Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

Simon Heeke; Carl M. Gay; Marcos R. Estecio; Hai Tran; Benjamin B. Morris; Bingnan Zhang; Ximing Tang; Maria Gabriela Raso; Pedro Rocha; Siqi Lai; Edurne Arriola; Paul Hofman; Veronique Hofman; Prasad Kopparapu; Christine M. Lovly; Kyle Concannon; Luana Guimaraes De Sousa; Whitney Elisabeth Lewis; Kimie Kondo; Xin Hu; Azusa Tanimoto; Natalie I. Vokes; Monique B. Nilsson; Allison Stewart; Maarten Jansen; Ildikó Horváth; Mina Gaga; Vasileios Panagoulias; Yael Raviv; Danny Frumkin; Adam Wasserstrom; Aharona Shuali; Catherine A. Schnabel; Yuanxin Xi; Lixia Diao; Qi Wang; Jianjun Zhang; Peter Van Loo; Jing Wang; Ignacio I. Wistuba; Lauren A. Byers; John V. Heymach

doi:10.1016/j.ccell.2024.01.001

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

Simon Heeke, Carl M. Gay, Marcos R. Estecio, Hai Tran, Benjamin B. Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M. Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin HuAzusa Tanimoto, Natalie I. Vokes, Monique B. Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A. Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I. Wistuba, Lauren A. Byers, John V. Heymach

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

2 Scopus citations

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

Original language	English (US)
Pages (from-to)	225-237.e5
Journal	Cancer cell
Volume	42
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2024.01.001
State	Published - Feb 12 2024

Keywords

biomarker
cfDNA
ctDNA
DNA methylation
epigenetics
gene expression
liquid biopsy
lung cancer
SCLC
subtyping

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2024.01.001

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Heeke, S., Gay, C. M., Estecio, M. R., Tran, H., Morris, B. B., Zhang, B., Tang, X., Raso, M. G., Rocha, P., Lai, S., Arriola, E., Hofman, P., Hofman, V., Kopparapu, P., Lovly, C. M., Concannon, K., De Sousa, L. G., Lewis, W. E., Kondo, K., ... Heymach, J. V. (2024). Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes. Cancer cell, 42(2), 225-237.e5. https://doi.org/10.1016/j.ccell.2024.01.001

Heeke, S , Gay, CM , Estecio, MR , Tran, H, Morris, BB, Zhang, B , Tang, X , Raso, MG, Rocha, P, Lai, S, Arriola, E, Hofman, P, Hofman, V, Kopparapu, P, Lovly, CM, Concannon, K, De Sousa, LG, Lewis, WE, Kondo, K, Hu, X, Tanimoto, A, Vokes, NI , Nilsson, MB , Stewart, A, Jansen, M, Horváth, I, Gaga, M, Panagoulias, V, Raviv, Y, Frumkin, D, Wasserstrom, A, Shuali, A, Schnabel, CA, Xi, Y , Diao, L, Wang, Q, Zhang, J , Van Loo, P, Wang, J, Wistuba, II , Byers, LA & Heymach, JV 2024, 'Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes', Cancer cell, vol. 42, no. 2, pp. 225-237.e5. https://doi.org/10.1016/j.ccell.2024.01.001

@article{d2da57cdc764410f8c5e0c13f1425251,

title = "Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes",

abstract = "Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.",

keywords = "biomarker, cfDNA, ctDNA, DNA methylation, epigenetics, gene expression, liquid biopsy, lung cancer, SCLC, subtyping",

author = "Simon Heeke and Gay, {Carl M.} and Estecio, {Marcos R.} and Hai Tran and Morris, {Benjamin B.} and Bingnan Zhang and Ximing Tang and Raso, {Maria Gabriela} and Pedro Rocha and Siqi Lai and Edurne Arriola and Paul Hofman and Veronique Hofman and Prasad Kopparapu and Lovly, {Christine M.} and Kyle Concannon and {De Sousa}, {Luana Guimaraes} and Lewis, {Whitney Elisabeth} and Kimie Kondo and Xin Hu and Azusa Tanimoto and Vokes, {Natalie I.} and Nilsson, {Monique B.} and Allison Stewart and Maarten Jansen and Ildik{\'o} Horv{\'a}th and Mina Gaga and Vasileios Panagoulias and Yael Raviv and Danny Frumkin and Adam Wasserstrom and Aharona Shuali and Schnabel, {Catherine A.} and Yuanxin Xi and Lixia Diao and Qi Wang and Jianjun Zhang and {Van Loo}, Peter and Jing Wang and Wistuba, {Ignacio I.} and Byers, {Lauren A.} and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = feb,

day = "12",

doi = "10.1016/j.ccell.2024.01.001",

language = "English (US)",

volume = "42",

pages = "225--237.e5",

journal = "Cancer cell",

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TY - JOUR

T1 - Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

AU - Heeke, Simon

AU - Gay, Carl M.

AU - Estecio, Marcos R.

AU - Tran, Hai

AU - Morris, Benjamin B.

AU - Zhang, Bingnan

AU - Tang, Ximing

AU - Raso, Maria Gabriela

AU - Rocha, Pedro

AU - Lai, Siqi

AU - Arriola, Edurne

AU - Hofman, Paul

AU - Hofman, Veronique

AU - Kopparapu, Prasad

AU - Lovly, Christine M.

AU - Concannon, Kyle

AU - De Sousa, Luana Guimaraes

AU - Lewis, Whitney Elisabeth

AU - Kondo, Kimie

AU - Hu, Xin

AU - Tanimoto, Azusa

AU - Vokes, Natalie I.

AU - Nilsson, Monique B.

AU - Stewart, Allison

AU - Jansen, Maarten

AU - Horváth, Ildikó

AU - Gaga, Mina

AU - Panagoulias, Vasileios

AU - Raviv, Yael

AU - Frumkin, Danny

AU - Wasserstrom, Adam

AU - Shuali, Aharona

AU - Schnabel, Catherine A.

AU - Xi, Yuanxin

AU - Diao, Lixia

AU - Wang, Qi

AU - Zhang, Jianjun

AU - Van Loo, Peter

AU - Wang, Jing

AU - Wistuba, Ignacio I.

AU - Byers, Lauren A.

AU - Heymach, John V.

PY - 2024/2/12

Y1 - 2024/2/12

N2 - Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

AB - Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

KW - biomarker

KW - cfDNA

KW - ctDNA

KW - DNA methylation

KW - epigenetics

KW - gene expression

KW - liquid biopsy

KW - lung cancer

KW - SCLC

KW - subtyping

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U2 - 10.1016/j.ccell.2024.01.001

DO - 10.1016/j.ccell.2024.01.001

M3 - Article

C2 - 38278149

AN - SCOPUS:85183950380

SN - 1535-6108

VL - 42

SP - 225-237.e5

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

Abstract

Keywords

ASJC Scopus subject areas

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