TheMYConcogene is one of the major regulators of normal and neoplastic B-cells (Klapproth & Wirth, 2010). The translocation t(8;14)(q24;q32) deregulates the gene by juxta-posing it to the immunoglobulin heavy chain gene (IGH@) promoter and it is the most typical lesion of Burkitt lymphoma (Klapproth & Wirth, 2010; Lenz & Staudt, 2010). MYC can also be deregulated by chromosomal translocations in diffuse large B-cell lymphoma (DLBCL) (Boermaet al, 2009; Klapp-roth & Wirth, 2010; Lenz & Staudt, 2010; Aukemaet al, 2011).
Two recent studies demonstrated thatMYCtranslocations are significantly associated with worse survival in patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide,
doxorubicin, vincristine, prednisolone) chemoimmunotherapy (Savage et al, 2009; Barrans et al, 2010). In a series of 245 DLBCL patients treated with the standard regimen R-CHOP, 35 cases (14%) presented aMYCrearrangement (Barranset al, 2010). The overall survival (OS) at 2 years was 35% for patients withMYCrearrangementversus61% for the remain-ing individuals (Barrans et al, 2010). Very similar data had been previously reported in a series of 135 DLBCL patients treated with R-CHOP (Savageet al, 2009): a 5-year OS of 33%
for the 12 DLBCL cases (9%) bearing MYC rearrangement versus 72% for the remaining patients (Savage et al, 2009).
Both papers suggest including the evaluation ofMYCstatus in
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the diagnostic panel for newly diagnosed DLBCL (Savageet al, 2009; Barrans et al, 2010). Whilst the clinical significance of the presence ofMYCrearrangements appears well established, the clinical implications of extra copies of the gene are less clear. Stasiket al(2010) examined the significance of increased MYCgene copy number (CN) in a small series of 30 DLBCL cases, of which only 13 were treated with R-CHOP. No statistical differences in outcome were observed, but the eight cases withMYC gains had a 2-year OS of 43% compared to 73% in the 22 cases without increasedMYCCN (Stasiket al, 2010). Previously, both the presence of MYC translocations and gains have been associated with a poorer outcome in a series of 156 patients with DLBCL treated with CHOP (Yoon et al, 2008).
With the aim of assessing the prognostic role ofMYCgains in the R-CHOP era, we have investigated a series of 166 cases of DLBCL treated with R-CHOP and analysed by array-based comparative genomic hybridization (Scandurra et al, 2010).
Gains affecting theMYClocus were detected in 17/166 (10%) patients, a percentage comparable toMYCtranslocations and to that previously reported (Yoon et al, 2008; Savage et al, 2009; Barrans et al, 2010). No patient had more than four copies of the gene. Cases withMYClocus gain expressedMYC mRNA at high levels, as evaluated by gene expression profiling
with the Affymetrix U133 plus 2Æ0 arrays, although not significantly more than cases withoutMYCgain (Fig 1A). Gain at the MYC locus was never the only aberration and was statistically associated with the presence of other aberrations, such as gains at 13q31Æ3, 7p/7q, 1q, 9q, 2p16-p15, 12p/12q, 5p/
5q and losses at 8p and 17p (Fig 1B, Table I). The pattern was (B)
Fig 1. Role ofMYClocus gains in in DLBCL: (A) levels ofMYCexpression in patients without and withMYCgain, as evaluated with Affymetrix U133 plus 2.0. RMA, Robust Multiarray Average; (B) Frequency plots of DNA gains (up) and losses (down) observed in 17 patients with a gain affecting theMYClocus and with a locus diploid status (X-axis, chromosome localization and physical mapping;Y-axis, percentage of cases bearing the aberration); (C) Kaplan–Meier estimates of overall survival (OS) according to the presence or absence ofMYCgain with or without concomitant del(8p).
Table I. Association between presence ofMYClocus gain and other concomitant genomic lesions among 166 cases of DLBCL as evaluated by applying Fisher’s exact test (P) followed by multiple test correction (Q).
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in DLBCL of the germinal centre B-cell type (Boerma et al, 2009; Lenz & Staudt, 2010). Three cases with concomitant MYCgain and translocation, as demonstrated by fluorescence in situ hybridization (FISH) using commercially available break-apart probes, were discarded from further analyses. After a median follow-up of 4Æ9 years (25th–75th percentiles ranging from 4 to 7 years), cases withMYCgain were associated with a poor OS (P =0Æ0012) and progression-free survival (P =0Æ0353) only in the presence of concomitant del(8p) (Fig 1C). Otherwise, no significant differences in outcome were observed (Fig 1C).
In conclusion, there are clear indications from the literature for the potential benefit of including the evaluation of MYC gene status by FISH in the diagnostic panel of newly diagnosed DLBCL patients. However, our data showed that the detection of extra copies ofMYCdid not determine a poor outcome in DLBCL patients treated with R-CHOP. Thus, proper attention should be paid by clinicians to the type of lesion reported, especially if patient-tailored therapeutic plans are to be considered. Prospective evaluation of MYC status in large series of cases will clarify the role of gainsversustranslocations in predicting a poor outcome in DLBCL patients.
Acknowledgements
MT interpreted data and co-drafted the manuscript. TCG, SMM, JV, WCC, AC, LB, AJMF, GG, collected and character-ized samples and critically revised the manuscript. IK and MM analysed data and critically revised the manuscript. EZ collected and characterized samples, analysed data, and critically revised the manuscript. FB designed the research, analysed and interpreted data, co-drafted the manuscript. All Authors approved the manuscript.
We would like to thank our Colleagues: Giorgio Inghirami (Turin, Italy), Maurilio Ponzoni (Milan, Italy), Silvia Franc-eschetti (Novara, Italy), Miguel A. Piris (Madrid, Spain), Fabio Facchetti and Alessandra Tucci (Brescia, Italy), Silvia Uccella, Graziella Pinotti, Maria Grazia Tibiletti (Varese, Italy), Giov-anni Martinelli and Giancarlo Pruneri (Milan, Italy), Thierry Lazure and Olivier Lambotte (Paris, France), Josep Fr.
Nomdedeu (Barcelona, Spain) for providing additional mate-rial and clinical information; Afua Adjeiwaa Mensah
(Bellin-putational life science/Ticino in rete’ program); Fondazione per la Ricerca e la Cura sui Linfomi (Lugano, Switzerland).
M.M. was recipient of fellowship from Alto Adige Bolzano-AIL Onlus.
1Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland,2Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland,
3Department of Pathology and Microbiology, University of Nebraska, Omaha, NE, USA,4Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain,5Division of Haematology, San Giovanni Battista Hospital and University, Turin, Italy,6Haematology/Bone Marrow Transplantation Unit, Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy,7Unit of Lymphoid Malignancies, Department of Oncology, San Raffaele H Scientific Institute, Milan, Italy,8Division of
Haematology, Department of Clinical and Experimental Medicine &
BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy, and9Division of Haematology, Azienda Ospedaliera S. Maurizio, Bolzano/Bozen, Italy
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