TY - JOUR
T1 - Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma
AU - Xu-Monette, Zijun Y.
AU - Wei, Li
AU - Fang, Xiaosheng
AU - Au, Qingyan
AU - Nunns, Harry
AU - Nagy, Mate
AU - Tzankov, Alexandar
AU - Zhu, Feng
AU - Visco, Carlo
AU - Bhagat, Govind
AU - Dybkaer, Karen
AU - Chiu, April
AU - Tam, Wayne
AU - Zu, Youli
AU - Hsi, Eric D.
AU - Hagemeister, Fredrick B.
AU - Sun, Xiaoping
AU - Han, Xin
AU - Go, Heounjeong
AU - Ponzoni, Maurilio
AU - Ferreri, Andres J.M.
AU - Møller, Michael B.
AU - Parsons, Benjamin M.
AU - van Krieken, J. Han
AU - Piris, Miguel A.
AU - Winter, Jane N.
AU - Li, Yong
AU - Xu, Bing
AU - Albitar, Maher
AU - You, Hua
AU - Young, Ken H.
N1 - Funding Information:
Q. Au reports personal fees from NeoGenomics outside the submitted work. M. Nagy reports personal fees from NeoGenomics during the conduct of the study, as well as other support from NeoGenomics outside the submitted work. E.D. Hsi reports other support from AbbVie and Eli Lilly, as well as personal fees from Seattle Genetics and Cytomx outside the submitted work. B.M. Parsons reports personal fees from Amgen, AstraZeneca, and BMS/Celgene outside the submitted work. M.A. Piris reports grants from Spanish Association Against Cancer (AECC) and Instituto de Investigacion Carlos III during the conduct of the study. M.A. Piris also reports grants and personal fees from Takeda; grants from Gilead; and personal fees from EUSA and NanoString outside the submitted work. J.N. Winter reports other support from Merck outside the submitted work. M. Albitar reports other support from Genomic Testing Cooperative outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
The study was supported in part by grants from the National Cancer Institute/ National Institutes of Health (R01CA233490, R01CA187415, R01CA138688, and
Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Humans
KW - Interleukin-1 Receptor-Like 1 Protein
KW - Lymphoma, Large B-Cell, Diffuse/drug therapy
KW - Prognosis
KW - Proteomics
KW - Proto-Oncogene Proteins c-bcl-2/genetics
KW - Proto-Oncogene Proteins c-myc/genetics
KW - Tumor Microenvironment/genetics
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U2 - 10.1158/1078-0432.CCR-21-2949
DO - 10.1158/1078-0432.CCR-21-2949
M3 - Article
C2 - 34980601
AN - SCOPUS:85125792941
SN - 1078-0432
VL - 28
SP - 972
EP - 983
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -