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

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• dc.contributor.author Heeke, Simon
• dc.contributor.author Rocha, Pedro P.
• dc.contributor.author Arriola Aperribay, Edurne
• dc.contributor.author Heymach, John V.
• dc.date.accessioned 2025-03-10T06:56:34Z
• dc.date.available 2025-03-10T06:56:34Z
• dc.date.issued 2024
• dc.description.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.
• dc.description.sponsorship Funding has been provided by the NIH; NIH/NCI Core grant CA016672(ATGC), NIH/NCI U24CA213274, NIH/NCI SCLC U01CA213273, NIH/NCI SCLC U01CA256780, NCI/NIH R01CA207295, NIH/NCI P50CA070907, NIH/NCI R50CA243698, NIH/NCI P30CA016672; 1R50CA265307, and NIH Cancer Center Support Grand (CCSG)- Bioinformatics Shared Resources (BISR); the CPRIT Core Facility Support Grants (#RP120348 and #RP170002), CPRIT Early Clinical Investigator Award (RP210159), LUNGevity Career Development Award, the Horizon 2020 research and innovation program (#829218); the AnnaRose King Cancer Research Fund, and the Camp fund, the Bruton endowment, John and Debbie Lyon Small Cell Lung Cancer Research fund and Rexanna's Foundation for Fighting Lung Cancer. This work was supported through generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Lung Cancer Moonshot Program. BBM is a TRIUMPH Fellow in the CPRIT Research Training Program (RP210028). C.M.L was supported by National Institutes of Health grant numbers CA217450, CA224276, and CA233259. PR was partially funded by ESMO, SEOM, and AECC. PVL was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (CC2008), the UK Medical Research Council (CC2008), and the Wellcome Trust (CC2008). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support toward the establishment of The Francis Crick Institute. P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). The authors would like to thank the MDACC ATGC core facility as well as the MDACC Epigenetics core for supporting this project. Furthermore, the authors would like to thank Dr. Revital Knirsh and Orna Savin for their support in the laboratory.
• dc.format.mimetype application/pdf
• dc.identifier.citation Heeke S, Gay CM, Estecio MR, Tran H, Morris BB, Zhang B, et al. Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes. Cancer Cell. 2024 Feb 12;42(2):225-37.e5. DOI: 10.1016/j.ccell.2024.01.001
• dc.identifier.doi http://dx.doi.org/10.1016/j.ccell.2024.01.001
• dc.identifier.issn 1535-6108
• dc.identifier.uri http://hdl.handle.net/10230/69886
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cancer Cell. 2024 Feb 12;42(2):225-37.e5
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/829218
• dc.rights © 2024 The Authors. Published by Elsevier Inc. 225 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword DNA methylation
• dc.subject.keyword SCLC
• dc.subject.keyword Biomarker
• dc.subject.keyword cfDNA
• dc.subject.keyword ctDNA
• dc.subject.keyword Epigenetics
• dc.subject.keyword Gene expression
• dc.subject.keyword Liquid biopsy
• dc.subject.keyword Lung cancer
• dc.subject.keyword Subtyping
• dc.title Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion