Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma

Michal Marek Hoppe; Patrick Jaynes; Fan Shuangyi; Yanfen Peng; Shruti Sridhar; Phuong Mai Hoang; Clementine Xin Liu; Sanjay De Mel; Limei Poon; Esther Hian Li Chan; Joanne Lee; Choon Kiat Ong; Tiffany Tang; Soon Thye Lim; Chandramouli Nagarajan; Nicholas F. Grigoropoulos; Soo Yong Tan; Susan Swee Shan Hue; Sheng Tsung Chang; Shih Sung Chuang; Shaoying Li; Joseph D. Khoury; Hyungwon Choi; Carl Harris; Alessia Bottos; Laura J. Gay; Hendrik F.P. Runge; Ilias Moutsopoulos; Irina Mohorianu; Daniel J. Hodson; Pedro Farinha; Anja Mottok; David W. Scott; Jason J. Pitt; Jinmiao Chen; Gayatri Kumar; Kasthuri Kannan; Wee Joo Chng; Yen Lin Chee; Siok Bian Ng; Claudio Tripodo; Anand D. Jeyasekharan

doi:10.1158/2159-8290.CD-22-0998

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma

Michal Marek Hoppe, Patrick Jaynes, Fan Shuangyi, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Clementine Xin Liu, Sanjay De Mel, Limei Poon, Esther Hian Li Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F. Grigoropoulos, Soo Yong Tan, Susan Swee Shan Hue, Sheng Tsung Chang, Shih Sung ChuangShaoying Li, Joseph D. Khoury, Hyungwon Choi, Carl Harris, Alessia Bottos, Laura J. Gay, Hendrik F.P. Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J. Hodson, Pedro Farinha, Anja Mottok, David W. Scott, Jason J. Pitt, Jinmiao Chen, Gayatri Kumar, Kasthuri Kannan, Wee Joo Chng, Yen Lin Chee, Siok Bian Ng, Claudio Tripodo, Anand D. Jeyasekharan

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1144-1163
Number of pages	20
Journal	Cancer discovery
Volume	13
Issue number	5
DOIs	https://doi.org/10.1158/2159-8290.CD-22-0998
State	Published - 2023

ASJC Scopus subject areas

Oncology

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Hoppe, M. M., Jaynes, P., Shuangyi, F., Peng, Y., Sridhar, S., Hoang, P. M., Liu, C. X., Mel, S. D., Poon, L., Chan, E. H. L., Lee, J., Ong, C. K., Tang, T., Lim, S. T., Nagarajan, C., Grigoropoulos, N. F., Tan, S. Y., Hue, S. S. S., Chang, S. T., ... Jeyasekharan, A. D. (2023). Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma. Cancer discovery, 13(5), 1144-1163. https://doi.org/10.1158/2159-8290.CD-22-0998

Hoppe, MM, Jaynes, P, Shuangyi, F, Peng, Y, Sridhar, S, Hoang, PM, Liu, CX, Mel, SD, Poon, L, Chan, EHL, Lee, J, Ong, CK, Tang, T, Lim, ST, Nagarajan, C, Grigoropoulos, NF, Tan, SY, Hue, SSS, Chang, ST, Chuang, SS, Li, S, Khoury, JD, Choi, H, Harris, C, Bottos, A, Gay, LJ, Runge, HFP, Moutsopoulos, I, Mohorianu, I, Hodson, DJ, Farinha, P, Mottok, A, Scott, DW, Pitt, JJ, Chen, J, Kumar, G, Kannan, K, Chng, WJ, Chee, YL, Ng, SB, Tripodo, C & Jeyasekharan, AD 2023, 'Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma', Cancer discovery, vol. 13, no. 5, pp. 1144-1163. https://doi.org/10.1158/2159-8290.CD-22-0998

@article{08743bb5487f42dda71947e7d3d99b70,

title = "Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma",

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.",

author = "Hoppe, {Michal Marek} and Patrick Jaynes and Fan Shuangyi and Yanfen Peng and Shruti Sridhar and Hoang, {Phuong Mai} and Liu, {Clementine Xin} and Mel, {Sanjay De} and Limei Poon and Chan, {Esther Hian Li} and Joanne Lee and Ong, {Choon Kiat} and Tiffany Tang and Lim, {Soon Thye} and Chandramouli Nagarajan and Grigoropoulos, {Nicholas F.} and Tan, {Soo Yong} and Hue, {Susan Swee Shan} and Chang, {Sheng Tsung} and Chuang, {Shih Sung} and Shaoying Li and Khoury, {Joseph D.} and Hyungwon Choi and Carl Harris and Alessia Bottos and Gay, {Laura J.} and Runge, {Hendrik F.P.} and Ilias Moutsopoulos and Irina Mohorianu and Hodson, {Daniel J.} and Pedro Farinha and Anja Mottok and Scott, {David W.} and Pitt, {Jason J.} and Jinmiao Chen and Gayatri Kumar and Kasthuri Kannan and Chng, {Wee Joo} and Chee, {Yen Lin} and Ng, {Siok Bian} and Claudio Tripodo and Jeyasekharan, {Anand D.}",

year = "2023",

doi = "10.1158/2159-8290.CD-22-0998",

language = "English (US)",

volume = "13",

pages = "1144--1163",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "5",

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TY - JOUR

T1 - Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma

AU - Hoppe, Michal Marek

AU - Jaynes, Patrick

AU - Shuangyi, Fan

AU - Peng, Yanfen

AU - Sridhar, Shruti

AU - Hoang, Phuong Mai

AU - Liu, Clementine Xin

AU - Mel, Sanjay De

AU - Poon, Limei

AU - Chan, Esther Hian Li

AU - Lee, Joanne

AU - Ong, Choon Kiat

AU - Tang, Tiffany

AU - Lim, Soon Thye

AU - Nagarajan, Chandramouli

AU - Grigoropoulos, Nicholas F.

AU - Tan, Soo Yong

AU - Hue, Susan Swee Shan

AU - Chang, Sheng Tsung

AU - Chuang, Shih Sung

AU - Li, Shaoying

AU - Khoury, Joseph D.

AU - Choi, Hyungwon

AU - Harris, Carl

AU - Bottos, Alessia

AU - Gay, Laura J.

AU - Runge, Hendrik F.P.

AU - Moutsopoulos, Ilias

AU - Mohorianu, Irina

AU - Hodson, Daniel J.

AU - Farinha, Pedro

AU - Mottok, Anja

AU - Scott, David W.

AU - Pitt, Jason J.

AU - Chen, Jinmiao

AU - Kumar, Gayatri

AU - Kannan, Kasthuri

AU - Chng, Wee Joo

AU - Chee, Yen Lin

AU - Ng, Siok Bian

AU - Tripodo, Claudio

AU - Jeyasekharan, Anand D.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

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U2 - 10.1158/2159-8290.CD-22-0998

DO - 10.1158/2159-8290.CD-22-0998

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JO - Cancer discovery

JF - Cancer discovery

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ER -

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma

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