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 WL Choi; J Han van Krieken; Maurilio Ponzoni; Andrés JM Ferreri; Qing Ye; Jane N Winter; John P Farnen; Miguel A Piris; Michael B Møller; M James You; Timothy McDonnell; L Jeffrey Medeiros; Ken H Young

Disclosures

Mod Pathol. 2014;27(7):958-971. 

In This Article

Abstract and Introduction

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.

Introduction

Diffuse large B-cell lymphoma accounts for 20–30% of all lymphoid malignancies. This entity encompasses distinct morphological, molecular, and phenotypic variants and clinicopathological subgroups.[1,2] However, most cases are classified as diffuse large B-cell lymphoma, not otherwise specified, because these cases do not meet the criteria of specific subtypes as proposed by the current World Health Organization classification system.[1] Despite recent advances in the classification and molecular profiling of diffuse large B-cell lymphoma, its biological heterogeneity still hampers reliable prognostication and more specific treatment. Thus, identification of specific subgroups at risk for resistance to conventional therapy or relapse as well as subgroups that will benefit from specific or targeted therapies is of central interest. Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center B-cell subtype, activated B-cell subtype, and unclassified subtype.[3–5] Patient outcomes vary between these subtypes, and the germinal center B-cell subtype has a better outcome with the current standard rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.[6] However, gene expression profiling does not capture all the biological parameters influencing diagnosis, clinical outcome, and response to therapy, nor is this modality feasible in daily practice.

The translocation t(8;14)(q24;q23), juxtaposing the C-MYC (MYC) gene to the immunoglobulin heavy chain (IGH) gene promoter, was the first translocation detected in lymphoid neoplasms.[7] It can be identified in almost all cases of Burkitt lymphoma, particularly endemic cases, 30–50% of unclassifiable B-cell lymphomas with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma and in a smaller percentage of cases of diffuse large B-cell lymphoma, not otherwise specified. In unselected diffuse large B-cell lymphoma series, rearrangements of the MYC gene were discovered in approximately 5 to 10% of cases.[8–13] Of these, 20 to 30% may have an additional break in the BCL2 and/or BCL6 gene,[14–16] fulfilling the criteria of so-called genetic double-hit lymphoma. The prognostic significance of MYC translocations in de novo diffuse large B-cell lymphomas, the gold standard for identifying such cases, their clinicopathological context, and gene expression profile are still debatable.[17] More recently, the prognostic significance of MYC translocations has been challenged by the recognition of so-called phenotypic double-hit diffuse large B-cell lymphoma.[14,18–21]

To date, no study has been sufficiently statistically powered to resolve the current debatable issues regarding MYC aberrations in diffuse large B-cell lymphoma and the significance of genetic MYC single-hits vs double-hits in the context of phenotypic double-hits. The goal of this study was to address the above issues in a large number of patients with de novo diffuse large B-cell lymphoma, who were treated with R-CHOP, and stratified according to cell of origin.

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