Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma.

Abstract

PURPOSE:

Diffuse large B-cell lymphoma (DLBCL) is molecularly and clinically heterogeneous, and can be subtyped according to genetic alterations, cell-of-origin, or microenvironmental signatures using high-throughput genomic data at the DNA or RNA level. Although high-throughput proteomic profiling has not been available for DLBCL subtyping, MYC/BCL2 protein double expression (DE) is an established prognostic biomarker in DLBCL. The purpose of this study is to reveal the relative prognostic roles of DLBCL genetic, phenotypic, and microenvironmental biomarkers.

EXPERIMENTAL DESIGN:

We performed targeted next-generation sequencing; IHC for MYC, BCL2, and FN1; and fluorescent multiplex IHC for microenvironmental markers in a large cohort of DLBCL. We performed correlative and prognostic analyses within and across DLBCL genetic subtypes and MYC/BCL2 double expressors.

RESULTS:

We found that MYC/BCL2 double-high-expression (DhE) had significant adverse prognostic impact within the EZB genetic subtype and LymphGen-unclassified DLBCL cases but not within MCD and ST2 genetic subtypes. Conversely, KMT2D mutations significantly stratified DhE but not non-DhE DLBCL. T-cell infiltration showed favorable prognostic effects within BN2, MCD, and DhE but unfavorable effects within ST2 and LymphGen-unclassified cases. FN1 and PD-1-high expression had significant adverse prognostic effects within multiple DLBCL genetic/phenotypic subgroups. The prognostic effects of DhE and immune biomarkers within DLBCL genetic subtypes were independent although DhE and high Ki-67 were significantly associated with lower T-cell infiltration in LymphGen-unclassified cases.

CONCLUSIONS:

Together, these results demonstrated independent and additive prognostic effects of phenotypic MYC/BCL2 and microenvironment biomarkers and genetic subtyping in DLBCL prognostication, important for improving DLBCL classification and identifying prognostic determinants and therapeutic targets.

• Authors: Zijun Y Xu-Monette, Li Wei, Xiaosheng Fang, Qingyan Au, Harry Nunns, Máté Nagy, Alexandar Tzankov, Feng Zhu, Carlo Visco, Govind Bhagat, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, Fredrick B Hagemeister, Xiaoping Sun, Xin Han, Heounjeong Go, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Benjamin M Parsons, J Han van Krieken, Miguel A Piris, Jane N Winter, Yong Li, Bing Xu, Maher Albitar, Hua You, Ken H Young
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 5 Pg. 972-983 (Mar 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 34980601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• BCL2 protein, human
• Interleukin-1 Receptor-Like 1 Protein
• MYC protein, human
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Humans
• Interleukin-1 Receptor-Like 1 Protein
• Lymphoma, Large B-Cell, Diffuse (drug therapy)
• Prognosis
• Proteomics
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Tumor Microenvironment (genetics)