Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma-Reference-Cited by-同舟云学术

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

Published:2022-03-01 Issue:5 Volume:28 Page:972-983
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Xu-Monette Zijun Y.¹,Wei Li¹²,Fang Xiaosheng³^ORCID,Au Qingyan⁴,Nunns Harry⁴,Nagy Máté⁴,Tzankov Alexandar⁵^ORCID,Zhu Feng¹,Visco Carlo⁶^ORCID,Bhagat Govind⁷^ORCID,Dybkaer Karen⁸^ORCID,Chiu April⁹,Tam Wayne¹⁰,Zu Youli¹¹,Hsi Eric D.¹²,Hagemeister Fredrick B.¹³,Sun Xiaoping¹⁴^ORCID,Han Xin¹⁴,Go Heounjeong¹⁵,Ponzoni Maurilio¹⁶^ORCID,Ferreri Andrés J.M.¹⁶,Møller Michael B.¹⁷^ORCID,Parsons Benjamin M.¹⁸^ORCID,van Krieken J. Han¹⁹^ORCID,Piris Miguel A.²⁰,Winter Jane N.²¹^ORCID,Li Yong²²,Xu Bing²³,Albitar Maher²⁴,You Hua²,Young Ken H.¹²⁵

Affiliation:

1. 1Hematopathology Division and Department of Pathology, Duke University Medical Center, Durham, North Carolina.

2. 2Children's Hospital of Chongqing Medical University, Chongqing, China.

3. 3Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

4. 4NeoGenomics Laboratories, Aliso Viejo, California.

5. 5Institute of Pathology, University Hospital Basel, Basel, Switzerland.

6. 6University of Verona, Verona, Italy.

7. 7Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, New York.

8. 8Aalborg University Hospital, Aalborg, Denmark.

9. 9Mayo Clinic, Rochester, Minnesota.

10. 10Weill Medical College of Cornell University, New York, New York.

11. 11The Methodist Hospital, Houston, Texas.

12. 12Cleveland Clinic, Cleveland, Ohio.

13. 13Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

14. 14Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

15. 15Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of South Korea.

16. 16San Raffaele H. Scientific Institute, Milan, Italy.

17. 17Odense University Hospital, Odense, Denmark.

18. 18Gundersen Lutheran Health System, La Crosse, Wisconsin.

19. 19Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

20. 20Hospital Universitario Marqués de Valdecilla, Santander, Spain.

21. 21Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

22. 22Department of Medicine, Baylor College of Medicine, Houston, Texas.

23. 23The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.

24. 24Genomic Testing Cooperative, LCA, Irvine, California.

25. 25Duke Cancer Institute, Durham, North Carolina.

Abstract

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.

Funder

National Cancer Institute National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/28/5/972/3051501/972.pdf

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