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Lymphoma

Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

A Corrigendum to this article was published on 09 April 2014

Abstract

Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development–namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.

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Acknowledgements

We thank our consortium program team of pathologists, hematologists and clinicians, and each of the contributing center principal physicians for their support in selection, evaluation and contribution of the cases. We thank our patients, former and current hematopathology and hematology/oncology fellows, and research scientists (Chih-Jian Lih, Paul M. Williams, Lynn Trinh and Yuchaun Tai) for their support. Technical and publication editing supports from Maitrayee Goswami and Virginia Mohlere from the Department of Scientific Publications are greatly appreciated. The abstract was presented as oral communication at the Lugano ICML Conference on June 16, 2011. CV is a honorable visiting hematologist supported by San Bortolo Hospital, Vicenza, Italy and The University of Texas MD Anderson Cancer Center. KHY is supported by The University of Texas MD Anderson Cancer Center Institutional R and D Fund, Institutional Research Grant Award, MD Anderson Cancer Center SPORE Research Development Program Award, Gundersen Lutheran Medical Foundation Award and Forward Lymphoma Fund. This study is also partially supported by the Zurich Stiftung zur Krebsbekaempfung and NCI/NIH (R01CA138688 and 1RC1CA146299). Publicly available data sets: All primary sequencing data will be made publicly available through the GEO archive through accession GSE#31312.

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Correspondence to K H Young.

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Author Contributions

Designed research: CV and KHY. Performed research: CV, YL, ZYXM, WL, SMM, MAP, MBM, LW and KHY. Contributed vital new reagents, resource, and analytical tools under approved IRB and MTA: CV, YL, RNM, AT, WW, WL, ESGD, SMM, KD, AC, WT, AO, YZ, GB, JNW, SON, CD, EDH, XFZ, RSG, WWLC, FZ, JT, XYZ, JHVK, QH, MAP, MBM, CEBR, LJM, LW and KHY. Collected data and follow-up under approved IRB and MTA: CV, ZYXM, RNM, TMG, AT, ESGD, SMM, KD, AC, WT, AO, YZ, GB, JNW, HYW, SON, CD, EDH, XFZ, RSG, WWLC, FZ, MC, JT, XYZ, JHVK, QH, WA, JE, MP, AJMF, MAP, MBM, CEBR, LJM and KHY. Contributed vital strategies, participated in discussions and provided scientific input: CV, YL, ZYXM, RNM, TMG, YL, AT, WW, WL, BSK, ESGD, SMM, KD, AC, WT, AO, YZ, GB, JNW, HYW, SON, CD, EDH, XFZ, RSG, WWLC, FZ, MC, JT, XYZ, JHVK, QH, WA, JE, MP, AJMF, MAP, MBM, CEBR, LJM, LW and KHY. Analyzed data: CV and KHY. Performed and supported statistical analysis: CV, AT and KHY. Wrote the paper: CV and KHY.

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Visco, C., Li, Y., Xu-Monette, Z. et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia 26, 2103–2113 (2012). https://doi.org/10.1038/leu.2012.83

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