio Ponzoni, Andrés J.M. Ferreri, Qing Ye, Jane N. Winter, John P. Farnen, Miguel A. Piris, Michael B. MøllerM. James You, Timothy Mcdonnell, L. Jeffrey Medeiros, Ken H. Young*

*Corresponding author for this work

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)958-971
Number of pages14
JournalModern Pathology
Volume27
Issue number7
DOIs
StatePublished - Jul 2014

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Keywords

  • FISH
  • MYC
  • diffuse large B-cell lymphoma
  • germinal center B-cell
  • prognosis
  • rearrangement
  • translocation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Tzankov, A., Xu-Monette, Z. Y., Gerhard, M., Visco, C., Dirnhofer, S., Gisin, N., Dybkaer, K., Orazi, A., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., Van Krieken, J. H., Ponzoni, M., Ferreri, A. J. M., Ye, Q., Winter, J. N., Farnen, J. P., Piris, M. A., ... Young, K. H. (2014). Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Modern Pathology, 27(7), 958-971. https://doi.org/10.1038/modpathol.2013.214