Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy

Hui-Zi Chen, MD, PhD; Russell Bonneville, BS; Anoosha Paruchuri, PhD; Julie W. Reeser, PhD; Michele R. Wing, PhD; Eric Samorodnitsky, PhD; Melanie A. Krook, PhD; Amy M. Smith, BS; Thuy Dao, BS; Jharna Miya, MS; Walter Wang, BS; Lianbo Yu, PhD; Aharon G. Freud, MD, PhD; Patricia Allenby, MD; Sharon Cole, MD; Gregory Otterson, MD; Peter Shields, MD; David P. Carbone, MD, PhD; Sameek Roychowdhury, MD, PhD

JTO Clinical and Research Reports (Apr 2021)

Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy

Hui-Zi Chen, MD, PhD,
Russell Bonneville, BS,
Anoosha Paruchuri, PhD,
Julie W. Reeser, PhD,
Michele R. Wing, PhD,
Eric Samorodnitsky, PhD,
Melanie A. Krook, PhD,
Amy M. Smith, BS,
Thuy Dao, BS,
Jharna Miya, MS,
Walter Wang, BS,
Lianbo Yu, PhD,
Aharon G. Freud, MD, PhD,
Patricia Allenby, MD,
Sharon Cole, MD,
Gregory Otterson, MD,
Peter Shields, MD,
David P. Carbone, MD, PhD,
Sameek Roychowdhury, MD, PhD

Affiliations

Hui-Zi Chen, MD, PhD: Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Genomic Sciences and Precision Medicine Center and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin
Russell Bonneville, BS: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio
Anoosha Paruchuri, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Julie W. Reeser, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Michele R. Wing, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Eric Samorodnitsky, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Melanie A. Krook, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Amy M. Smith, BS: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Thuy Dao, BS: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Jharna Miya, MS: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Walter Wang, BS: Medical Scientist Training Program, The Ohio State University, Columbus, Ohio
Lianbo Yu, PhD: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio
Aharon G. Freud, MD, PhD: Division of Hematopathology, Department of Pathology, The Ohio State University, Columbus, Ohio
Patricia Allenby, MD: Division of Autopsy Services, Department of Pathology, The Ohio State University, Columbus, Ohio
Sharon Cole, MD: Orion Cancer Care, Inc., Blanchard Valley Health System, Findlay, Ohio
Gregory Otterson, MD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; James Thoracic Center, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Peter Shields, MD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; James Thoracic Center, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
David P. Carbone, MD, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; James Thoracic Center, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Sameek Roychowdhury, MD, PhD: Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; The James Cancer Hospital, The Ohio State University, Columbus, Ohio; Corresponding author. Address for correspondence: Sameek Roychowdhury, MD, PhD, Division of Medical Oncology, Department of Internal Medicine; Comprehensive Cancer Center; and The James Cancer Hospital, The Ohio State University, 460 West 12th Avenue, Biomedical Research Tower, Room 508, Columbus, OH 43210.

Journal volume & issue: Vol. 2, no. 4
p. 100164

Abstract

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Introduction: Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. Methods: We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. Results: Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (YAP1, POU2F3) revealed a more inflamed phenotype. Conclusions: Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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