Faculty, Staff and Student Publications

Publication Date

5-4-2023

Journal

Cancer Discovery

Abstract

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance.

Keywords

Humans, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-bcl-6, Prognosis, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, Oncogenes, Lymphoma, Large B-Cell, Diffuse

DOI

10.1158/2159-8290.CD-22-0998

PMID

37071673

PMCID

PMC10157367

PubMedCentral® Posted Date

April 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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