Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival

Nathaniel D. Anderson, Yael Babichev, Fabio Fuligni, Federico Comitani, Mehdi Layeghifard, Rosemarie E. Venier, Stefan C. Dentro, Anant Maheshwari, Sheena Guram, Claire Wunker, J. Drew Thompson, Kyoko E. Yuki, Huayun Hou, Matthew Zatzman, Nicholas Light, Marcus Q. Bernardini, Jay S. Wunder, Irene L. Andrulis, Peter Ferguson, Albiruni R. Abdul Razak, Carol J. Swallow, James J. Dowling, Rima S. Al-Awar, Richard Marcellus, Marjan Rouzbahman, Moritz Gerstung, Daniel Durocher, Ludmil B. Alexandrov, Brendan C. Dickson, Rebecca A. Gladdy () and Adam Shlien ()
Additional contact information
Nathaniel D. Anderson: The Hospital for Sick Children
Yael Babichev: Mount Sinai Hospital
Fabio Fuligni: The Hospital for Sick Children
Federico Comitani: The Hospital for Sick Children
Mehdi Layeghifard: The Hospital for Sick Children
Rosemarie E. Venier: Mount Sinai Hospital
Stefan C. Dentro: European Bioinformatics Institute
Anant Maheshwari: The Hospital for Sick Children
Sheena Guram: Mount Sinai Hospital
Claire Wunker: Mount Sinai Hospital
J. Drew Thompson: The Hospital for Sick Children
Kyoko E. Yuki: The Hospital for Sick Children
Huayun Hou: The Hospital for Sick Children
Matthew Zatzman: The Hospital for Sick Children
Nicholas Light: The Hospital for Sick Children
Marcus Q. Bernardini: University Health Network
Jay S. Wunder: Mount Sinai Hospital
Irene L. Andrulis: University of Toronto
Peter Ferguson: University Health Network
Albiruni R. Abdul Razak: University Health Network
Carol J. Swallow: Mount Sinai Hospital
James J. Dowling: The Hospital for Sick Children
Rima S. Al-Awar: Ontario Institute for Cancer Research
Richard Marcellus: Ontario Institute for Cancer Research
Marjan Rouzbahman: University of Toronto
Moritz Gerstung: European Bioinformatics Institute
Daniel Durocher: Mount Sinai Hospital
Ludmil B. Alexandrov: University of California, San Diego
Brendan C. Dickson: University of Toronto
Rebecca A. Gladdy: Mount Sinai Hospital
Adam Shlien: The Hospital for Sick Children

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24677-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24677-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24677-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().