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Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL...

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Autores principales: Kim, Eugene, Jiang, Yanwen, Xu, Tao, Bazeos, Alexandra, Knapp, Andrea, Bolen, Christopher R., Humphrey, Kathryn, Nielsen, Tina G., Penuel, Elicia, Paulson, Joseph N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892802/
https://www.ncbi.nlm.nih.gov/pubmed/35236331
http://dx.doi.org/10.1186/s12885-022-09237-5
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author Kim, Eugene
Jiang, Yanwen
Xu, Tao
Bazeos, Alexandra
Knapp, Andrea
Bolen, Christopher R.
Humphrey, Kathryn
Nielsen, Tina G.
Penuel, Elicia
Paulson, Joseph N.
author_facet Kim, Eugene
Jiang, Yanwen
Xu, Tao
Bazeos, Alexandra
Knapp, Andrea
Bolen, Christopher R.
Humphrey, Kathryn
Nielsen, Tina G.
Penuel, Elicia
Paulson, Joseph N.
author_sort Kim, Eugene
collection PubMed
description BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab [G]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] vs rituximab [R]-CHOP) and 86 patients in CAVALLI (venetoclax+[G/R]-CHOP). RESULTS: When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B. CONCLUSIONS: This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09237-5.
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spelling pubmed-88928022022-03-10 Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma Kim, Eugene Jiang, Yanwen Xu, Tao Bazeos, Alexandra Knapp, Andrea Bolen, Christopher R. Humphrey, Kathryn Nielsen, Tina G. Penuel, Elicia Paulson, Joseph N. BMC Cancer Research BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab [G]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] vs rituximab [R]-CHOP) and 86 patients in CAVALLI (venetoclax+[G/R]-CHOP). RESULTS: When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B. CONCLUSIONS: This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09237-5. BioMed Central 2022-03-03 /pmc/articles/PMC8892802/ /pubmed/35236331 http://dx.doi.org/10.1186/s12885-022-09237-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kim, Eugene
Jiang, Yanwen
Xu, Tao
Bazeos, Alexandra
Knapp, Andrea
Bolen, Christopher R.
Humphrey, Kathryn
Nielsen, Tina G.
Penuel, Elicia
Paulson, Joseph N.
Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title_full Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title_fullStr Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title_full_unstemmed Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title_short Prognostic mutational subtyping in de novo diffuse large B-cell lymphoma
title_sort prognostic mutational subtyping in de novo diffuse large b-cell lymphoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892802/
https://www.ncbi.nlm.nih.gov/pubmed/35236331
http://dx.doi.org/10.1186/s12885-022-09237-5
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