Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Miriam Magallón-Lorenz; Ernest Terribas; Sara Ortega-Bertran; Edgar Creus-Bachiller; Marco Fernández; Gerard Requena; Inma Rosas; Helena Mazuelas; Itziar Uriarte-Arrazola; Alex Negro; Tereza Lausová; Elisabeth Castellanos; Ignacio Blanco; George DeVries; Hiroyuki Kawashima; Eric Legius; Hilde Brems; Viktor Mautner; Lan Kluwe; Nancy Ratner; Margaret Wallace; Juana Fernández-Rodriguez; Conxi Lázaro; Jonathan A Fletcher; David Reuss; Meritxell Carrió; Bernat Gel; Eduard Serra

doi:10.1016/j.isci.2023.106096

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

iScience. 2023 Jan 31;26(2):106096. doi: 10.1016/j.isci.2023.106096. eCollection 2023 Feb 17.

Authors

Miriam Magallón-Lorenz¹, Ernest Terribas¹, Sara Ortega-Bertran^{2

3}, Edgar Creus-Bachiller^{2

3

4}, Marco Fernández⁵, Gerard Requena⁵, Inma Rosas^{6

7}, Helena Mazuelas¹, Itziar Uriarte-Arrazola¹, Alex Negro^{6

7}, Tereza Lausová^{8

9}, Elisabeth Castellanos^{6

7}, Ignacio Blanco^{6

10}, George DeVries¹¹, Hiroyuki Kawashima¹², Eric Legius¹³, Hilde Brems¹³, Viktor Mautner¹⁴, Lan Kluwe¹⁴, Nancy Ratner¹⁵, Margaret Wallace¹⁶, Juana Fernández-Rodriguez^{2

3

4}, Conxi Lázaro^{2

3

4}, Jonathan A Fletcher¹⁷, David Reuss^{8

9}, Meritxell Carrió¹, Bernat Gel^{1

18}, Eduard Serra^{1

4}

Affiliations

¹ Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916 Badalona, Barcelona, Spain.
² Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, 08098 Barcelona, Spain.
³ Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
⁴ Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵ Cytometry Core Facility, Germans Trias & Pujol Research Institute (IGTP), Badalona, Barcelona, Spain.
⁶ Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916 Badalona, Barcelona, Spain.
⁷ Clinical Genomics Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Germans Trias i Pujol University Hospital (HGTP), Can Ruti Campus, 08916 Badalona, Barcelona, Spain.
⁸ Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁹ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
¹⁰ Genetic Counseling Unit, Clinical Genetics Service, Northern Metropolitan Clinical Laboratory, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
¹¹ Hines VA Hospital, Hines, IL 60141, USA.
¹² Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Palliative Care Team, Niigata University Medical and Dental Hospital, Niigata, Japan.
¹³ Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹⁴ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁶ Department of Molecular Genetics & Microbiology, and UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA.
¹⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA 02115, USA.
¹⁸ Departament de Fonaments Clínics, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), 08036 Barcelona, Spain.

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas of the peripheral nervous system that develop either sporadically or in the context of neurofibromatosis type 1 (NF1). MPNST diagnosis can be challenging and treatment outcomes are poor. We present here a resource consisting of the genomic characterization of 9 widely used human MPNST cell lines for their use in translational research. NF1-related cell lines recapitulated primary MPNST copy number profiles, exhibited NF1, CDKN2A, and SUZ12/EED tumor suppressor gene (TSG) inactivation, and presented no gain-of-function mutations. In contrast, sporadic cell lines collectively displayed different TSG inactivation patterns and presented kinase-activating mutations, fusion genes, altered mutational frequencies and COSMIC signatures, and different methylome-based classifications. Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis.

Keywords: Biological sciences; Cancer; Neuroscience; Omics.